CURRENT Diagnosis and Treatment Pediatrics, (Current Pediatric Diagnosis & Treatment) 22nd Edition

34. Endocrine Disorders

Philip S. Zeitler, MD, PhD

Sharon H. Travers, MD

Kristen Nadeau, MD

Jennifer M. Barker, MD

Megan Moriarty Kelsey, MD

Michael S. Kappy, MD, PhD

GENERAL CONCEPTS

The classic concept that endocrine effects are the result of substances secreted into the blood with effects on a distant target cell has been updated to account for other ways in which hormonal effects occur. Specifically, some hormone systems involve the stimulation or inhibition of metabolic processes in neighboring cells (eg, within the pancreatic islets or cartilage). This phenomenon is termed paracrine. Other hormone effects reflect the action of hormones on the same cells that produced them. This action is termed autocrine. The discoveries of local production of insulin, glucagon, ghrelin, somatostatin, cholecystokinin, and many other hormones in the brain and gut support the concept of paracrine and autocrine processes in these tissues.

Another significant discovery in endocrine physiology was an appreciation of the role of specific hormone receptors in target tissues, without which the hormonal effects cannot occur. For example, in the complete androgen insensitivity syndrome (AIS), androgen receptors are defective, and the 46,XY individual develops varying degrees of undervirilization of the external genitalia and internal (wolffian) duct system despite the presence of testes and adequate testosterone production. Similarly, in nephrogenic diabetes insipidus or Albright hereditary osteodystrophy (AHO) (pseudohypoparathyroidism [PHP]), affected children have defective antidiuretic hormone or parathyroid hormone (PTH) receptor function, respectively, and show the metabolic effects of diabetes insipidus or hypoparathyroidism despite more-than-adequate hormone secretion. Alternatively, abnormal activation of a hormone receptor leads to the effects of the hormone without its abnormal secretion. Examples of this phenomenon include McCune-Albright syndrome (precocious puberty and hyperthyroidism), testotoxicosis (familial male precocious puberty), and hypercalciuric hypocalcemia.

Hormones are of three main chemical types: peptides and proteins, steroids, and amines. The peptide hormones include the releasing factors secreted by the hypothalamus, the hormones of the anterior and posterior pituitary gland, pancreatic islet cells, parathyroid glands, lung (angiotensin II), heart and brain (atrial and brain natriuretic hormones), and local growth factors such as insulin-like growth factor 1 (IGF-1). Steroid hormones are secreted primarily by the adrenal cortex, gonads, and kidney (active vitamin D [1,25(OH)₂ D3]). The amine hormones are secreted by the adrenal medulla (epinephrine) and the thyroid gland (triiodothyronine [T₃] and thyroxine [T₄]).

As a rule, peptide hormones and epinephrine act after binding to specific receptors on the surface of their target cell. The metabolic effects of these hormones are usually stimulation or inhibition of the activity of preexisting enzymes or transport proteins (posttranslational effects). The steroid hormones, thyroid hormone, and active vitamin D, in contrast, act more slowly and bind to cytoplasmic receptors inside the target cell and subsequently to specific regions on nuclear DNA, where they direct a read-out of specific protein(s). Their metabolic effects are generally caused by stimulating or inhibiting the synthesis of new enzymes or transport proteins (transcriptional effects), thereby increasing or decreasing the amount rather than the activity of these proteins in the target cell.

Metabolic processes that require rapid response, such as blood glucose or calcium homeostasis, are usually controlled by peptide hormones and epinephrine, while processes that respond more slowly, such as pubertal development and metabolic rate, are controlled by steroid hormones and thyroid hormone. The control of electrolyte homeostasis is intermediate and is regulated by a combination of peptide and steroid hormones (Table 34–1).

Hormone secretion is regulated, for the most part, by feedback in response to changes in the internal environment. When the metabolic imbalance is corrected, stimulation of the hormone secretion ceases and may even be inhibited. Overcorrection of the imbalance stimulates secretion of a counterbalancing hormone or hormones, so that homeostasis is maintained within relatively narrow limits.

Hypothalamic-pituitary control of hormonal secretion is also regulated by feedback. End-organ failure (endocrine gland insufficiency) leads to decreased circulating concentrations of endocrine gland hormones and thence to increased secretion of the respective hypothalamic releasing and pituitary hormones (see Table 34–1; Figure 34–1). If restoration of normal circulating concentration of hormones occurs, feedback inhibition at the pituitary and hypothalamus results in cessation of the previously stimulated secretion of releasing and pituitary hormones and restoration of their circulating concentrations to normal.

 Figure 34–1. General scheme of the hypothalamus-pituitary-endocrine gland axis. Releasing hormones synthesized in the hypothalamus are secreted into the hypophyseal portal circulation. Trophic hormones are secreted by the pituitary gland in response, and they in turn act on specific endocrine glands to stimulate the secretion of their respective hormones. The endocrine gland hormones exert their respective effects on various target tissues (end organs) and exert a negative feedback (feedback inhibition) on their own secretion by acting at the level of the pituitary and hypothalamus. This system is characteristic of those hormones listed in Table 34–1 (third level).

Similarly, if there is autonomous endocrine gland hyperfunction (eg, McCune-Albright syndrome, Graves disease, or adrenal tumor), the specific hypothalamic releasing and pituitary hormones are suppressed (see Figure 34–1).

Bethin K, Fuqua JS: General concepts and physiology. In: Kappy MS, Allen DB, Geffner ME (eds): Pediatric Practice-Endocrinology. McGraw Hill; 2010:1–22.

DISTURBANCES OF GROWTH

Disturbances of growth and development are the most common problems evaluated by a pediatric endocrinologist. While most cases represent normal developmental variants, it is critical to identify abnormal growth patterns, as deviations from the norm can be the first or only manifestation of an endocrine disorder. Height velocity is the most critical parameter in evaluating a child’s growth. A persistent increase or decrease in height percentiles between age 2 years and the onset of puberty always warrants evaluation. Similarly, substantial deviations from target height may be indications of underlying endocrine or skeletal disorders. It is more difficult to distinguish normal from abnormal growth in the first 2 years of life, as infants may have catch-up or catch-down growth during this period. Similarly, the variable timing of the onset of puberty makes early adolescence another period during which evaluation of growth abnormalities may require careful consideration.

Appropriate standards must be used to evaluate growth. The National Center for Health Statistics provides standard cross-sectional growth charts for North American children (see Chapter 2) and the World Health Organization (WHO) growth charts use an ethnically more diverse sample. Normal growth standards may vary with country of origin. Growth charts are available for some ethnic groups in North America and for some syndromes with specific growth disturbance such as Turner or Down syndromes.

A child’s growth and height potential is determined largely by genetic factors. The target (midparental) height of a child is calculated from the mean parental height plus 6.5 cm for boys or minus 6.5 cm for girls. This calculation helps identify a child’s genetic growth potential. Most children achieve an adult height within 8 cm of the midparental height. Another parameter that determines growth potential is skeletal maturation or bone age. Beyond the neonatal period, bone age is evaluated by comparing a radiograph of the child’s left hand and wrist with the standards of Greulich and Pyle. Delayed or advanced bone age is not diagnostic of any specific disease, but the extent of skeletal maturation allows determination of remaining growth potential as a percentage of total height and allows prediction of ultimate height.

It is important to distinguish normal variants of growth (familial short stature and constitutional growth delay) from pathologic conditions (Table 34–2). Pathologic short stature is more likely in children whose growth velocity is abnormal (crossing major height percentiles on the growth curve) or who are significantly short for their family. Children with chronic illness or nutritional deficiencies may have poor linear growth, but this is typically associated with inadequate weight gain. In contrast, endocrine causes of short stature are usually associated with normal or excessive weight gain.

1. Familial Short Stature & Constitutional Growth Delay

Children with familial short stature typically have normal birth weight and length. In the first 2 years of life, their linear growth velocity decelerates as they near their genetically determined percentile. Once the target percentile is reached, the child resumes normal linear growth parallel to the growth curve, usually between 2 and 3 years of age. Skeletal maturation and timing of puberty are consistent with chronologic age. The child grows along his/her own growth percentile and the final height is short but appropriate for the family (Figure 34–2). For example, an infant boy of a mother who is 5 ft 0 in and father who is 5 ft 5 in (calculated midparental height 5 ft 5 in) may have a birth length at the 50th percentile. However, this child’s length percentile will drift downward during the first 2 years of life and will settle in at the fifth percentile where it will stay.

 Figure 34–2. Typical pattern of growth in a child with familial short stature. After attaining an appropriate percentile during the first 2 years of life, the child will have normal linear growth parallel to the growth curve. Skeletal maturation and the timing of puberty are consistent with chronologic age. The height percentile the child has been following is maintained, and final height is short but appropriate for the family.

Children with constitutional growth delay do not necessarily have short parents but have a growth pattern similar to those with familial short stature. The difference is that children with constitutional growth delay have a delay in skeletal maturation and a delay in the onset of puberty. In these children, growth continues beyond the time the average child stops growing, and final height is appropriate for target height (Figure 34–3). There is often a history of other family members being “late bloomers.”

 Figure 34–3. Typical pattern of growth in a child with constitutional growth delay. Growth slows during the first 2 years of life, similarly to children with familial short stature. Subsequently the child will have normal linear growth parallel to the growth curve. However, skeletal maturation and the onset of puberty are delayed. Growth continues beyond the time the average child has stopped growing, and final height is appropriate for target height.

2. Growth Hormone Deficiency

Human growth hormone (GH) is produced by the anterior pituitary gland. Secretion is stimulated by growth hormone–releasing hormone (GHRH) and inhibited by somatostatin. GH is secreted in a pulsatile pattern in response to sleep, exercise, and hypoglycemia and has direct growth-promoting and metabolic effects (Figure 34–4). GH also promotes growth indirectly by stimulating production of insulin-like growth factors, primarily IGF-1.

 Figure 34–4. The GHRH/GH/IGF-1 system. The effects of GH on growth are partly due to its direct anabolic effects in muscle, liver, and bone. In addition, GH stimulates many tissues to produce IGF-1 locally, which stimulates the growth of the tissue itself (paracrine effect of IGF-1). The action of GH on the liver results in the secretion of IGF-1 (circulating IGF-1), which stimulates growth in other tissues (endocrine effect of IGF-1). The action of growth hormone on the liver also enhances the secretion of IGF-binding protein 3 (IGFBP-3) and acid-labile subunit (ALS), which form a high-molecular-weight complex with IGF-1. The function of this complex is to transport IGF-1 to its target tissues, but the complex also serves as a reservoir and possible inhibitor of IGF-1 action. In various chronic illnesses, the direct metabolic effects of GH are inhibited; the secretion of IGF-1 in response to GH is blunted, and in some cases IGFBP-3 synthesis is enhanced, resulting in marked inhibition in the growth of the child. IGF-1, insulin-like growth factor 1; GH, growth hormone; GHRH, growth hormone–releasing hormone.

Growth hormone deficiency (GHD) is characterized by decreased growth velocity and delayed skeletal maturation in the absence of other explanations. Laboratory tests indicate subnormal GH secretion or action. GHD may be isolated or coexist with other pituitary hormone deficiencies and may be congenital (septo-optic dysplasia or ectopic posterior pituitary), genetic (GH or GHRH gene mutation), or acquired (craniopharyngioma, germinoma, histiocytosis, or cranial irradiation). Idiopathic GHD is the most common deficiency state with an incidence of about 1:4000 children. Patients have also been described with a GH resistance syndrome caused by mutations in the GH receptor or other components of the GH signaling pathway. The presentation of GH resistance is similar to that of GHD, but short stature is often severe, with little or no response to GH therapy. Some mutations, such as Laron dwarfism, are accompanied by facial and skeletal dysmorphology.

Infants with GHD have normal birth weight with only slightly reduced length, suggesting that GH is a minor contributor to intrauterine growth. GH deficient infants may present with hypoglycemia, particularly when associated with other pituitary deficiencies such as central adrenal insufficiency. Micropenis may be a feature of newborn males with gonadotropin and GH deficiency. Isolated GHD and hypopituitarism may be unrecognized until late in infancy or childhood as growth retardation may be delayed until later childhood. Regardless of onset, the primary manifestation of idiopathic or acquired GHD is subnormal growth velocity (Figure 34–5). Because GH promotes lipolysis, many GH deficient children have excess truncal adiposity.

 Figure 34–5. Typical pattern of growth in a child with acquired growth hormone deficiency (GHD). Children with acquired GHD have an abnormal growth velocity and fail to maintain height percentile during childhood. Other phenotypic features (central adiposity and immaturity of facies) may be present. Children with congenital GHD will cross percentiles during the first 2 years of life, similarly to the pattern seen in familial short stature and constitutional delay, but will fail to attain a steady height percentile subsequently.

Laboratory tests to assess GH status may be difficult to interpret. Children with normal short stature have a broad range of GH secretion patterns and there is significant overlap between normal and GH deficient children. Random samples for measurement of serum GH are of no value in the diagnosis of GHD, as GH secretion is pulsatile. Serum concentrations of IGF-1 give reasonable estimations of GH secretion and action in the adequately nourished child (see Figure 34–4), and are often used as a first step in the evaluation for GHD. IGF-binding protein 3 (IGFBP-3) is a much less sensitive marker of GH deficiency, but may be useful in the underweight child or in children under 4 years of age, since it is less affected by age or nutritional status. Provocative studies using such agents as insulin, arginine, levodopa, clonidine, or glucagon are traditionally done to clarify GH secretion, but are not physiologic and are often poorly reproducible, ultimately limiting their value in the clarification of GH secretion. When results of GH tests are equivocal and the clinical suspicion very high, a trial of GH treatment may help determine whether an abnormally short child will benefit from GH. Currently, the recommended treatment schedule for GHD is subcutaneous recombinant GH given subcutaneously 7 days per week with total weekly dose of 0.15–0.3 mg/kg.

GH therapy is approved by the U.S. Food and Drug Administration (FDA) for children with GHD and growth restriction associated with chronic renal failure, for girls with Turner syndrome, children with Prader-Willi and Noonan’s syndromes, and children born small for gestational age (SGA) who fail to demonstrate catch-up growth by age 4. Dose ranges for these non-GHD indications are generally different than for GHD (lower doses with Prader-Willi syndrome, higher doses with Turner syndrome and SGA). GH therapy has also been approved for children with idiopathic short stature whose current height is more than 2.25 standard deviations below the normal range for age. Final height may be 5–7 cm taller in this population. This last indication is controversial and the role of GH for idiopathic short stature is still unclear, especially due to the expense, long duration of treatment, and unclear psychological consequences. Side effects of recombinant GH are uncommon but include benign intracranial hypertension and slipped capital femoral epiphysis. With early diagnosis and treatment, children with GHD reach normal or near-normal adult height. Recombinant IGF-1 injections may be used to treat children with GH resistance or IGF-1 deficiency, but improvements in growth are not as substantial as seen with GH therapy for GH deficiency.

3. Small for Gestational Age/Intrauterine Growth Restriction

SGA infants have birth weights below the 10th percentile for the population’s birth weight–gestational age relationship. SGA infants include constitutionally small infants and infants with intrauterine growth restriction (IUGR).

SGA/IUGR may be a result of poor maternal environment, intrinsic fetal abnormalities, congenital infections, or fetal malnutrition. Intrinsic fetal abnormalities causing SGA/IUGR (often termed primordial short stature) include Russell-Silver, Seckel, Noonan, Bloom, and Cockayne syndromes, and progeria. Many children with mild SGA/IUGR and no intrinsic fetal abnormalities exhibit catch-up growth during the first 3 years. However, 15%–20% remain short throughout life, particularly those whose growth restriction in utero occurred over more than just the last 2–3 months of gestation. Catch-up growth may also be inadequate in preterm SGA/IUGR infants with poor postnatal nutrition. Children who do not show catch-up growth may have normal growth velocity, but follow a lower height percentile than expected for the family. In contrast to children with constitutional growth delay, those with SGA/IUGR have skeletal maturation that corresponds to chronologic age or is only mildly delayed.

GH therapy for SGA/IUGR children with growth delay is FDA approved and appears to increase growth velocity and final adult height.

4. Disproportionate Short Stature

There are more than 200 sporadic and genetic skeletal dysplasias that may cause disproportionate short stature. Measurements of arm span and upper-to-lower body segment ratio are helpful in determining whether a child has normal body proportions. If disproportionate short stature is found, a skeletal survey may be useful to detect specific radiographic features characteristic of some disorders. The effect of GH on most of these rare disorders is unknown.

5. Short Stature Associated With Syndromes

Short stature is associated with many syndromes, including Turner, Down, Noonan, and Prader-Willi. Girls with Turner syndrome often have recognizable features such as micrognathia, webbed neck, low posterior hairline, edema of hands and feet, multiple pigmented nevi, and an increased carrying angle. However, short stature can be the only obvious manifestation of Turner syndrome. Consequently, any girl with unexplained short stature for family warrants a chromosomal evaluation. Although girls with Turner syndrome are not usually GH deficient, GH therapy can improve final height by an average of 6.0 cm. Duration of GH therapy is a significant predictor of long-term height gain; consequently, it is important that Turner syndrome be diagnosed early and GH started as soon as possible.

GH is approved for treatment of growth failure in Prader-Willi syndrome. Many affected individuals are GH deficient and GH improves growth, body composition, and physical activity. A few deaths have been reported in Prader-Willi children receiving GH, all of which occurred in very obese children, children with respiratory impairments, sleep apnea, or unidentified respiratory infections. The role of GH, if any, in these deaths is unknown. However, as a precaution, it is recommended that all Prader-Willi patients be evaluated for upper airway obstruction and sleep apnea prior to starting GH therapy.

Children with Down syndrome should be evaluated for GHD only if their linear growth is abnormal compared with the Down syndrome growth chart.

6. Psychosocial Short Stature (Psychosocial Dwarfism)

Psychosocial short stature refers to growth retardation associated with emotional deprivation. Undernutrition probably contributes to growth retardation in some of these children. Other symptoms include unusual eating and drinking habits, bowel and bladder incontinence, social withdrawal, and delayed speech. GH secretion in children with psychosocial short stature is diminished, but GH therapy is usually not beneficial. A change in the psychological environment at home usually results in improved growth and improvement of GH secretion, personality, and eating behaviors.

 Clinical Evaluation

Laboratory investigation should be guided by the history and physical examination. Data included in history and physical include history of chronic illness and medications, birth weight and height, pattern of growth since birth, familial growth patterns, pubertal stage, dysmorphic features, body segment proportion, and psychological health. In a child with poor weight gain as the primary disturbance, a nutritional assessment is indicated. The following laboratory tests may be useful as guided by history and clinical judgment:

1. Radiograph of left hand and wrist for bone age

2. Complete blood count (to detect chronic anemia or leukocyte markers of infection)

3. Erythrocyte sedimentation rate (often elevated in collagen-vascular disease, cancer, chronic infection, and inflammatory bowel disease)

4. Urinalysis, blood urea nitrogen, and serum creatinine (occult renal disease)

5. Serum electrolytes, calcium, and phosphorus (renal tubular disease and metabolic bone disease)

6. Stool examination for fat, or measurement of serum tissue transglutaminase (malabsorption or celiac disease)

7. Karyotype (girls) and/or Noonan’s testing

8. Thyroid function tests: thyroxine (T₄) and thyroid-stimulating hormone (TSH)

9. IGF-1 (IGFBP-3 is an alternative for children < 4 or in malnourished individuals)

Allen DB, Cuttler L: Clinical practice. Short stature in childhood—challenges and choices. N Engl J Med 2013 Mar 28; 368(13):1220–1228 [PMID: 23534561].

Clayton PE et al: Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab 2007;92:804 [PMID: 17200164].

Cook DM, Rose SR. A review of guidelines for use of growth hormone in pediatric and transition patients. Pituitary 2012 Sep;15(3):301–310 [PMID: 22271255].

Ozono K et al. Pediatric aspects of skeletal dysplasia. Pediatr Endocrinol Rev 2012 Oct;10(Suppl 1):35–43 [PMID: 23330244].

Rosenbloom AL: Mecasermin (recombinant human insulin-like growth factor 1). Adv Ther 2009;26:40 [PMID: 19198769].

Although growth disturbances are usually associated with short stature, potentially serious pathologic conditions may also be associated with tall stature and excessive growth (Table 34–3). Excessive GH secretion is rare and generally associated with a functioning pituitary adenoma. GH excess leads to gigantism if the epiphyses are open and to acromegaly if the epiphyses are closed. The diagnosis is confirmed by finding elevated random GH and IGF-1 levels and failure of GH suppression during an oral glucose tolerance test. Precocious puberty can also cause tall stature for age or rapid growth, but would be associated with early signs of puberty and an advanced bone age. Obese youth are also often tall for age, but do not achieve a taller final height.

Because the upper limit of acceptable height in both sexes is increasing, concerns about excessive growth in girls are less frequent than in the past. When such concerns arise, the family history, growth curve, pubertal stage, and assessment of skeletal maturation allow estimation of final adult height. Reassurance, counseling, and education may alleviate family and personal concerns. Rarely, when the predicted height is excessive and felt to be psychologically unacceptable, brief estrogen therapy may be used to accelerate bone maturation and shorten the growth period.

Neylon OM, Werther GA, Sabin MA. Overgrowth syndromes. Curr Opin Pediatr 2012 Aug;24(4):505–511 [PMID: 227059].

DISORDERS OF THE POSTERIOR PITUITARY GLAND

The posterior pituitary (neurohypophysis) is an extension of the ventral hypothalamus. Its two principal hormones—oxytocin and arginine vasopressin—are synthesized in the supraoptic and paraventricular nuclei of the ventral hypothalamus. After synthesis, these peptide hormones are packaged in granules with specific neurophysins and transported via the axons to their storage site in the posterior pituitary. Vasopressin is essential for water balance; it acts primarily on the kidney to promote reabsorption of water from urine. Oxytocin is most active during parturition and breast feeding and is not discussed further here.

Vasopressin release is controlled primarily by serum osmolality and intravascular volume. Release is stimulated by minor increases in plasma osmolality (detected by osmoreceptors in the anterolateral hypothalamus) and large decreases in intravascular volume (detected by baroreceptors in the cardiac atria). Disorders of vasopressin release and action include (1) central (neurogenic) diabetes insipidus, (2) nephrogenic diabetes insipidus (see Chapter 24), and (3) the syndrome of inappropriate secretion of anti-diuretic hormone (see Chapter 45).

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Polydipsia, polyuria (> 2 L/m²/d), nocturia, dehydration, and hypernatremia.

 Inability to concentrate urine after fluid restriction (urine specific gravity < 1.010; urine osmolality < 300 mOsm/kg).

 Plasma osmolality > 300 mOsm/kg with urine osmolality < 600 mOsm/kg.

 Low plasma vasopressin with antidiuretic response to exogenous vasopressin.

 General Considerations

Central diabetes insipidus (DI) is an inability to synthesize and release vasopressin. Without vasopressin, the kidneys cannot concentrate urine, causing excessive urinary water loss. Genetic causes of central DI are rare and include mutations in the vasopressin gene (mostly in the neurophysin portion of the vasopressin precursor) and the WFS1 gene that causes DI, diabetes mellitus, optic atrophy, and deafness (Wolfram or DIDMOAD syndrome). Transcription factor mutations, such as PROP1 and PIT1, that are known to be associated with other anterior pituitary hormone deficiencies are not typically associated with DI. Midline brain abnormalities, such as septo-optic dysplasia and holoprosencephaly, are also associated with central DI. Traumatic brain injury or neurosurgery in or near the hypothalamus or pituitary can cause transient or permanent DI. Traumatic DI often has three phases. Initially, transient DI is caused by edema in the hypothalamus or pituitary area. In 2–5 days, unregulated release of vasopressin from dying neurons causes the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Finally, permanent DI occurs if a sufficient number of vasopressin neurons are destroyed.

Tumors and infiltrative diseases of the hypothalamus and pituitary may cause DI. In children with craniopharyngioma, DI usually develops after neurosurgical intervention. In contrast, germinomas often present with DI. Germinomas may be undetectable for several years; consequently, children with unexplained DI should have regularly repeated magnetic resonance imaging (MRI). Infiltrative diseases such as histiocytosis and lymphocytic hypophysitis can cause DI. In these conditions, as in germinomas, MRI scans characteristically show thickening of the pituitary stalk. Infections involving the base of the brain also cause transient DI.

 Clinical Findings

Onset of DI is often abrupt, characterized by polyuria, nocturia, enuresis, and intense thirst. Children with DI typically crave cold water. Hypernatremia, hyperosmolality, and dehydration occur if insufficient fluid intake due to lack of access or impaired thirst mechanism does not keep up with urinary losses. In infants, symptoms may also include failure to thrive, vomiting, constipation, and unexplained fevers. Some infants may present with severe dehydration, circulatory collapse, and seizures. Vasopressin deficiency may be masked in patients with panhypopituitarism due to the impaired excretion of free water associated with adrenal insufficiency. Treating these patients with glucocorticoids may unmask their DI.

DI is confirmed when serum hyperosmolality is associated with urine hypoosmolarity. If the history indicates that the child can go through the night comfortably without drinking, outpatient testing is appropriate. Oral fluid intake is prohibited after midnight. Osmolality, sodium, and specific gravity of the first morning void are obtained. If urine specific gravity is greater than 1.015, DI is excluded. If urine is not concentrated, a blood sample is obtained within a few minutes of the urine collection for osmolality, sodium, creatinine, and calcium concentration.

If screening results are unclear or if symptoms preclude safely withholding fluids at home, a water deprivation test performed in the hospital is indicated. In this test, fluid is withheld and the child is monitored. Serum osmolality greater than 290 mOsm/kg associated with inappropriately dilute urine (osmolality less than 600 mOsm/kg) is diagnostic for DI. Low serum vasopressin concentration and an antidiuretic response to vasopressin administration at the end of the test distinguishes central from nephrogenic DI. Children with central DI should have a head MRI scan with contrast to look for tumors or infiltrative processes. The posterior pituitary “bright spot” on MRI is often absent in DI.

Primary polydipsia must be distinguished from DI. Children with primary polydipsia tend to have lower serum sodium levels and usually can concentrate their urine with overnight fluid deprivation. Some may have secondary nephrogenic DI due to dilution of the renal medullary interstitium and decreased renal concentrating ability, but this resolves with restriction of fluid intake.

 Treatment

Central DI is treated with oral or intranasal desmopressin acetate (DDAVP). The aim of therapy is to provide antidiuresis that allows uninterrupted sleep and approximately 1 hour of diuresis before the next dose. It is important to note that postsurgical DI can be associated with disruption of thirst mechanism and, for these patients, a prescribed volume of fluid intake needs to be determined. Children hospitalized with acute-onset DI can be managed with intravenous vasopressin. Due to the amount of antidiuresis, intravenous fluids will need to be restricted to two-thirds the maintenance rate and electrolytes closely monitored to avoid water intoxication. Infants with DI should not be treated with DDAVP. Treatment with DDAVP in association with the volume of formula or breast milk needed to ensure adequate caloric intake could cause water intoxication. For this reason, infants are treated with extra free water, rather than DDAVP, to maintain normal hydration. A formula with a low renal solute load and chlorothiazides may be helpful in infants with central DI.

Cheetham T, Baylis PH: Diabetes insipidus in children: pathophysiology, diagnosis and management. Paediatr Drugs 2002;4:785 [PMID: 12431131].

Di Iorgi N et al: Diabetes insipidus—diagnosis and management. Horm Res Paediatr 2012;77:69 [PMID: 22433947].

Rivkees SA et al: The management of central diabetes insipidus in infancy: desmopressin, low renal solute load formula, thiazide diuretics. J Pediatr Endocrinol Metab 2007;20:459 [PMID: 17550208].

Wise-Faberowski L et al: Perioperative management of diabetes insipidus in children. J Neurosurg Anesthesiol 2004;16:14 [PMID: 14676564].

THYROID GLAND

The fetal thyroid synthesizes thyroid hormone as early as the 10th week of gestation. Thyroid hormone appears in the fetal serum by the 11th week of gestation and progressively increases throughout gestation. The fetal pituitary-thyroid axis functions largely independently of the maternal pituitary-thyroid axis because maternal TSH cannot cross the placenta. However, maternal thyroid hormone can cross the placenta in limited amounts.

At birth, there is a TSH surge peaking at about 70 mU/L within 30–60 minutes. Thyroid hormone serum level increases rapidly during the first days of life in response to this TSH surge. The TSH level decreases to childhood levels within a few weeks. The physiologic neonatal TSH surge can produce a false-positive newborn screen for hypothyroidism (ie, high TSH) if the blood sample for the screen is collected on the first day of life.

Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the anterior pituitary gland to release TSH. In turn, TSH stimulates the thyroid gland to take up iodine, and to synthesize and release the active hormones, thyroxine (T₄) and triiodothyronine (T₃). This process is regulated by negative feedback involving the hypothalamus, pituitary, and thyroid (see Figure 34–1).

T₄ is the predominant thyroid hormone secreted by the thyroid gland. Most circulating T₃ and T₄ are bound to thyroxine-binding globulin (TBG), albumin, and prealbumin. Less than 1% of T₃ and T₄ exist as free T₃ (FT₃) and free T₄ (FT₄). T₄ is deiodinated in the tissues to either T₃ (active) or reverse T₃ (inactive). In peripheral tissues, T₃ binds to high-affinity nuclear thyroid hormone receptors in the cytoplasm and translocates to the nucleus, exerting its biologic effects by modifying gene expression.

The T₄ level is low in hypothyroidism. It may also be low in premature infants, malnutrition, severe illness, and following therapy with T₃. It is not clear whether premature infants with low T₄ benefit from treatment. Long-term studies have been proposed to assess cognitive outcomes for high-risk patients.

Total T₄ is also low in situations that decrease TBG. TBG levels are decreased in familial TBG deficiency, nephrosis, and in patients receiving androgens. In sepsis, TBG cleavage is increased. Treatment with certain medications (heparin, furosemide, salicylates, and phenytoin) results in abnormal binding to TBG. However, since these effects involve primarily TBG levels, and not thyroid function per se, TSH and FT₄ levels remain in the normal range. Conversely, Total T₃ and T₄ levels may be elevated in conditions associated with increased TBG levels (congenital TBG excess, pregnancy, estrogen therapy) and increased thyroid hormone binding to transport proteins. However, free hormone levels are not affected and patients are euthyroid.

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Growth retardation, decreased physical activity, weight gain, constipation, dry skin, cold intolerance, and delayed puberty.

 Neonates with congenital hypothyroidism often look normal but may have thick tongue, large fontanels, poor muscle tone, hoarseness, umbilical hernia, jaundice, and intellectual retardation.

 T₄, FT₄, and T₃ resin uptake are low; TSH levels are elevated in primary hypothyroidism.

 General Considerations

Thyroid hormone deficiency may be congenital or acquired (Table 34–4). It can be due to defects in the thyroid gland (primary hypothyroidism) or in the hypothalamus or pituitary (central hypothyroidism).

Congenital hypothyroidism occurs in about 1:3000–1:4000 infants. Untreated, it causes severe neurocognitive impairment. Most cases are sporadic resulting from hypoplasia or aplasia of the thyroid gland or failure of the gland to migrate to its normal anatomic location (ie, lingual or sublingual thyroid gland). Another cause of congenital hypothyroidism is dyshormonogenesis due to enzymatic defects in thyroid hormone synthesis. Since antithyroid drugs, including propylthiouracil (PTU) and methimazole, freely cross the placenta, goitrous hypothyroid newborns may be born to hyperthyroid mothers treated with these drugs during pregnancy.

Low T₄ levels may also be caused by decreased TSH secretion associated with prolonged glucocorticoid use, dopamine, or somatostatin. Cabbage, soybeans, aminosalicylic acid, thiourea derivatives, resorcinol, phenylbutazone, cobalt, and excessive iodine intake can cause goiter and hypothyroidism during pregnancy. Many of these agents cross the placenta and should be used with caution during pregnancy. Iodine deficiency also causes hypothyroidism. In severe maternal iodine deficiency, both the fetus and the mother are T₄-deficient, with irreversible brain damage in the fetus.

Juvenile hypothyroidism, particularly if goiter is present, is usually a result of chronic lymphocytic (Hashimoto) thyroiditis.

Several hundred patients with resistance to thyroid hormone have been described and present with elevations in T₄ and/or FT₄, with normal TSH. There is often a family history of the disorder. Clinical manifestations are highly variable due to differential expression of thyroid hormone receptor isoforms in different tissues

 Clinical Findings

A. Symptoms and Signs

Even when the thyroid gland is completely absent, most newborns with congenital hypothyroidism appear normal at birth and gain weight normally for the first few months of life without treatment. Since congenital hypothyroidism must be treated as early as possible to prevent intellectual impairment, the diagnosis should be based on the newborn screening test and not on signs or symptoms. Jaundice associated with an unconjugated hyperbilirubinemia may be present in newborns with congenital hypothyroidism. Some infants may have obvious findings of thick tongue, hypotonia, large fontanelles, constipation, umbilical hernia, hoarse cry, and dry skin.

Juvenile hypothyroidism often presents with short stature and abnormal weight gain. Other findings include delayed epiphyseal development, delayed closure of fontanels, and retarded dental eruption. The skin may be dry, thick, scaly, coarse, pale, cool, or mottled, or have a yellowish tinge. The hair may be dry, coarse, or brittle. Lateral thinning of the eyebrows may occur. Musculoskeletal findings include hypotonia and a slow relaxation component of deep tendon reflexes (best appreciated in the ankles). Muscular hypertrophy (Kocher-Debré-Semélaigne syndrome) is not commonly seen in congenital hypothyroidism. Other findings include physical and mental sluggishness, nonpitting myxedema, constipation, large tongue, hypothermia, bradycardia, hoarse voice or cry, umbilical hernia, and transient deafness. Puberty may be delayed. Metromenorrhagia may occur in older girls. Sometimes, hypothyroidism induces pseudopuberty. Galactorrhea can also occur, due to stimulation of prolactin secretion.

In hypothyroidism resulting from enzymatic defects, ingestion of goitrogens, or chronic lymphocytic thyroiditis, the thyroid gland may be enlarged. Thyroid enlargement in children is usually symmetrical, and the gland is moderately firm and not nodular. In chronic lymphocytic thyroiditis, however, the thyroid frequently has a cobblestone surface.

B. Laboratory Findings

Total T₄ and FT₄ levels are decreased. T₃ resin uptake (T₃RU) is low. In primary hypothyroidism, the serum TSH level is elevated. In central hypothyroidism, the TSH level may be low or inappropriately normal. Circulating autoantibodies to thyroid peroxidase and thyroglobulin may be present. Serum prolactin may be elevated, resulting in galactorrhea. Serum GH may be decreased, with subnormal GH response to stimulation in children with severe primary hypothyroidism, as well as low IGF-1 or IGFBP-3 levels, or both.

C. Imaging

Thyroid imaging, while helpful in establishing the cause of congenital hypothyroidism, does not affect the treatment plan and is not necessary. Bone age is delayed. Centers of ossification, especially of the hip, may show multiple small centers or a single stippled, porous, or fragmented center (epiphyseal dysgenesis). Cardiomegaly is common. Longstanding primary hypothyroidism may be associated with thyrotrophic hyperplasia characterized by an enlarged sella or pituitary gland.

D. Screening Programs for Neonatal Hypothyroidism

All newborns should be screened for congenital hypothyroidism shortly after birth as most do not have suggestive physical findings. Depending on the state, the newborn screen measures either the total T₄ or TSH level. Abnormal newborn screening results should be confirmed immediately with a T₄ and TSH level. Treatment should be started as soon as possible. Initiation of treatment in the first month of life and good compliance during infancy usually results in a normal neurocognitive outcome.

E. Conditions Associated With Hypothyroidism

Children with Down syndrome, Turner syndrome, and autoimmune diseases such as celiac disease, vitiligo, alopecia, and type 1 diabetes are at an increased risk for the development of acquired autoimmune hypothyroidism. A detailed family history may reveal the presence of multiple autoimmune diseases in the family members of the affected individual. Individuals at a high risk based on a chromosomal disorder or other autoimmune disease benefit from careful monitoring of growth and development, routine screening (in the case of Down syndrome, Turner syndrome, and type 1 diabetes), and a low threshold for measurement of thyroid function.

Central hypothyroidism is associated with other disorders of the hypothalamus and pituitary including congenital defects such as septo-optic dysplasia and acquired defects such as tumors in the hypothalamic/pituitary region.

 Treatment

Levothyroxine (75–100 mcg/m²/d) is the drug of choice for acquired hypothyroidism. In neonates with congenital hypothyroidism, the initial dose is 10–15 mcg/kg/d. Serum total T₄ or FT₄ concentrations are used to monitor the adequacy of initial therapy because the normally high neonatal TSH may not normalize for several days to weeks. Subsequently, T₄ and TSH are used in combination, as elevations of serum TSH are sensitive early indicators of the need for increased medication or better compliance.

Delahunty C et al: Levels of neonatal thyroid hormone in preterm infants and neurodevelopmental outcomes at 5½ years: millennium cohort study. J Clin Endocrinol Metabl 2010;95: 4898–4908 [PMID: 20719832].

LaFranchi S: Approach to the diagnosis and treatment of congenital hypothyroidism. J Clin Endocrinol Metab 2011;96: 2959–2967 [PMID: 21976744].

Schmaltz C: Thyroid hormones in the neonate: an overview of physiology and clinical correlation. Adv Neonatal Care 2012;12:217–222 [PMID: 22864001].

van der Sluijs Veer L et al: Evaluation of cognitive and motor development in toddlers with congenital hypothyroidism diagnosed by neonatal screening. J Dev Behav Pediatr 2012;33: 633–640 [PMID: 23027136].

1. Chronic Lymphocytic Thyroiditis (Chronic Autoimmune Thyroiditis, Hashimoto Thyroiditis)

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Firm, freely movable, nontender, diffusely enlarged thyroid gland.

 Thyroid function is usually normal but may be elevated or decreased depending on the stage of the disease.

 General Considerations

Chronic lymphocytic thyroiditis is the most common cause of goiter and acquired hypothyroidism in childhood. It is more common in girls, and the incidence peaks during puberty. The disease is caused by an autoimmune attack on the thyroid. Increased risk of thyroid autoimmunity (and other endocrine autoimmune disorders) is associated with certain histocompatibility alleles.

 Clinical Findings

A. Symptoms and Signs

The thyroid is characteristically enlarged, firm, freely movable, nontender, and symmetrical. It may be nodular. Onset is usually insidious. Occasionally patients note a sensation of tracheal compression or fullness, hoarseness, and dysphagia. No local signs of inflammation or systemic infection are present. Most patients are euthyroid. Some patients are symptomatically hypothyroid, and few patients are symptomatically hyperthyroid.

B. Laboratory Findings

Laboratory findings vary. Serum concentrations of TSH, T₄, and FT₄ are usually normal. Some patients are hypothyroid with an elevated TSH and low thyroid hormone levels. A few patients are hyperthyroid with a suppressed TSH and elevated thyroid hormone levels. Thyroid antibodies (antithyroglobulin, antithyroid peroxidase) are frequently elevated. Thyroid uptake scan adds little to the diagnosis. Surgical or needle biopsy is diagnostic but seldom necessary.

 Treatment

There is controversy about the need to treat chronic lymphocytic thyroiditis with normal thyroid function. Full replacement doses of thyroid hormone may decrease the size of the thyroid, but may also result in hyperthyroidism. Hypothyroidism commonly develops over time. Consequently, patients require lifelong surveillance. Children with documented hypothyroidism should receive thyroid hormone replacement.

2. Acute (Suppurative) Thyroiditis

Acute thyroiditis is rare. The most common causes are group A streptococci, pneumococci, Staphylococcus aureus, and anaerobes. Oropharyngeal organisms are thought to reach the thyroid via a patent foramen cecum and thyroglossal duct remnant. Thyroid abscesses may form. The patient is toxic with fever and chills. The thyroid gland is enlarged and exquisitely tender with associated erythema, hoarseness, and dysphagia. Thyroid function tests are typically normal. Patients have a leukocytosis, “left shift,” and elevated erythrocyte sedimentation rate. Specific antibiotic therapy should be administered.

3. Subacute (Nonsuppurative) Thyroiditis

Subacute thyroiditis (de Quervain thyroiditis) is rare. It is thought to be caused by viral infection with mumps, influenza, echovirus, coxsackievirus, Epstein-Barr virus, or adenovirus. Presenting features are similar to acute thyroiditis—fever, malaise, sore throat, dysphagia, and thyroid pain that may radiate to the ear. The thyroid is firm and enlarged. Sedimentation rate is elevated. In contrast to acute thyroiditis, the onset is generally insidious and serum thyroid hormone concentrations may be elevated.

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Nervousness, emotional lability, hyperactivity, fatigue, tremor, palpitations, excessive appetite, weight loss, increased perspiration, and heat intolerance.

 Goiter, exophthalmos, tachycardia, widened pulse pressure, systolic hypertension, weakness, and smooth, moist, warm skin.

 TSH is suppressed. Thyroid hormone levels (T₄, FT₄, T₃, T₃RU) are elevated.

 General Considerations

In children, most cases of hyperthyroidism are due to Graves disease, caused by antibodies directed at the TSH receptor that stimulate thyroid hormone production. Hyperthyroidism may also be due to acute, subacute, or chronic thyroiditis; autonomous functioning thyroid nodules; tumors producing TSH; McCune-Albright syndrome; exogenous thyroid hormone excess; and acute iodine exposure.

 Clinical Findings

A. Symptoms and Signs

Hyperthyroidism is more common in females than males. In children, it most frequently occurs during adolescence. The course of hyperthyroidism tends to be cyclic, with spontaneous remissions and exacerbations. Symptoms include worsening school performance, poor concentration, fatigue, hyperactivity, emotional lability, nervousness, personality disturbance, insomnia, weight loss (despite increased appetite), palpitations, heat intolerance, increased perspiration, diarrhea, polyuria, and irregular menses. Signs include tachycardia, systolic hypertension, increased pulse pressure, tremor, proximal muscle weakness, and moist, warm, skin. Accelerated growth and development may occur. Thyroid storm is a rare condition characterized by fever, cardiac failure, emesis, delirium, coma, and death. Most cases of Graves disease are associated with a diffuse firm goiter. A thyroid bruit and thrill may be present. Many cases are associated with exophthalmos, but severe ophthalmopathy is rare.

B. Laboratory Findings

TSH is suppressed. T₄, FT₄, T₃, and FT₃ are elevated except in rare cases in which only the serum T₃ is elevated (T₃ thyrotoxicosis). The presence of thyroid-stimulating immunoglobulin (TSI) confirms the diagnosis of Graves disease. TSH receptor–binding antibodies (TRaB) are usually elevated.

C. Imaging

In Graves disease, radioactive iodine uptake by the thyroid is increased, whereas in subacute and chronic thyroiditis it is decreased. An autonomous hyperfunctioning nodule takes up iodine and appears as a “hot nodule” while the surrounding tissue has decreased iodine uptake. In children with hyperthyroidism, bone age may be advanced. In infants, accelerated skeletal maturation may be associated with premature fusion of the cranial sutures. Long-standing hyperthyroidism causes osteoporosis.

 Differential Diagnosis

Hypermetabolic states (severe anemia, chronic infections, pheochromocytoma, and muscle-wasting disease) may resemble hyperthyroidism clinically but differ in thyroid function tests.

 Treatment

A. General Measures

In untreated hyperthyroidism, strenuous physical activity should be avoided. Bed rest may be required in severe cases.

B. Medical Treatment

1. β-Adrenergic blocking agents— These agents are adjuncts to therapy. They can rapidly ameliorate symptoms such as nervousness, tremor, and palpitations, and are indicated in severe disease with tachycardia and hypertension. β₁-Specific agents such as atenolol are preferred because they are more cardioselective.

2. Antithyroid agents (propylthiouracil and methimazole)— Antithyroid agents are frequently used in the initial treatment of childhood hyperthyroidism. These drugs interfere with thyroid hormone synthesis, and usually take a few weeks to produce a clinical response. Adequate control is usually achieved within a few months. If medical therapy is unsuccessful, more definitive therapy, such as radioablation of the thyroid or thyroidectomy, should be considered.

In response to reports of severe hepatotoxicity related to PTU, recent recommendations state that PTU should not be used in infants, children, or adolescents, except when methimazole is contraindicated due to hypersensitivity or pregnancy.

A. INITIAL DOSAGE— Methimazole is initiated at a dose of 10–60 mg/d (0.5–1 mg/kg/d) given once a day. Initial dosing is continued until FT₄ or T₄ have normalized and signs and symptoms have subsided.

B. MAINTENANCE— The optimal dose of antithyroid agent for maintenance treatment remains unclear. Recent studies suggest that 10–15 mg/d of methimazole provides adequate long-term control in most patients with a minimum of side effects. If the TSH becomes elevated, many providers decrease the dose of the antithyroid agent. Some providers continue the same dose of antithyroid agent and add exogenous thyroid hormone replacement. Treatment usually continues for 2 years with the goal of inducing remission. If thyroid hormone levels are stable, a trial off medication could be considered at that point.

C. TOXICITY— If rash, vasculitis, arthralgia, arthritis, granulocytopenia, or hepatitis occur, the drug must be discontinued.

3. IODIDE— Large doses of iodide usually produce a rapid but short-lived blockade of thyroid hormone synthesis and release. This approach is recommended only for acute management of severely thyrotoxic patients.

C. Radiation Therapy

Radioactive iodine ablation of the thyroid is usually reserved for children with Graves disease who do not respond to antithyroid agents, develop adverse effects from the antithyroid agents, fail to achieve remission after several years of medical therapy, or have poor medication adherence. With recent concerns regarding potential hepatotoxicity of antithyroid medications, some pediatric endocrinologists advocate radioablation as first-line therapy for children with Graves disease. Antithyroid agents should be discontinued 4–7 days prior to radioablation to allow radioiodine uptake by the thyroid.¹³¹ I is administered orally which concentrates in the thyroid and results in gradual ablation of the gland. In the first 2 weeks following radioablation, hyperthyroidism may worsen as thyroid tissue is destroyed and thyroid hormone is released. Therapy with a β-adrenergic antagonist may be necessary for a few months until FT₄and T₄ fall into the normal range. In most cases, hypothyroidism develops and thyroid hormone replacement is needed. Long-term follow-up studies have not shown any increased incidence of thyroid cancer, leukemia, infertility, or birth defects when ablative doses of ¹³¹ I were used.

D. Surgical Treatment

Subtotal and total thyroidectomy are infrequently used in children with Graves disease. Surgery is indicated for extremely large goiters, goiters with a suspicious nodule, very young or pregnant patients, or patients refusing radioiodine ablation. Before surgery, a β-adrenergic blocking agent is given to treat symptoms, and antithyroid agents are given for several weeks to minimize the surgical risks associated with hyperthyroidism. Iodide (eg, Lugol solution, 1 drop every 8 hours, or saturated solution of potassium iodide, 1–2 drops daily) is given for 1–2 weeks prior to surgery to reduce thyroid vascularity and inhibit release of thyroid hormone. Surgical complications include hypoparathyroidism, recurrent laryngeal nerve damage, and rarely, death. An experienced thyroid surgeon is crucial to good surgical outcome. After thyroidectomy, patients become hypothyroid and need thyroid hormone replacement.

 Course & Prognosis

Partial remissions and exacerbations may continue for several years. Treatment with an antithyroid agent results in prolonged remissions in one-third to two-thirds of children.

Bauer AJ: Approach to the pediatric patient with Graves’ disease: when is definitive therapy warranted? J Clin Endocrinol Metab 2011;96:580–588 [PMID: 21378220].

Lee JA et al: The optimal treatment for pediatric Graves’ disease is surgery. J Clin Endocrinol Metab 2007;92:80 [PMID: 17341575].

Rivkees SA, Dinauer C: An optimal treatment for pediatric Graves’ disease is radioiodine. J Clin Endocrinol Metab 2007;92:797 [PMID: 17341574].

Yuan L, Yang J: Radioiodine treatment in pediatric Graves’ disease and thyroid carcinoma. J Pediatr Endocrinol Metab 2011;24:877–883 [PMID: 22308835].

 Neonatal Graves Disease

Transient congenital hyperthyroidism (neonatal Graves disease) occurs in about 1% of infants born to mothers with Graves disease. It occurs when maternal TSH receptor antibodies cross the placenta and stimulate excess thyroid hormone production in the fetus and newborn. Neonatal Graves disease can be associated with irritability, IUGR, poor weight gain, flushing, jaundice, hepatosplenomegaly, and thrombocytopenia. Severe cases may result in cardiac failure and death. Hyperthyroidism may develop several days after birth, especially if the mother was treated with PTU (which crosses the placenta). Symptoms develop as PTU levels decline in the newborn. Thyroid studies should be obtained at birth and repeated within the first week. Immediate management should focus on the cardiac manifestations. Temporary treatment may be necessary with iodide, antithyroid agents, β-adrenergic antagonists, or corticosteroids. Hyperthyroidism gradually resolves over 1–3 months as maternal antibodies decline. As TSH receptor antibodies may still be present in the serum of previously hyperthyroid mothers after thyroidectomy or radioablation, neonatal Graves disease should be considered in all infants of mothers with a history of hyperthyroidism.

Lewis KA et al: Neonatal Graves disease associated with severe metabolic abnormalities. Pediatrics 2011;128(1):e232–e236 [PMID: 21646263].

Papendieck P et al: Thyroid disorders of neonates born to mothers with Graves’ disease. J Pediatr Endocrinol Metab 2009;22:547 [PMID: 19694202].

Polak M et al: Fetal and neonatal thyroid function in relation to maternal Graves’ disease. Best Pract Res Clin Endocrinol Metab 2004;18:289 [PMID: 15157841].

Thyroid cancer is rare in childhood. Children usually present with a thyroid nodule or an asymptomatic asymmetrical neck mass. Dysphagia and hoarseness are unusual symptoms. Thyroid function tests are usually normal. A “cold” nodule is often seen on a technetium or radioiodine uptake scan of the thyroid. Fine-needle aspiration biopsy of the nodule assists in the diagnosis.

The most common thyroid cancer is papillary thyroid carcinoma, a well-differentiated carcinoma arising from the thyroid follicular cell. Children frequently present with local metastases to the cervical lymph nodes and occasionally with pulmonary metastases. Despite its aggressive presentation, children with papillary thyroid carcinoma have a relatively good prognosis, with a 20-year survival rate greater than 90%. Treatment consists of total thyroidectomy and removal of all involved lymph nodes, usually followed by radioiodine ablation to destroy residual thyroid remnant and metastatic tissue left behind after surgery. Thyroid hormone replacement is started to suppress TSH secretion and stimulation of residual thyroid tissue and to treat the hypothyroidism that results from surgical removal of the thyroid gland. Since papillary thyroid carcinoma in children is associated with a high recurrence rate, regular follow-up with serum thyroglobulin levels (a tumor marker), neck ultrasound, and radioiodine whole body scan are required.

Follicular thyroid carcinoma, medullary thyroid carcinoma, anaplastic carcinoma, and lymphoma are less common thyroid malignancies. Medullary thyroid carcinoma, due to autosomal dominant mutations in the RET protooncogene, arises from the thyroid C cells, which secrete calcitonin. It can occur sporadically or can be inherited in multiple endocrine neoplasia (MEN) type 2 and familial medullary thyroid carcinoma. It is associated with elevated serum calcitonin levels. In affected families, all members should be screened for the mutation, and those identified with the mutation should be treated with prophylactic thyroidectomy in early childhood.

Kloos RT et al: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009;19:565 [PMID: 19469690].

Osipoff JN, Wilson TA: Consultation with the specialist: thyroid nodules. Pediatr Rev 2012 Feb;33(2):75–81 [PMID: 22301033].

Rapkin L, Pashankar FD: Management of thyroid carcinoma in children and young adults. J Pediatr Hematol Oncol 2012;34(Suppl 2):S39–S46 [PMID: 22525405].

Waguespack SG et al: Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol 2011;23(7):596–607 [PMID: 21862994].

DISORDERS OF CALCIUM & PHOSPHORUS METABOLISM

Serum calcium concentration is tightly regulated by the coordinated actions of the parathyroid glands, kidney, liver, and small intestine. Low serum calcium concentrations, detected by calcium-sensing receptors on the surface of parathyroid cells, stimulate parathyroid hormone (PTH) release. PTH in turn promotes release of calcium and phosphorus from bone, reabsorption of calcium from urinary filtrate, and excretion of phosphorus in the urine. Another essential cofactor in calcium homeostasis is 1,25-dihydroxy vitamin D (calcitriol). The first step in production of this active form of vitamin D occurs in the liver where dietary vitamin D is hydroxylated to 25-hydroxy vitamin D. The final step in formation of calcitriol is 1-hydroxylation, which takes place in the kidney under control of PTH. The primary effect of calcitriol is to promote the absorption of calcium from the intestines. In concert with PTH, however, it also facilitates calcium and phosphorus mobilization from bones. Deficiencies or excesses of PTH or calcitriol, abnormalities in their receptors, or abnormalities of vitamin D metabolism lead to clinically significant aberrations in calcium homeostasis. Although calcitonin, released from the thyroid gland C cells, also reduces serum calcium concentration, changes in its serum concentration rarely cause clinically relevant disease.

A normal serum calcium concentration is approximately 8.9–10.2 mg/dL. The normal concentration of ionized calcium is approximately 1.1–1.3 mmol/L. Serum calcium levels in newborns, which are slightly lower than in older children and adults, may be as low as 7 mg/dL in premature infants. Fifty to sixty percent of calcium in the serum is protein-bound and metabolically fairly inactive. Thus, measurement of ionized serum calcium, the metabolically active form, is helpful if serum proteins are low or in conditions such as acidosis that cause abnormal calcium binding to protein.

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Tetany with facial and extremity numbness, tingling, cramps, spontaneous muscle contractures, carpopedal spasm, positive Trousseau and Chvostek signs, loss of consciousness, and convulsions.

 Diarrhea, prolongation of electrical systole (QT interval), and laryngospasm.

 In hypoparathyroidism or PHP: defective nails and teeth, cataracts, and ectopic calcification in the subcutaneous tissues and basal ganglia.

 General Considerations

Hypocalcemia is a consistent feature of conditions such as hypoparathyroidism, pseudohypoparathyroidism (PHP), transient tetany of the newborn, and severe vitamin D deficiency rickets, and may be present in rare disorders of vitamin D action (receptor defects). Hypocalcemia may also occur as a result of intestinal malabsorption of calcium, chronic renal disease, tumor lysis syndrome, rhabdomyolysis, or as the result of an activating mutation in the calcium-sensing receptor of the parathyroid glands and kidneys (hypercalciuric hypocalcemia) (see Table 34–5).

Deficient PTH secretion may be due to deficient parathyroid tissue (DiGeorge syndrome), autoimmunity, or sometimes, magnesium deficiency. Decreased PTH action may be due to magnesium deficiency, vitamin D deficiency, or defects in the PTH receptor (PHP). Occasionally, PTH deficiency is idiopathic. Table 34–6 summarizes the characteristics of disorders of PTH secretion and action.

Autoimmune parathyroid destruction with subsequent hypoparathyroidism may be isolated, or associated with other autoimmune disorders in the APECED syndrome (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, or APS-1). Hypoparathyroidism may also result from unavoidable surgical removal in patients with thyroid cancer. Other features of the DiGeorge syndrome (a deletion of 22.q11) include congenital absence of the thymus (with thymus-dependent immunologic deficiency) and cardiovascular anomalies, especially coarctation of the aorta.

Autosomal dominant hypocalcemia, also called familial hypercalciuric hypocalcemia, is associated with a gain-of-function mutation in the calcium receptor, which causes a low serum PTH despite hypocalcemia, and excessive urinary loss of calcium. A family history of hypocalcemia may be the clue that differentiates this condition from other causes of hypocalcemia.

Transient neonatal hypoparathyroidism (transient tetany of the newborn) is caused both by a relative deficiency of PTH secretion and PTH action (see Table 34–6). The early form of this condition (first 2 weeks of life) occurs in newborns with birth asphyxia. In mothers with hyperparathyroidism, maternal hypercalcemia may suppress fetal PTH secretion and cause early transient neonatal hypoparathyroidism. Likewise, women with gestational diabetes may have relative hyperparathyroidism in the third trimester and their infants may experience transient hypoparathyroidism. Associated hypomagnesemia often aggravates the symptoms associated with hypocalcemia. The late form of neonatal hypoparathyroidism (after 2 weeks of age) occurs in infants receiving high-phosphate formulas (whole cow’s milk is a well-known example). Phosphate binds calcium and produces functional hypocalcemia.

Tumor lysis syndrome and rhabdomyolysis cause cellular destruction that liberates large amounts of intracellular phosphate that complex with serum calcium, producing functional hypocalcemia. Malabsorption states such as celiac disease impair the absorption of calcium, vitamin D, and magnesium, all of which cause hypocalcemia (see Table 34–6). Hypomagnesemia, due to losses from the gastrointestinal tract or kidney, may cause or augment the severity of hypocalcemia by impairing the release of PTH.

Rickets is a term describing the characteristic clinical and bony radiologic features associated with vitamin D deficiency (see Chapter 11). Vitamin D deficiency, caused by lack of sunlight exposure or dietary deficiency, is the most common cause of rickets. Occult vitamin D deficiency is probably more common than is currently recognized. This concern forms the basis for the 2008 recommendation by the American Academy of Pediatrics that breast-fed infants receive vitamin D supplementation of at least 400 IU/d, or supplementation of breast feeding women with 3–4000 IU/d. Rickets can also be caused by defects in the metabolism of vitamin D (see Table 34–5), including liver disease (impaired 25-hydroxylation), kidney disease [impaired 1-hydroxylation of 25-(OH) vitamin D], genetic deficiency of 1α-hydroxylase (vitamin D–dependent rickets), or end-organ resistance to vitamin D (vitamin D–resistant rickets).

Familial hypophosphatemic rickets has skeletal findings similar to those of vitamin D–related rickets. The defect in this condition is abnormal renal phosphate loss related to abnormal fibroblast growth factor 23 (FGF23) regulation. Dietary deficiency of calcium may also cause rickets but more often causes osteopenia.

 Clinical Findings

A. Symptoms and Signs

Prolonged hypocalcemia from any cause is associated with tetany, photophobia, blepharospasm, and diarrhea. The symptoms of tetany are numbness, muscle cramps, twitching of the extremities, carpopedal spasm, and laryngospasm. Tapping the face in front of the ear causes facial spasms (Chvostek sign). Some patients with hypocalcemia exhibit bizarre behavior, irritability, loss of consciousness, and convulsions. Retarded physical and mental development may be present. Headache, vomiting, increased intracranial pressure, and papilledema may occur. In early infancy, respiratory distress may be a presenting finding.

B. Laboratory Findings

In rickets, calcium levels may be low or normal (see Tables 34–5 and 34–6). Phosphate levels in hypocalcemia disorders may be low, normal, or high depending on the cause of the hypocalcemia. Magnesium levels may also be low. PTH levels are reduced in many hypocalcemic conditions, but may be elevated in PHP or severe vitamin D deficiency. Measurement of urinary excretion of calcium as the calcium-creatinine ratio can assist in diagnosis and monitoring of therapy in children on calcitriol therapy.

C. Imaging

Soft tissue and basal ganglia calcification may occur in idiopathic hypoparathyroidism and PHP. Various skeletal changes are associated with rickets, including cupped and irregular long bone metaphyses. Torsional deformities can result in genu varum (bowleg). Accentuation of the costochondral junction gives the rachitic rosary appearance seen on the chest wall.

 Differential Diagnosis

Tables 34–5 and 34–6 outline the features of disorders associated with hypocalcemia. In individuals with hypoalbuminemia, the total serum calcium may be low and yet the functional serum ionized calcium is normal. Ionized calcium is the test of choice for hypocalcemia in patients with low serum albumin.

 Treatment

A. Acute or Severe Tetany

Hypocalcemia is corrected acutely by administration of intravenous calcium gluconate or calcium chloride; 10 mg/kg is the usual dose in acute treatment. Intravenous calcium infusions should not exceed 50 mg/min because of possible cardiac arrhythmia. Cardiac monitoring should be performed during calcium infusion.

B. Maintenance Management of Hypoparathyroidism or Chronic Hypocalcemia

The objective of treatment is to maintain the serum calcium and phosphate at near-normal levels without excess urinary calcium excretion.

1. Diet— Diet should be high in calcium with added calcium supplements starting at a dose of 50–75 mg of elemental calcium per kilogram of body weight per day divided in three to four doses. The dose may be changed based on response of serum level and urinary calcium excretion. Therapy should be monitored to prevent hypercalcemia. Supplemental calcium can often be discontinued in patients with rickets after vitamin D therapy has stabilized.

2. Vitamin D supplementation— A variety of vitamin D preparations are available. Ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃) are the most commonly used oral preparations. Calcitriol (1,25-dihydroxy vitamin D₃) is also available. Cholecalciferol is slightly more active than ergocalciferol in therapy of most vitamin D deficiency states. If there is impaired metabolism of dietary vitamin D to 25-OH vitamin D as seen in hepatic dysfunction, or to its active end product, 1,25-dihydroxy vitamin D, or impaired PTH function, supplementation with calcitriol is recommended. Selection and dosage of vitamin D supplements varies with the underlying condition and the response to therapy. Monitoring of therapy is essential to avoid toxicity.

3. Monitoring— Dosage of calcium and vitamin D must be tailored for each patient. Monitoring serum calcium, urine calcium, and serum alkaline phosphatase levels at 1- to 3-month intervals is necessary to ensure adequate therapy and to prevent hypercalcemia and nephrocalcinosis.

The major goals of monitoring in vitamin D deficiency are to ensure (1) maintenance of serum calcium and phosphorus concentrations within normal ranges, (2) normalization of alkaline phosphatase activity for age, (3) regression of skeletal changes, and (4) maintenance of an age-appropriate urine calcium-creatinine ratio. The ratio should be less than 0.8 in newborns, 0.3–0.6 in children, and less than 0.25 in adolescents (when using creatinine and calcium measured in milligrams per deciliter).

Monitoring goals are somewhat different in hypophosphatemic rickets. Serum calcium and alkaline phosphatase, and urinary calcium to creatinine ratio should be maintained within normal limits. Monitoring of serum PTH is necessary to ensure that secondary hyperparathyroidism does not develop from excessive phosphate treatment or inadequate calcitriol replacement.

In PHP, PTH production is adequate, but target organs (renal tubule, bone, or both) fail to respond because of receptor resistance. Resistance to PTH action is due to a heterozygous inactivating mutation in the stimulatory G protein subunit associated with the PTH receptor, which leads to impaired signaling. Resistance to other G protein–dependent hormones such as TSH, GHRH, and follicle-stimulating hormone (FSH)/luteinizing hormone (LH), may also be present.

There are several types of PHP with variable biochemical and phenotypic features (see Table 34–6). Biochemical abnormalities in PHP (hypocalcemia and hyperphosphatemia) are similar to those seen in hypoparathyroidism, but the PTH levels are elevated. PHP may be accompanied by a characteristic phenotype known as Albright hereditary osteodystrophy (AHO), which includes short stature; round, full facies; irregularly shortened fourth metacarpal; a short, thick-set body; delayed and defective dentition; and mild mental retardation. Corneal and lenticular opacities and ectopic calcification of the basal ganglia and subcutaneous tissues (osteoma cutis) may occur with or without abnormal serum calcium levels. Treatment is the same as for hypoparathyroidism.

Pseudopseudohypoparathyroidism (PPHP) describes individuals with the AHO phenotype, but normal calcium homeostasis. PHP and PPHP can occur in the same cohort. Genomic imprinting is probably responsible for the different phenotypic expression of disease. Heterozygous loss of the maternal allele causes PHP and heterozygous loss of the paternal allele causes PPHP.

Allgrove J: A practical approach to rickets. Endocr Dev 2009;16:115–132 [Epub 2009 Jun 3] [Review] [PMID: 19494664].

Gattineni J, Baum M: Regulation of phosphate transport by fibroblast growth factor 23 (FGF23): implications for disorders of phosphate metabolism. Pediatr Nephrol 2010 Apr;25(4): 591–601 [Review] [PMID: 19669798].

Hendy GN, Guarnieri V, Canaff L: Calcium-sensing receptor and associated diseases. Prog Mol Biol Transl Sci 2009;89:31–95 [Epub 2009 Oct 7] [Review] [PMID: 20374733].

Malloy PJ, Feldman D: Genetic disorders and defects in vitamin D action. Endocrinol Metab Clin North Am 2010 Jun;39(2): 333–346 [PMID: 20511055].

Shaw N: A practical approach to hypocalcaemia in children. Endocr Dev 2009;16:73–92 [Review] [PMID: 19494662].

Hypercalcemia is defined as a serum calcium level > 11 mg/dL. Severe hypercalcemia is a level > 13.5 mg/dL.

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Abdominal pain, polyuria, polydipsia, hypertension, nephrocalcinosis, failure to thrive, renal stones, intractable peptic ulcer, constipation, uremia, and pancreatitis.

 Bone pain or pathologic fractures, subperiosteal bone resorption, renal parenchymal calcification or stones, and osteitis fibrosa cystica.

 Impaired concentration, altered mental status, mood swings, and coma.

 General Considerations

More than 80% of hypercalcemic children or adolescents have either hyperparathyroidism or a malignant tumor. Table 34–7 summarizes the differential diagnosis of childhood hypercalcemia.

Hyperparathyroidism is rare in childhood and may be primary or secondary. The most common cause of primary hyperparathyroidism is parathyroid adenoma. Diffuse parathyroid hyperplasia or multiple adenomas may occur in families. Familial hyperparathyroidism may be an isolated disease, or it may be associated with MEN type 1, or rarely type 2A. Hypercalcemia of malignancy is associated with solid and hematologic malignancies and is due either to local destruction of bone by tumor or to ectopic secretion of PTH-related protein. When ectopic PTH-related protein is present, calcium is elevated, serum PTH is suppressed, and serum PTH–related protein is elevated. Chronic renal disease with impaired phosphate excretion is the most common secondary cause of hyperparathyroidism.

Iqbal CW, Wahoff DC: Diagnosis and management of pediatric endocrine neoplasms. Curr Opin Pediatr 2009 Jun;21(3): 379–385 [Review] [PMID: 19421059].

Toke J et al: Parathyroid hormone-dependent hypercalcemia. Wien Klin Wochenschr 2009;121(7–8):236–245 [Review] [PMID: 19562279].

Waller S: Parathyroid hormone and growth in chronic kidney disease. Pediatr Nephrol 2011 Feb;26(2):195–204 [Epub 2010 Aug 9] [Review] [PMID: 20694820].

 Clinical Findings

A. Symptoms and Signs

1. Due to hypercalcemia— Manifestations include hypotonicity and muscle weakness; apathy, mood swings, and bizarre behavior; nausea, vomiting, abdominal pain, constipation, and weight loss; hyperextensibility of joints; and hypertension, cardiac irregularities, bradycardia, and shortening of the QT interval. Coma occurs rarely. Calcium deposits occur in the cornea or conjunctiva (band keratopathy) and are detected by slit-lamp examination. Intractable peptic ulcer and pancreatitis occur in adults but rarely in children.

2. Due to increased calcium and phosphate excretion— Loss of renal concentrating ability causes polyuria, polydipsia, and calcium phosphate deposition in renal parenchyma or as urinary calculi with progressive renal damage.

3. Due to changes in the skeleton— Initial findings include bone pain, osteitis fibrosa cystica, subperiosteal bone absorption in the distal clavicles and phalanges, absence of lamina dura around the teeth, spontaneous fractures, and moth-eaten appearance of the skull on radiographs. Later, there is generalized demineralization with high risk of subperiosteal cortical bone.

B. Imaging

Bone changes may be subtle in children. Technetium sestamibi scintigraphy is preferred over conventional procedures (ultrasound, computed tomography [CT], and MRI) for localizing parathyroid tumors.

 Treatment

A. Symptomatic

Initial management is vigorous hydration with normal saline and forced calcium diuresis with a loop diuretic such as furosemide (1 mg/kg given every 6 hours). If response is inadequate, glucocorticoids or calcitonin may be used. Bisphosphonates, standard agents for the management of acute hypercalcemia in adults, are being used more often in refractory pediatric hypercalcemia.

B. Chronic

Treatment options vary with the underlying cause. Resection of parathyroid adenoma or subtotal removal of hyperplastic parathyroid glands is the preferred treatment. Postoperatively, hypocalcemia due to the rapid remineralization of chronically calcium-deprived bones may occur. A diet high in calcium and vitamin D is recommended immediately postoperatively and is continued until serum calcium concentrations are normal and stable. Treatment of secondary hyperparathyroidism from chronic renal disease is primarily directed at controlling serum phosphorus levels with phosphate binders. Pharmacologic doses of calcitriol are used to suppress PTH secretion. Long-term therapy for hypercalcemia of malignancy is the treatment of the underlying disorder.

 Course & Prognosis

The prognosis after resection of a single adenoma is excellent. The prognosis following subtotal parathyroidectomy for diffuse hyperplasia or removal of multiple adenomas is usually good and depends on correction of the underlying defect. In patients with multiple sites of parathyroid adenoma or hyperplasia, MEN is likely, and other family members may be at risk. Genetic counseling and DNA analysis to determine the specific gene defect are indicated.

Familial hypocalciuric hypercalcemia is distinguished by low to normal urinary calcium excretion as a result of high renal reabsorption of calcium. PTH is normal or slightly elevated. In most cases, the genetic defect is a mutation in the membrane-bound calcium-sensing receptor expressed on parathyroid and renal tubule cells. It is inherited as an autosomal dominant trait with high penetrance. There is a low rate of new mutations. Most patients are asymptomatic, and treatment is unnecessary. A severe form of symptomatic neonatal hyperparathyroidism may occur in infants homozygous for the receptor mutation.

Vitamin D intoxication is almost always the result of ingestion of excessive amounts of vitamin D. Signs, symptoms, and treatment of vitamin D–induced hypercalcemia are the same as those in other hypercalcemic conditions. Treatment depends on the stage of hypercalcemia. Severe hypercalcemia requires hospitalization and aggressive intervention. Due to the storage of vitamin D in the adipose tissue, several months of a low-calcium, low–vitamin D diet may be required.

Williams syndrome is an uncommon disorder of infancy characterized by elfin-appearing facies and hypercalcemia in infancy. Other features include failure to thrive, mental and motor retardation, cardiovascular abnormalities (primarily supravalvular aortic stenosis), irritability, purposeless movements, constipation, hypotonia, polyuria, polydipsia, and hypertension. A gregarious and affectionate personality is the rule in children with the syndrome. Hypercalcemia may not appear until several months after birth. Treatment consists of restriction of dietary calcium and vitamin D (Calcilo formula) and, in severe cases, moderate doses of glucocorticoids or even bisphosphonates.

A defect in the metabolism of, or responsiveness to, vitamin D is postulated as the cause of Williams syndrome. Elastin deletions localized to chromosome 7 have been identified in more than 90% of patients. Fluorescent in situ hybridization analysis (FISH) may be the best initial diagnostic tool. The risk of hypercalcemia generally resolves by age 4 and dietary restrictions can be relaxed.

Abrupt immobilization, particularly in a rapidly growing adolescent, may cause hypercalcemia and hypercalciuria. Abnormalities often appear 1–3 weeks after immobilization. Medical or dietary intervention may be required in severe cases.

Hypophosphatasia is a rare autosomal recessive condition characterized by deficiency of alkaline phosphatase activity in serum, bone, and tissues. Enzyme deficiency leads to poor skeletal mineralization with clinical and radiographic features similar to rickets. Six different clinical forms are identified. The perinatal form is characterized by severe skeletal deformity and death within a few days of birth. The infantile form includes failure to thrive, hypotonia, and craniosynostosis. The childhood form manifests with variable skeletal findings, reduced bone mineral density, and premature loss of deciduous teeth. Serum calcium levels may be elevated. The diagnosis of hypophosphatasia is made by demonstrating elevated urinary phosphoethanolamine associated with low serum alkaline phosphatase. Therapy is generally supportive. Children who survive the neonatal period may experience gradual improvement. Calcitonin may be of value for the acute treatment of hypercalcemia.

Bringhurst RF, Demay MB, Krane SM, Kronenberg HM: Bone and mineral metabolism in health and disease; Khosla Sandeep: approach to hypercalcemia and hypocalcemia; Potts JT Jr: Diseases of the parathyroid gland: In: Lameson JL (ed): Harrison’s Endocrinology. 2nd ed. McGraw-Hill; 2010.

Lietman SA, Germain-Lee EL, Levine MA: Hypercalcemia in children and adolescents. Curr Opin Pediatr 2010 Aug;22(4):508–515 [Review] [PMID: 20601885].

Varghese J, Rich T, Jimenez C: Benign familial hypocalciuric hypercalcemia. Endocr Pract 2011 Mar–Apr;17(Suppl 1):13–17 [Review] [PMID: 21478088].

GONADS (OVARIES & TESTES)

The fetal gonads develop from bipotential anlagen in the genital ridge. In infants with a Y chromosome, the transcription factor SRY located on the short arm of the Y at location YP11.3 directs the formation of testes from the bipotential gonads. Without expression of SRY, ovaries develop; however, a 46,XX complement of chromosomes is necessary for the development of normal ovaries. WT1 and many other transcription factors, including but not limited to SF1, DAX1, WNT4, and SOX9, are also important in gonadal differentiation. Two pairs of internal reproductive structures, the müllerian and wolffian ducts, develop in both sexes (Figure 34–6). Once testicular differentiation has been determined, the fetal testes produce two substances critical for male differentiation of these ducts. Antimüllerian hormone (AMH) from the sertoli cells of the testis promotes the regression of müllerian structures, and high local concentrations of testosterone from the Leydig cells stimulate growth of the wolffian structures. These structures become the epididymis, vas deferens, and seminal vesicle. In the absence of testes, as in a XX fetus, the lack of AMH production permits the müllerian structures to develop into the paired fallopian tubes, the midline uterus, and the upper portion of the vagina. The wolffian structures, without exposure to high local concentrations of testosterone, regress.

 Figure 34–6. Differentiation of internal reproductive ducts. (Reprinted, with permission from Kronenberg H(ed): Williams Textbook of Endocrinology, 11th ed. Saunders Elsevier; 2008.)

The external genitalia (Figure 34–7) develop from sexually indifferent structures called the genital tubercle (precursor of the penis or clitoris), the labioscrotal swellings (precursors of the scrotum or labia majora), and the urethral folds (precursors of the penile urethra or labia minora). Normal development of male external genitalia depends on an adequate circulating concentration of testosterone, which is converted to dihydrotestosterone (DHT) in the target tissues by the enzyme 5α-reductase. Sexual differentiation of the external genitalia is completed at about 12 weeks of gestation. Excessive androgen exposure of a female infant prior to this will lead to variable degrees of masculinization of the external genitalia, including posterior labial fusion and formation of penile urethra. Exposure after 12 weeks of gestation will only result in clitoromegaly.

 Figure 34–7. Differentiation of external genitalia ducts. (Adapted from Spaulding MH: The development of the external genitalia in the human embryo. Contrib Embryol 1921;13:69–88.)

Disorders of sexual development (DSD) is now the preferred terminology replacing terms such as “intersex” and “pseudo-hermaphrodite,” as these contain pejorative elements. DSD result from incomplete or disordered genital or gonadal development that causes a discordance between genetic sex, gonadal sex, and phenotypic sex. When an infant is born with genital ambiguity, immediate consultation with pediatric endocrinology, urology, and, if possible, psychiatry/psychology and genetics is required. Disorders of sexual development stem from alterations in three main processes: gonadal differentiation, steroidogenesis, or androgen action.

1. Disorders of Gonadal Differentiation

These abnormalities include XY gonadal dysgenesis, mosaicism involving the Y chromosome, XX sex reversal, and true hermaphroditism. Gonadal dysgenesis occurs as a result of abnormal gonadal development. Individuals with complete 46,XY gonadal dysgenesis have streak gonads that do not produce AMH or testosterone. Therefore, external genitalia and internal reproductive structures in complete gonadal dysgenesis are normal female external genitalia. Affected individuals typically present as girls with delayed puberty and amenorrhea. Partial XY gonadal dysgenesis is associated with incomplete testis development resulting in a phenotype of varying degrees of virilization. Mutations in the transcription factors SRY, WT1, SF1, and SOX9 have all been implicated in 46,XY gonadal dysgenesis. It is important to recognize that some of these mutations are associated with abnormalities separate from sexual development. For example, WT1 mutations are associated with increased risk of Wilms tumor and nephropathy.

Mosaicism occurs when cells with two or more karyotypes are found in the same individual. The most common form of mosaicism is 45,X/46,XY. The majority of these individuals have normal male external genitalia but some may have ambiguity due to abnormal testicular formation. These individuals may also share some features of Turner syndrome such as short stature. XX sex reversal, characterized by masculine or ambiguous genital development in an XX individual, can be caused by translocation of the SRY gene to the X chromosome. A true hermaphrodite is defined as having both ovarian and testicular tissue and most often has a karyotype of 46,XX. Dysgenetic gonads have an increased risk for neoplastic transformation; therefore, if gonads are intra-abdominally located and cannot be brought down to the scrotum, gonadectomy is recommended.

2. Disorders of Steroidogenesis (Figure 34–8)

Testosterone biosynthesis in the testicular leydig cells depends on the function of multiple enzymes which are responsible for conversion of intermediary metabolites. Enzymatic defects in this pathway result in decreased or absent testosterone synthesis and in affected XY individuals, there will be reduced or lack of virilization of the external genitalia. Wolffian duct derivatives can be absent, hypoplastic, or normal depending on the degree of the enzyme inactivity. Sertoli cell production of AMH is preserved so müllerian development is also inhibited. Disorders in this category include StAR deficiency, 3β-hydroxysteroid dehydrogenase deficiency, 17α-hydroxylase/17,20 lyase deficiency, and 17β-hydroxysteroid dehydrogenase deficiency. Additionally, defects in conversion of testosterone to dihydrotestosterone (DHT) from 5α-reductase deficiency also results in undervirilization. In this disorder, there is a deficiency of the type 2 isoenzyme of 5α-reductase, which is the primary isoenzyme present in the fetus. The type 1 isoenzyme becomes expressed at puberty at that time more DHT is produced and will masculinize the external genitalia. Since the gonads and adrenal gland share common enzymes of steroid hormone production, some of the enzymatic defects associated with male undervirilization may also affect production of cortisol and aldosterone, leading to cortisol deficiency and salt wasting (see later section on the Adrenal Cortex).

 Figure 34–8. The corticosteroid hormone synthetic pathway. The pathways illustrated are present in differing amounts in the steroid-producing tissues: adrenal glands, ovaries, and testes. In the adrenal glands, mineralocorticoids from the zona glomerulosa, glucocorticoids from the zona fasciculata, and androgens (and estrogens) from the zona reticularis are produced. The major adrenal androgen is androstenedione, because the activity of 17-ketoreductase is relatively low. The adrenal gland does secrete some testosterone and estrogen, however. The pathways leading to the synthesis of mineralocorticoids and glucocorticoids are not present to any significant degree in the gonads; however, the testes and ovaries each produce both androgens and estrogens. Further metabolism of testosterone to dihydrotestosterone occurs in target tissues of the action of the enzyme 5α-reductase. DHEA, dehydroepiandrosterone.

In an XX individual, the most common disorder in this category is congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency. In the classic salt-losing form of this disorder, infant girls present with genital ambiguity but have normal uterus and ovaries. A less common form of CAH is 3β-hydroxysteroid dehydrogenase deficiency, which presents in the same manner.

3. Disorders of Androgen Action

Androgen Insensitivity Syndrome (AIS) is caused by a mutation in the androgen receptor gene located on the proximal, long arm of the X chromosome at Xq11–12. In complete androgen insensitivity syndrome (CAIS), there is no androgen action; thus, 46,XY affected individuals have female external genitalia with a short, blind-ending vagina. The production of AMH in these individuals leads to müllerian regression and the absence of testosterone action leads to absent or rudimentary wolffian structures. Gonads are located either intra-abdominally or in the inguinal canal. Some of these individuals present when surgery for an inguinal hernia reveals testis in the hernia sack. With partial androgen insensitivity syndrome (PAIS), the degree of virilization and ambiguity depends on the degree of abnormality in androgen binding.

4. Evaluation

A complete family and maternal history should be completed focusing on previous affected offspring, neonatal deaths, history of consanguinity, and maternal exposure to any drugs or hormones. On physical examination, dysmorphic features, other congenital anomalies, and hyperpigmentation of nipples and labia/scrotum should be noted. The genital examination should include measuring the width and length of the stretched phallus and noting the position of the urethral meatus. The normal stretched penile length (SPL) is greater than 2.5 cm (and diameter greater than 0.9 cm) in term infants, greater than 2 cm in 34-week infants, greater than 1.5 cm in 30-week infants, and greater than 0.8 cm in 25-week infants. The labioscrotal and inguinal regions should be palpated for presence of gonads. Since ovaries and streak gonads do not typically descend, the presence of a palpable gonad is suggestive of a 46,XY or 45X/46,XY karyotype. The labioscrotal area should also be evaluated for the degree of fusion and rugation.

In all infants, karyotype, FISH for SRY, electrolytes, LH, FSH, and testosterone should be done initially. Additional laboratory evaluation is usually based on these results. A pelvic ultrasound can be helpful to evaluate for the presence of a uterus; however, ultrasound findings can be unreliable so should be done in an institution which has expertise in pediatric imaging. Many times, laparoscopic examination is necessary to delineate internal structures. If the karyotype is 46,XX, a 17-hydroxyprogesterone level should be sent as the most common diagnosis will be congenital adrenal hyperplasia due to 21-hydroxylase deficiency. If the karyotype is 46,XY, then tests to evaluate for disorders of testicular development, steroidogenesis, and androgen action are recommended. It is important that gender assignment be avoided until expert evaluation by a multidisciplinary team is performed. The team should develop a plan for diagnosis, gender assignment, and treatment options before making any recommendations. Open communications with the parents is essential and their participation in decision making encouraged.

Barbaro M, Wedell A, Nordenström A: Disorders of sex development. Semin Fetal Neonatal Med 2011;16(2):119–127 [PMID: 21303737].

Houk CP, Hughes IA, Ahmed SF, Lee PA: Writing Committee for the International Intersex Consensus Conference Participants. Summary of consensus statement on intersex disorders and their management. Pediatrics 2006;118(2):753–757 [PMID: 16882833].

Lambert SM, Vilain EJ, Kolon TF: A practical approach to ambiguous genitalia in the newborn period. Urol Clin N Am 2010;37(2):195–205 [PMID: 20569798].

Oakes MB, Eyvazzadeh AD, Quint E, Smith YR: Complete androgen insensitivity syndrome—a review. J Pediatr Adolesc Gynecol 2008;21(6):305–310 [PMID: 19064222].

ABNORMALITIES IN FEMALE PUBERTAL DEVELOPMENT & OVARIAN FUNCTION

1. Precocious Puberty in Girls

Precocious puberty is defined as pubertal development occurring below the age limit set for normal onset of puberty. Puberty is considered precocious in girls if the onset of secondary sexual characteristics occurs before age 8 years in Caucasian girls and 7 years for African-American and Hispanic girls. Precocious puberty is more common in girls than in boys. This disparity is explained by the large number of girls with central idiopathic precocity, a rare condition in boys. Girls showing signs of puberty between 6 and 8 years of age often have a benign, slowly progressing form that requires no intervention. The age of pubertal onset may be advanced by obesity.

Central (gonadotropin-releasing hormone [GnRH]–dependent) precocious puberty involves activation of the hypothalamic GnRH pulse generator, an increase in gonadotropin secretion, and a resultant increase in production of sex steroids (Table 34–8). The sequence of hormonal and physical events in central precocious puberty is identical to that of normal puberty. Central precocious puberty in girls is generally idiopathic but may be secondary to a central nervous system (CNS) abnormality that disrupts the prepubertal restraint on the GnRH pulse generator. Such CNS abnormalities include, but are not limited to, hypothalamic hamartomas, CNS tumors, cranial irradiation, hydrocephalus, and trauma. Peripheral precocious puberty (GnRH-independent) occurs independent of gonadotropin secretion. In girls, peripheral precocious puberty can be caused by ovarian or adrenal tumors, ovarian cysts, congenital adrenal hyperplasia, McCune-Albright syndrome, or exposure to exogenous estrogen. Estrogen-secreting ovarian or adrenal tumors are rare. Girls with these tumors typically present with markedly elevated estrogen levels and rapidly progressive pubertal changes. McCune-Albright syndrome is a triad of irregular café au lait lesions, polyostotic fibrous dysplasia, and GnRH-independent precocious puberty. It is caused by an activating mutation in the gene encoding the α-subunit of Gs, the G protein that stimulates adenyl cyclase. Endocrine cells with this mutation have autonomous hyperfunction and secrete excess amounts of their respective hormones.

 Clinical Findings

A. Symptoms and Signs

Female central precocious puberty usually starts with breast development, followed by pubic hair growth and menarche. However, the order may vary and girls less than 5 years of age may not have pubic hair development. Girls with ovarian cysts or tumors generally have signs of estrogen excess such as breast development and possibly vaginal bleeding. Adrenal tumors or CAH produce signs of adrenarche (ie, pubic hair, axillary hair, acne, and sometimes, increased body odor). Children with precocious puberty usually have accelerated growth and skeletal maturation, and may temporarily be tall for age. However, because skeletal maturation advances at a more rapid rate than linear growth, final adult stature may be compromised.

B. Laboratory Findings

One of the first steps in evaluating a child with early pubertal development is obtaining a radiograph of the left hand and wrist to determine skeletal maturity (bone age). An estradiol level can also be drawn to rule out an ovarian tumor or cyst. If the bone age is advanced, further evaluation is warranted. In central precocious puberty, the basal serum concentrations of FSH and LH may still be in the prepubertal range. Thus, documentation of the maturity of the hypothalamic-pituitary axis depends on demonstrating a pubertal LH response after stimulation with a GnRH agonist. In peripheral precocious puberty, basal serum FSH and LH are low, and the LH response to GnRH stimulation is suppressed by feedback inhibition of the hypothalamic-pituitary axis by the autonomously secreted gonadal steroids (see Figure 34–1). In girls with an ovarian cyst or tumor, estradiol levels will be markedly elevated. In girls with signs of adrenarche and an advanced bone age, androgen levels (testosterone, androstenedione, dehydroepiandrosterone-sulfate) and possibly adrenal intermediate metabolites (such as 17-hydroxyprogesterone) should be measured.

C. Imaging

When a diagnosis of central precocious puberty is made, a MRI of the brain should be done to evaluate for CNS lesions. It is unlikely that an abnormality will be found in girls 6–8 years of age, so the need for an MRI in this age group should be individually assessed. In girls whose laboratory tests suggest peripheral precocious puberty, an ultrasound of the ovaries and adrenal gland is indicated.

 Treatment

Girls with central precocious puberty can be treated with GnRH analogues that downregulate pituitary GnRH receptors and thus decrease gonadotropin secretion. Currently, the two most common GnRH analogues used are (1) leuprolide, which is given as a monthly intramuscular injection or (2) histrelin subdermal implant, which is replaced annually. With treatment, physical changes of puberty regress or cease to progress and linear growth slows to a prepubertal rate. Projected final heights often increase as a result of slowing of skeletal maturation. After stopping therapy, pubertal progression resumes, and ovulation and pregnancy have been documented. Therapy is instituted for both psychosocial and final height considerations.

Treatment of peripheral precocious puberty is dependent on the underlying cause. In a girl with an ovarian cyst, intervention is generally not necessary, as the cyst usually regresses spontaneously. Serial ultrasounds are recommended to document this regression. Treatment with glucocorticoids is indicated for congenital adrenal hyperplasia. Surgical resection is indicated for the rare adrenal or ovarian tumor.

In McCune-Albright syndrome, therapy with antiestrogens (eg, tamoxifen), agents that block estrogen synthesis (ketoconazole), or aromatase inhibitors (eg, letrozole) may be effective. Regardless of the cause of precocious puberty or the medical therapy selected, attention to the psychological needs of the patient and family is essential.

2. Benign Variants of Precocious Puberty

Benign premature thelarche (benign early breast development) occurs most commonly in girls younger than 2 years of age. Girls present with isolated breast development without other signs of puberty such as linear growth acceleration and pubic hair development. The breast development is typically present since birth and often waxes and wanes in size. It may be unilateral or bilateral. Benign thelarche is thought to be caused by greater ovarian hormone production during infancy. Treatment is parental reassurance regarding the self-limited nature of the condition. Observation of the child every few months is also indicated. Onset of thelarche after age 36 months or in association with other signs of puberty requires evaluation.

Benign premature adrenarche (benign early adrenal maturation) is manifested by early development of pubic hair, axillary hair, acne, and/or body odor. Benign premature adrenarche is characterized by normal linear growth and no or minimal bone age advancement. The timing of true puberty is not affected, and no treatment is required. Approximately 15% of girls with premature adrenarche are at risk for developing polycystic ovarian syndrome during puberty.

Carel JC et al: Consensus statement on the use of gonadotropin–releasing hormone analogs in children. Pediatrics 2009;123(4): e752–e762 [PMID: 19332438].

Kaplowitz P: Update on precocious puberty: girls are showing signs of puberty earlier, but most do not require treatment. Adv Pediatr 2011;58(1):243–258 [PMID: 21736984].

Oberfield SE, Sopher AB, Gerken ET: Approach to the girl with early onset pubic hair. J Clin Endocrinol Metab 2011;96(6):1610–1622 [PMID: 216024454].

3. Delayed Puberty

Delayed puberty in girls should be evaluated if there are no pubertal signs by age 13 years or menarche by 16 years. Failure to complete pubertal development to Tanner stage V within 4 years of onset is also considered delay. Primary amenorrhea refers to the absence of menarche, and secondary amenorrhea refers to the absence of menses for at least 6 months after regular menses have been established. The most common cause of delayed puberty is constitutional growth delay (Table 34–9). This growth pattern, characterized by short stature, normal growth velocity, and a delay in skeletal maturation, is described in detail earlier in this chapter. The timing of puberty is commensurate to the bone age, not the chronologic age. Girls may also have delayed puberty from any condition that delays growth and skeletal maturation, such as hypothyroidism and GHD.

Primary hypogonadism in girls refers to a primary abnormality of the ovaries. The most common diagnosis in this category is Turner syndrome, in which the lack of or an abnormal second X chromosome leads to early loss of oocytes and accelerated stromal fibrosis. Other types of primary ovarian insufficiency are less common, including 46,XY gonadal dysgenesis, 46,XX gonadal dysgenesis, galactosemia, and autoimmune ovarian failure. Radiation and chemotherapy can also cause primary ovarian insufficiency. Girls who are premutation carriers for fragile X syndrome are also at increased risk of premature ovarian failure.

Central hypogonadism refers to a hypothalamic or pituitary deficiency of GnRH or FSH/LH, respectively. Central hypogonadism can be functional (reversible), caused by stress, undernutrition, prolactinemia, excessive exercise, or chronic illness. Permanent central hypogonadism is typically associated with conditions that cause multiple pituitary hormone deficiencies, such as congenital hypopituitarism, CNS tumors, or cranial irradiation. Isolated gonadotropin deficiency is rare but may occur in Kallmann syndrome, which is also characterized by hyposmia or anosmia. There are many genes that have been implicated in both isolated gonadotropin deficiency and Kallmann syndrome. In either primary or central hypogonadism, signs of adrenarche are generally present.

Delayed menarche or secondary amenorrhea may result from primary ovarian failure or central hypogonadism, or may be the consequence of hyperandrogenism, anatomic obstruction precluding menstrual outflow, or müllerian agenesis. This latter disorder is called Mayer-Rokitansky-Küster-Hauser syndrome and is characterized by an absent vagina and various uterine abnormalities, with or without renal and skeletal anomalies.

Girls with complete AIS (androgen receptor defect) typically present with primary amenorrhea, breast development, and absence of sexual hair. The affected individual (46,XY) has functioning testes that produce antimüllerian hormone during fetal life. Thus, no müllerian duct (oviduct or uterus) development occurs. External genitalia are female because of the lack of androgen action. At puberty, if the gonads have not been removed, testosterone produced in the testes is aromatized to estrogen resulting in breast development.

 Clinical Evaluation

The history should ascertain whether and when puberty commenced, level of exercise, nutritional intake, stressors, sense of smell, symptoms of chronic illness, and family history of delayed puberty. Past growth records should be assessed to determine if height and weight velocity have been appropriate. Physical examination includes body proportions, breast and genital development, and stigmata of Turner syndrome. Pelvic examination or pelvic ultrasonography should be considered, especially in girls with primary amenorrhea.

A bone age radiograph should be obtained first. If the bone age is lower than that consistent with pubertal onset (< 12 years in girls), evaluations should focus on finding the cause of the bone age delay. If short stature and normal growth velocity are present, constitutional growth delay is likely. If growth rate is abnormal, laboratory studies may include a complete blood count, erythrocyte sedimentation rate, chemistry panel, and renal and liver function tests to look for unsuspected chronic medical illness. Evaluation for hypothyroidism and GHD may also be indicated. Measurement of FSH and LH may not be helpful in the setting of delayed bone age since prepubertal levels are normally low. Determination of a karyotype should be considered if there is short stature, or any stigmata of Turner syndrome.

If the patient has attained a bone age of more than 12 years and there are minimal or no signs of puberty on physical examination, FSH and LH levels will distinguish between primary ovarian failure and central hypogonadism. Primary ovarian failure is also called hypergonadotropic hypogonadism, as there is lack of estrogen feedback to the brain with elevated FSH and LH. If gonadotropins are elevated, a karyotype is the next step, as Turner syndrome is the most common cause of female hypergonadotropic hypogonadism. Central hypogonadism is characterized by low gonadotropin levels, and evaluation is geared toward determining if the hypogonadism is functional or permanent. Laboratory tests should be directed toward identifying chronic disease and hyperprolactinemia. Cranial MRI may be helpful.

In girls with adequate breast development and amenorrhea, a progesterone challenge may be helpful to determine if sufficient estrogen is being produced. Girls who are producing estrogen have a withdrawal bleed after 5–10 days of oral progesterone, whereas those who are estrogen-deficient have little or no bleeding. The exception is girls with an absent uterus (androgen insensitivity or Mayer-Rokitansky-Küster-Hauser syndrome). They have sufficient estrogen but cannot have withdrawal bleeding. The most common cause of amenorrhea in girls with sufficient estrogen is polycystic ovarian syndrome. Girls who are estrogen-deficient should be evaluated similarly to those who have delayed puberty.

 Treatment

Replacement therapy in hypogonadal girls begins with estrogen alone at the lowest available dosage. Oral preparations such as estradiol or topical patches are used. Cyclic estrogen–progesterone therapy is started 12–18 months later, and eventually the patient may be switched over to a birth control pill for convenience. Progesterone therapy is needed to counteract the effects of estrogen on the uterus, as unopposed estrogen promotes endometrial hyperplasia. Estrogen is also necessary to promote bone mineralization and prevent osteoporosis.

Bondy CA: Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;92:10 [PMID: 17047017].

Nelson LM: Clinical practice: primary ovarian insufficiency. N Engl J Med 2009;360:606 [PMID: 19196677].

4. Secondary Amenorrhea

See discussion of amenorrhea in Chapter 4.

1. Precocious Puberty in Boys

Puberty is considered precocious in boys if secondary sexual characteristics appear before age 9 years. While the frequency of central precocious puberty is much lower in boys than girls, boys are more likely to have an associated CNS abnormality (see Table 34–8).

Several types of gonadotropin-independent (peripheral) precocious puberty occur in boys (see Table 34–8). Increased adrenal androgen production from an adrenal tumor or from a virilizing form of CAH will cause pubertal changes in boys. Familial male-limited gonadotropin-independent puberty (familial testotoxicosis) is a condition in which a mutated LH receptor on the Leydig cell is autonomously activated, resulting in testicular production of testosterone despite prepubertal LH levels. McCune-Albright syndrome can also occur in boys. Leydig cell tumors of the testis cause rapid onset of unilateral testicular enlargement and physical signs of testosterone excess. Human chorionic gonadotropin (HCG)–secreting tumors such as teratomas, CNS germinomas, and hepatoblastomas also cause early puberty in boys, as HCG stimulates testosterone production from Leydig cells.

 Clinical Findings

A. Symptoms and Signs

In precocious development, increased linear growth rate and growth of pubic hair are the most common presenting signs. Testicular size may differentiate central precocity, in which the testes enlarge, from gonadotropin-independent causes such as CAH, in which the testes usually remain small (< 2 cm in the longitudinal axis). However, in familial testotoxicosis and HCG-mediated precocious puberty, there is some testicular enlargement but not to the degree as seen in central precocity. Tumors of the testis are associated with either asymmetrical or unilateral testicular enlargement.

B. Laboratory Findings

Elevated testosterone levels verify early pubertal status but do not differentiate the source. As in girls, basal serum LH and FSH concentrations may not be in the pubertal range in boys with central precocious puberty, but the LH response to GnRH stimulation testing is pubertal. Sexual precocity caused by CAH is usually associated with abnormal plasma dehydroepiandrosterone, androstenedione, 17-hydroxyprogesterone (in CAH due to 21-hydroxylase deficiency), 11-deoxycortisol (in CAH due to 11-hydroxylase deficiency), or a combination of these steroids (see the section Adrenal Cortex, later). Serum β-HCG concentrations can signify the presence of an HCG-producing tumor (eg, CNS dysgerminoma or hepatoma) in boys who present with precocious puberty and testicular enlargement but suppressed gonadotropins following GnRH testing.

C. Imaging

In all boys with central precocious puberty, cranial MRI should be obtained to evaluate for a CNS abnormality. If testing suggests peripheral precocious puberty, and laboratory studies are not consistent with CAH, ultrasonography may be useful in detecting hepatic, adrenal, and testicular tumors.

 Treatment

Treatment of central precocious puberty in boys is with GnRH analogues, similar to treatment in girls. Boys with McCune-Albright syndrome or familial testotoxicosis can be treated with agents that block steroid synthesis (ketoconazole), or with a combination of antiandrogens (spironolactone) and aromatase inhibitors (anastrozole or letrozole) which block the conversion of testosterone to estrogen.

2. Delayed Puberty

Boys should be evaluated for delayed puberty if they have no secondary sexual characteristics by 14 years of age or if more than 5 years have elapsed since the first signs of puberty without completion of genital growth.

The most common cause of delayed puberty in boys, as in girls, is constitutional growth delay, a normal variant of growth that is described in detail earlier in this chapter. Hypogonadism in boys may be primary, due to absence, malfunction, or destruction of testicular tissue, or central, due to pituitary or hypothalamic insufficiency. Primary testicular insufficiency may be due to anorchia, Klinefelter syndrome (47,XXY), or other sex chromosome abnormalities, enzymatic defects in testosterone synthesis, or inflammation or destruction of the testes following infection (mumps), autoimmune disorders, radiation, trauma, or tumor.

Central hypogonadism may accompany panhypopituitarism, Kallmann syndrome (GnRH deficiency with anosmia), or isolated LH or FSH deficiencies. Destructive lesions in or near the anterior pituitary (especially craniopharyngioma and glioma) or infection may also result in hypothalamic or pituitary dysfunction. Prader-Willi syndrome and Laurence-Moon syndrome (Bardet-Biedl syndrome) are frequently associated with LH and FSH deficiency in boys and girls secondary to GnRH deficiency. Deficiencies in gonadotropins may be partial or complete. Functional or reversible gonadotropin may occur with chronic illness, malnutrition, hyperprolactinemia, hypothyroidism, or excessive exercise.

 Clinical Evaluation

The history should focus on whether and when puberty has started, testicular descent, symptoms of chronic illness, nutritional intake, sense of smell, and family history of delayed puberty. Physical examination should include body proportions, height and weight, pubertal stage, and testicular location, size, and consistency. Testes less than 2 cm in length are prepubertal; testes more than 2.5 cm in length suggest early pubertal growth.

A radiograph of the left hand and wrist to assess bone age should be the first step in evaluating a boy with delayed puberty. If bone age is delayed (< 12 years) and growth velocity is normal, constitutional growth delay is the most likely diagnosis.

Laboratory evaluation includes LH and FSH levels (especially if bone age is > 12 years). Elevated gonadotropin levels indicate primary hypogonadism or testicular failure. The most common cause of primary hypogonadism in boys is Klinefelter syndrome; however, the usual presentation of this disorder is not delayed puberty but failure to complete puberty with a discrepancy noted between testicular size (small) and degree of virilization. If gonadotropin values are low, the working diagnosis is central hypogonadism and further evaluation should focus on looking for pituitary hormone deficiencies, chronic disease or undernutrition (or both), hyperprolactinemia, and CNS abnormalities.

 Treatment

Boys with simple constitutional delay may be offered a short (4–6 months) course of low-dose depot testosterone (50–75 mg/mo) to stimulate their pubertal appearance and “jump-start” their endogenous development. In adolescents with permanent hypogonadism, treatment with depot testosterone, beginning with 50–75 mg intramuscularly each month, may be used until growth is complete. Thereafter, adult dosing (150–200 mg every 2–3 weeks) may be used. An alternative to intramuscular injections is testosterone gel, either in single-dose packets or in a pump set to dispense a preset dose. Gel is applied daily after showering. Specific therapy for GnRH deficiency with pulsatile subcutaneous GnRH may promote fertility in patients with hypothalamic-pituitary insufficiency. However, the inconvenience of treatment and the need for repeated doses for long periods of time have limited its application in pediatrics.

3. Cryptorchidism

Cryptorchidism (undescended testis) is very common, affecting 2%–4% of full-term male newborns and up to 30% of premature infants. Short-term postnatal endogenous testosterone secretion decreases the incidence of cryptorchidism to 1% by 3 months of age. After 6 months of age, spontaneous descent occurs only very rarely. Consequently, intervention is typically considered beginning at this time.

Infertility and testicular malignancy are major risks of cryptorchidism. Fertility is impaired by approximately 33% after unilateral cryptorchidism and by 66% after bilateral disease. The cancer risk for adults after cryptorchidism in childhood is reported to be 5–10 times greater than normal. However, histologic changes clearly occur as early as age 6 months in children with undescended testes.

The cause of most cases of cryptorchidism is not completely understood. Cryptorchidism can occur in an isolated fashion or associated with other findings. Abnormalities in the hypothalamic-pituitary-gonadal axis predispose to cryptorchidism. Androgen biosynthesis or receptor defects also predispose to cryptorchidism and undervirilization.

The diagnosis of bilateral cryptorchidism in an apparently normal male newborn should never be made until the possibility that the child is actually a fully virilized female with potentially fatal salt-losing CAH has been considered.

 Clinical Findings

In infants between 2 and 6 months of age, LH, FSH, and testosterone levels help determine whether testes are present. After this time, an HCG stimulation test can be done to confirm the presence or absence of functional abdominal testes. Ultrasonography, CT scanning, and MRI may detect testes in the inguinal region, but these studies are not completely reliable in finding abdominal testes.

 Differential Diagnosis

In palpating the testis, the cremasteric reflex that causes the testis to retract into the inguinal canal or abdomen (pseudocryptorchidism) may be elicited. To prevent retraction during examination, the fingers first should be placed across the abdominal ring and the upper portion of the inguinal canal to obstruct testicular ascent. Examination while the child is in the squatting position or in a warm bath is helpful. No treatment for retractile testes is necessary, and the prognosis for testicular descent and function is excellent.

 Treatment

The current recommendation for treatment of cryptorchidism is that surgical orchidopexy be performed by an experienced surgeon if descent has not occurred by 6–12 months of age. The recommended timing of surgical intervention is based on the assumption that early surgery to relocate the testis into the low-temperature environment of the scrotum will allow normal germ cell development and decrease the risk for future infertility and cancer. However, in a certain number of cases, there is a primary abnormality of the testis which is thought to be responsible for the undescent and future risks. Hormonal therapy with HCG to induce descent of the testis only has a success rate of about 20%, and even less when retractile testes are excluded. HCG doses range from 250 to 1000 international units and are given twice weekly for 5 weeks. In the future, there may be a role for therapy with a GnRH analogue in addition to surgery as preliminary studies suggest that this treatment stimulates germ cell development and thus may improve future fertility.

4. Gynecomastia

Gynecomastia is a common, self-limited condition that may occur in up to 75% of normal pubertal boys. Adolescent gynecomastia typically resolves within 2 years but may not totally resolve if the degree of gynecomastia is extreme (> 2 cm of tissue). Gynecomastia may sometimes occur as part of Klinefelter syndrome, or it may occur in boys who are taking drugs such as antidepressants or marijuana. Medical therapy using antiestrogens and aromatase inhibitors have been used but generally the results are not deemed satisfactory. Surgical intervention is a reasonable option for prolonged and/or severe cases (see Chapter 4).

Bonami M et al: New understanding of the genetic basis of isolated idiopathic central hypogonadism. Asian J Androl 2012;14(1):49–56 [PMID: 22138902].

Harrington J, Palmert MR: Clinical review: distinguishing constitutional growth delay and puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available diagnostic tests. J Clin Endocrinol Metab 97(9):3056–3067 [PMID: 22723321].

Hutson JM, Balic A, Nation T, Southwell B: Cryptorchidism. Semin Pediatr Surg 2010;19(3):215–224 [PMID: 20610195].

Layman LC: Hypogonadotropic hypogonadism. Endocrinol Metab Clin North Am 2007;36:283 [PMID: 17543719].

ADRENAL CORTEX

The adult adrenal cortex has a regional distribution of terminal steroid production. The outermost zona glomerulosa is the predominant source of aldosterone. The middle zona fasciculata makes cortisol and small amounts of mineralocorticoids. The innermost zona reticularis produces mainly androgens and estrogens. A fetal zone, or provisional cortex, that predominates during fetal development, produces glucocorticoids, mineralocorticoids, androgens, and estrogens. The fetal zone is relatively deficient in 3β-hydroxysteroid dehydrogenase (see Figure 34–8); hence placentally produced progesterone is the major precursor used in fetal adrenal production of cortisol and aldosterone.

The adrenal cortical production of cortisol is under the control of pituitary adrenocorticotropic hormone (ACTH; see Figure 34–1 and Table 34–1), which is in turn regulated by the hypothalamic peptide, corticotropin-releasing hormone (CRH). The complex interaction of CNS influences on CRH secretion, coupled with negative feedback of serum cortisol, leads to a diurnal pattern of ACTH and cortisol release. ACTH concentration is greatest during the early morning hours with a smaller peak in the late afternoon and a nadir at night. The pattern of serum cortisol concentration follows this pattern with a lag of a few hours. In the absence of cortisol feedback, there is dramatic CRH and ACTH hypersecretion.

Glucocorticoids are critical for gene expression in a many cell types. In excess, glucocorticoids are both catabolic and antianabolic; that is, they promote the release of amino acids from muscle and increase gluconeogenesis while decreasing incorporation of amino acids into muscle protein. They also antagonize insulin activity and facilitate lipolysis. Glucocorticoids help maintain blood pressure by promoting peripheral vascular tone and sodium and water retention.

Mineralocorticoids (primarily aldosterone in humans) promote sodium retention and stimulate potassium excretion in the distal renal tubule. Although ACTH can stimulate aldosterone production, the predominant regulator of aldosterone secretion is the volume- and sodium-sensitive renin-angiotensin-aldosterone system. Elevations of serum potassium also directly influence aldosterone release from the cortex.

Androgen (dehydroepiandrosterone and androstenedione) production by the zona reticularis is insignificant before puberty. At the onset of puberty, androgen production increases and may be an important factor in the dynamics of puberty in both sexes. The adrenal gland is a major source of androgen in the pubertal and adult female.

The leading causes of adrenal insufficiency are hereditary enzyme defects (congenital adrenal hyperplasia), autoimmune destruction of the glands (Addison disease), central adrenal insufficiency caused by intracranial neoplasm or its treatment, or congenital midline defects associated with optic nerve hypoplasia (septo-optic dysplasia). Rare forms of familial adrenal insufficiency occur in association with cerebral sclerosis and spastic paraplegia (adrenoleukodystrophy) or in association with achalasia and alacrimia in the triple A syndrome or Allgrove syndrome. Addison disease may be familial and has been described in association with hypoparathyroidism, mucocutaneous candidiasis, hypothyroidism, pernicious anemia, hypogonadism, and diabetes mellitus as one of the polyglandular autoimmune syndromes. Less commonly, the gland is destroyed by tumor, calcification, or hemorrhage (Waterhouse-Friderichsen syndrome). Adrenal disease secondary to opportunistic infections (fungal or tuberculous) is reported in AIDS. In children, central adrenal insufficiency due to anterior pituitary tumor is rare. Salt-losing disorders can occur from homozygous mutations affecting the aldosterone synthase enzyme (CYP11B2) or from partial or complete unresponsiveness of the mineralocorticoid receptor to aldosterone action (pseudohypoaldosteronism). A transient autosomal dominant form of pseudohypoaldosteronism has been reported in infancy. It is speculated to be secondary to a maturation disorder of function or number of aldosterone receptors and usually resolves by the first year of life.

Acute illness, surgery, trauma, or hyperthermia may precipitate an adrenal crisis in patients with adrenal insufficiency. Patients with primary adrenal insufficiency are at greater risk for life-threatening crisis than patients with central ACTH deficiency because mineralocorticoid secretion and low-level autonomous cortisol secretion remain intact in central ACTH deficiency.

 Clinical Findings

A. Symptoms and Signs

1. Acute form (adrenal crisis)—Manifestations include nausea, vomiting, diarrhea, abdominal pain, dehydration, fever (sometimes followed by hypothermia), weakness, hypotension, circulatory collapse, confusion, and coma. Increased pigmentation may be associated with primary adrenal insufficiency caused by melanocyte-stimulating activity of the hypersecreted parent molecule of ACTH, pro-opiomelanocortin.

2. Chronic form—Manifestations include fatigue, hypotension, weakness, failure to gain weight, weight loss, salt craving (primary insufficiency), vomiting, and dehydration. Diffuse tanning with increased pigmentation over pressure points, scars, and mucous membranes may be present in primary adrenal insufficiency. A small heart may be seen on chest radiograph.

B. Laboratory Findings

1. Suggestive of adrenocortical insufficiency—In primary adrenal insufficiency, serum sodium and bicarbonate levels, arterial partial pressure of carbon dioxide, blood pH, and blood volume are decreased. Serum potassium and urea nitrogen levels are increased. Urinary sodium level and the ratio of urinary sodium to potassium are inappropriate for the degree of hyponatremia. In central adrenal insufficiency, serum sodium levels may be mildly decreased as a result of impaired water excretion. Eosinophilia and moderate lymphopenia occur in both forms of insufficiency.

2. Confirmatory tests

A. ACTH (COSYNTROPIN) STIMULATION TEST— In primary adrenal insufficiency (originating in the gland itself), plasma cortisol and aldosterone concentrations do not increase significantly over baseline 60 minutes after an intravenous dose of ACTH (250 mcg). To diagnose central adrenal insufficiency, a low dose of ACTH is given (1 mcg).

B. BASELINE SERUM ACTH CONCENTRATION—Values are elevated in primary adrenal failure and low in central adrenal insufficiency.

C. URINARY FREE CORTISOL— Values are decreased.

D. CRH TEST— This test assesses responsiveness of the entire hypothalamic-pituitary-adrenal axis. After administration of ovine CRH, serum concentrations of ACTH and cortisol are measured over 2 hours. Verification of an intact axis or localization of the site of impairment is possible with careful interpretation of results.

 Differential Diagnosis

Acute adrenal insufficiency must be differentiated from severe acute infections, diabetic coma, various disturbances of the CNS, and acute poisoning. In the neonatal period, adrenal insufficiency may be clinically indistinguishable from respiratory distress, intracranial hemorrhage, or sepsis. Chronic adrenocortical insufficiency must be differentiated from anorexia nervosa, certain muscular disorders (myasthenia gravis), salt-losing nephritis, and chronic debilitating infections, and must be considered in cases of recurrent spontaneous hypoglycemia.

 Treatment

A. Acute Insufficiency (Adrenal Crisis)

1. Hydrocortisone sodium succinate— Hydrocortisone sodium succinate is given initially at a dose of 50 mg/m² intravenously over 2–5 minutes or intramuscularly; thereafter, it is given intravenously, 12.5 mg/m², every 4–6 hours until stabilization is achieved and oral therapy can be tolerated.

2. Fluids and electrolytes— In primary adrenal insufficiency, 5%–10% glucose in normal saline, 10–20 mL/kg intravenously, is given over the first hour and repeated if necessary to reestablish vascular volume. Normal saline is continued thereafter at 1.5–2 times the maintenance fluid requirements. Intravenous boluses of glucose (10% glucose, 2 mL/kg) may be needed every 4–6 hours to treat hypoglycemia. In central adrenal insufficiency, routine fluid management is generally adequate after restoration of vascular volume and institution of cortisol replacement.

3. Fludrocortisone— When oral intake is tolerated, fludrocortisone, 0.05–0.15 mg daily, is started and continued as necessary every 12–24 hours for primary adrenal insufficiency.

4. Inotropic agents— Rarely, inotropic agents such as dopamine and dobutamine are needed. However, adequate cortisol replacement is critical because pressor agents may be ineffective in adrenal insufficiency.

5. Waterhouse-Friderichsen syndrome with fulminant infections— The use of adrenocorticosteroids and norepinephrine in the treatment or prophylaxis of fulminant infections remains controversial. Corticosteroids may augment the generalized Shwartzman reaction in fatal cases of meningococcemia. However, corticosteroids should be considered if there is possible adrenal insufficiency, particularly if there is hypotension and circulatory collapse.

B. Maintenance Therapy

Following initial stabilization, the most effective substitution therapy is hydrocortisone, combined with fludrocortisone in primary adrenal insufficiency. Overtreatment should be avoided as it causes obesity, growth retardation, and other cushingoid features. Additional hydrocortisone, fludrocortisone, or sodium chloride, singly or in combination, may be necessary with acute illness, surgery, trauma, or other stress reactions. Supportive adrenocortical therapy should be given whenever surgical operations are performed in patients who have at some time received prolonged therapy with adrenocorticosteroids.

1. Glucocorticoids— A maintenance dosage of 6–10 mg/m²/d of hydrocortisone (or equivalent) is given orally in two or three divided doses. The dosage of all glucocorticoids is increased to 30–50 mg/m²/d during intercurrent illnesses or other times of stress.

2. Mineralocorticoids— In primary adrenal insufficiency, fludrocortisone is given, 0.05–0.15 mg orally daily as a single dose or in two divided doses. Periodic monitoring of blood pressure is recommended to avoid overdosing.

3. Salt— The child should be given ready access to table salt. Frequent blood pressure determinations in the recumbent position should be made to check for hypertension. In the infant, supplementation of 3–5 mEq Na⁺/kg/d by adding a solution of 4 mg/mL to formula or breast milk is generally required until table foods are introduced.

C. Corticosteroids in Patients with Adrenocortical Insufficiency Who Undergo Surgery

1. Before operation— Hydrocortisone sodium succinate, 30–50 mg/m² IM or intravenously 1 hour before surgery.

2. During operation— Hydrocortisone sodium succinate, 25–100 mg intravenously with 5%–10% glucose in saline as a continuous drip throughout surgery.

3. During recovery— Hydrocortisone sodium succinate, 12.5 mg/m² intravenously every 4–6 hours until oral doses are tolerated. The oral hydrocortisone dose of three to five times the maintenance dose is continued until the acute stress is over, at which time the patient can be returned to the maintenance dose.

 Course & Prognosis

The course of acute adrenal insufficiency is rapid, and death may occur within a few hours, particularly in infants, unless adequate treatment is given. Spontaneous recovery is unlikely. Patients who have received long-term treatment with adrenocorticosteroids may exhibit adrenal collapse if they undergo surgery or other acute stress. Pharmacologic doses of glucocorticoids during these episodes may be needed throughout life. In all forms of acute adrenal insufficiency, the patient should be observed carefully once the crisis has passed and evaluated with laboratory tests to assess the degree of permanent adrenal insufficiency.

Patients with chronic adrenocortical insufficiency who receive adequate therapy can lead normal lives.

Akirav EM, Ruddle NH, Herold KC: The role of AIRE in human autoimmune disease. Nat Rev Endocrinol 2011 Jan;7(1):25–33 [Epub 2010 Nov 23] [PMID: 21102544].

Michels AW, Eisenbarth GS: Immunologic endocrine disorders. J Allergy Clin Immunol 2010 Feb;125(Suppl 2):S226–S237 [PMID: 20176260].

Michels AW, Gottlieb PA: Autoimmune polyglandular syndromes. Nat Rev Endocrinol 2010 May;6(5):270–277 [Epub 2010 Mar 23] [PMID: 20309000].

Reisch N, Arlt W: Fine tuning for quality of life: 21st century approach to treatment of Addison’s disease. Endocrinol Metab Clin North Am 2009;38(2):407–418, ix–x [PMID: 19328419].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES–CONGENITAL

 Adrenal Hyperplasia: 21-OHase Deficiency.

 Genital virilization in females, with labial fusion, urogenital sinus, enlargement of the clitoris, or other evidence of androgen action.

 Salt-losing crises in infant males or isosexual precocity in older males with infantile testes.

 Increased linear growth and advanced skeletal maturation.

 Elevation of plasma 17-hydroxyprogesterone concentrations in the most common form; may be associated with hyponatremia, hyperkalemia, and metabolic acidosis, particularly in newborns.

 General Considerations

Autosomal recessive mutations in the enzymes of adrenal steroidogenesis in the fetus cause impaired cortisol biosynthesis with increased ACTH secretion. ACTH excess subsequently results in adrenal hyperplasia with increased production of adrenal hormone precursors which are conveyed through the unblocked androgen pathway with resulting increase in androgen production. Increased pigmentation, especially of the scrotum, labia majora, and nipples, is common with excessive ACTH secretion. CAH is most commonly (> 90% of patients) the result of homozygous or compound heterozygous mutations in the cytochrome P-450 C21 (CYP21A2) gene causing 21-hydroxylase deficiency (see Figure 34–8). In its severe form, excess adrenal androgen production starting in the first trimester of fetal development causes virilization of the female fetus and life-threatening hypovolemic, hyponatremic shock (adrenal crisis) in the newborn. There are also other enzyme defects that less commonly result in CAH. The clinical syndromes associated with these defects are shown in Figure 34–8 and Table 34–10.

Studies of patients with 21-hydroxylase deficiency indicate that the clinical type (salt-wasting or non–salt-wasting) is usually consistent within a kindred and that a close genetic linkage exists between the 21-hydroxylase gene and the human leukocyte antigen complex on chromosome 6. Prenatal diagnosis is now possible by allele-specific PCR or direct sequencing of the fetal CYP21A2 gene. This can be done when there is a known index case in the family. Population studies indicate that the defective gene is present in 1:250–1:100 people and that the worldwide incidence of the disorder is 1:15,000 with increased incidence is certain ethnic groups. Mass screening for this enzyme defect, using a microfilter paper technique to measure serum 17-hydroxyprogesterone, has been established in all 50 U.S. states and many other countries worldwide.

Nonclassic presentations of 21-hydroxylase deficiency have been reported with increasing frequency. Affected persons have a normal phenotype at birth but may develop evidence of virilization during later childhood, adolescence, or early adulthood. In these cases, results of hormonal studies are characteristic of 21-hydroxylase deficiency with cosyntropin stimulated 17-OHP levels being intermediate between those of nonaffected individuals and those with the classic form of the disease. Many individuals with the nonclassic form of the disease can be asymptomatic or only mildly symptomatic and do not need treatment. However, they can carry a severe CYP21A2 mutation and produce offspring with the classic form. Thus, it is recommended that these individuals should receive genetic counseling.

 Clinical Findings

A. Symptoms and Signs

1. In females— Abnormality of the external genitalia varies from mild enlargement of the clitoris to complete fusion of the labioscrotal folds, forming an empty malrotated scrotum, a penile urethra, a penile shaft, and with clitoral enlargement sufficient to form a normal-sized glans (see Figure 34–7). Signs of adrenal insufficiency (salt loss) may occur in the first days of life but more typically appear in the second or third week. Rarely, signs of adrenal insufficiency do not occur for months or years. With milder enzyme defects, salt loss may not occur, and virilization predominates (simple virilizing form). In untreated non–salt-losing 21-hydroxylase or 11-hydroxylase deficiency, growth rate and skeletal maturation are accelerated and patients appear muscular. Pubic hair appears early (often before the second birthday), acne may be excessive, and the voice may deepen. Excessive pigmentation may develop. Isosexual central precocious puberty may occur if treatment is not initiated before the bone age is significantly advanced. Final adult height is often compromised.

2. In males— The male infant usually appears normal at birth but may present with salt-losing crisis in the first 2–4 weeks of life. In milder forms, salt-losing crises may not occur. In this circumstance, enlargement of the penis and increased pigmentation may be noted during the first few months. Other symptoms and signs are similar to those of affected females. The testes are not enlarged except in the rare male in whom aberrant adrenal cells (adrenal rests) are present in the testes, producing unilateral or asymmetrical bilateral enlargement. In the rare isolated defect of StAR protein, 17α-hydroxylase, or 3β-hydroxysteroid dehydrogenase activity, ambiguous genitalia may be present because of impaired androgen production (see Figure 34–8). Individuals with PORD present with skeletal malformations similar to the Antler Bixley syndrome in addition to genital ambiguity. Rare cases of 17α-hydroxylase mutations affecting only the 17–20 lyase functions of the enzyme have been reported. In those cases, patients present with isolated androgen deficiency and normal cortisol and aldosterone levels.

B. Laboratory Findings

1. Blood— Hormonal studies are essential for accurate diagnosis. Findings characteristic of the enzyme deficiencies are shown in Table 34–10.

2. Genetic studies— Rapid chromosomal diagnosis should be obtained in any newborn with ambiguous genitalia.

3. Urine— The diagnosis of P450 oxidoreductase deficiency is best done by gas chromatography/mass spectrometry analysis of urinary steroid metabolites, as serum steroids can be misleading. Pathognomonic findings include: increased pregnenolone and progesterone metabolites, increased 17-OHP metabolites, and decreased androgen metabolites.

C. Imaging

Ultrasonography, CT scanning, and MRI may be useful in defining pelvic anatomy or enlarged adrenals or in localizing an adrenal tumor. Contrast-enhanced radiographs of the vagina and pelvic ultrasonography may be helpful in delineating the internal anatomy in a newborn with ambiguous genitalia.

 Treatment

A. Medical Treatment

Treatment goals in CAH are to replace deficient steroids with the smallest dose of glucocorticoid that will produce normalization of growth velocity and skeletal maturation by adequately suppressing excess build-up of androgen precursors. Excessive glucocorticoids cause the undesirable side effects of Cushing syndrome. Mineralocorticoid replacement sustains normal electrolyte homeostasis, but excessive mineralocorticoids cause hypertension and hypokalemia. Undervirilized males with the less frequent forms of CAH may require adult androgen replacement therapy in addition to glucocorticoid and mineralocorticoid replacement.

1. Glucocorticoids— Supraphysiologic doses of hydrocortisone are often needed to suppress androgen excess in CAH. Initially, parenteral or oral hydrocortisone (30–50 mg/m²/d) suppresses abnormal adrenal steroidogenesis within 2 weeks. When adrenal suppression has been accomplished, as evidenced by normalization of serum 17-hydroxyprogesterone, patients are placed on maintenance doses of 10–15 mg/m²/d in three divided doses. Dosage is adjusted to maintain normal growth rate and skeletal maturation. Various serum and urine androgens have been used to monitor therapy, including 17-hydroxyprogesterone, androstenedione, and urinary pregnanetriol. No one test is universally accepted. In adolescent girls, normal menses are a sensitive index of the adequacy of therapy. Therapy should be continued throughout life in both males and females because of the possibility of malignant degeneration of the hyperplastic adrenal gland. In pregnant females with CAH, suppression of adrenal androgen secretion is critical to avoid virilization of the fetus, particularly a female fetus. Suppression of adrenal androgen production is best begun before conception. Hydrocortisone is the preferred choice for glucocorticoid replacement therapy in pregnant women with CAH because it does not cross the placenta.

2. Mineralocorticoids— Fludrocortisone, 0.05–0.15 mg, is given orally once a day or in two divided doses. Periodic monitoring of blood pressure and plasma renin activity are recommended to adjust dosing.

B. Surgical Treatment

For affected females, consultation with a urologist or gynecologist experienced in female genital reconstruction should be arranged as soon as possible during infancy.

 Course & Prognosis

When therapy is initiated in early infancy, abnormal metabolic effects and progression of masculinization can be avoided. Treatment with glucocorticoids permits normal growth, development, and sexual maturation. If not adequately controlled, CAH results in sexual precocity and masculinization throughout childhood. Affected individuals will be tall as children but short as adults because of a rapid rate of skeletal maturation and premature closure of the epiphyses. If treatment is delayed or inadequate until somatic development is completed (12–14 years as determined by bone age), true central precocious puberty may occur in males and females.

Patient education stressing lifelong therapy is important to ensure compliance in adolescence and later life. Virilization and multiple surgical genital reconstructions are associated with a high risk of psychosexual disturbances in female patients. Ongoing psychological evaluation and support is a critical component of care.

Finkielstain GP et al: Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2012;97:4429–4438 [PMID: 22990093].

Nimkarn S, New MI: Prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Mol Cell Endocrinol 2009;300(1–2):192–196 [PMID: 19101608].

Reisch N, Arlt W, Krone N: Health problems in congenital adrenal hyperplasia due to 21-hydoxylase deficiency. Horm Res Paediatr 2011 May 15 [Epub ahead of print] [PMID: 21597280].

Speiser PW et al: Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:4133–4160 [PMID: 20823466].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Cushing Syndrome.

 Truncal adiposity, thin extremities, moon facies, muscle wasting, weakness, plethora, easy bruising, purple striae, decreased growth rate, and delayed skeletal maturation.

 Hypertension, osteoporosis, and glycosuria.

 Elevated serum corticosteroids, low serum potassium, eosinopenia, and lymphopenia.

 General Considerations

Cushing syndrome may result from excessive secretion of adrenal steroids autonomously (adenoma or carcinoma), excess pituitary ACTH secretion (Cushing disease), ectopic ACTH secretion, or chronic exposure to exogenous glucocorticoids. In children younger than 12 years, Cushing syndrome is usually iatrogenic (secondary to exogenous ACTH or glucocorticoids). It may rarely be due to adrenal tumor, adrenal hyperplasia, pituitary adenoma, or extrapituitary ACTH-producing tumor.

 Clinical Findings

A. Symptoms and Signs

1. Excess glucocorticoid— Manifestations include adiposity, most marked on the face, neck, and trunk (a fat pad in the interscapular area is characteristic); fatigue; plethoric facies; purplish striae; easy bruising; osteoporosis; hypertension; glucose intolerance; back pain; muscle wasting and weakness; and marked retardation of growth and skeletal maturation.

2. Excess mineralocorticoid— Patients have hypokalemia, mild hypernatremia with water retention, increased blood volume, edema, and hypertension.

3. Excess androgen— Hirsutism, acne, and varying degrees of virilization are present. Menstrual irregularities occur in older girls.

B. Laboratory Findings

1. Blood

A. PLASMA CORTISOL— Values are elevated, with loss of normal diurnal variation. Determination of cortisol level between midnight and 2 AM may be a sensitive indicator of the loss of diurnal variation.

B. SERUM CHLORIDE AND POTASSIUM— Both values are usually low, but serum sodium and bicarbonate concentrations may be elevated with metabolic alkalosis.

C. SERUM ACTH— ACTH concentration is decreased in adrenal tumor and increased with ACTH-producing pituitary or extrapituitary tumors.

D. CBC— Polymorphonuclear leukocytosis with lymphopenia and eosinopenia are common. Polycythemia occurs.

2. Salivary cortisol— This is a less invasive means by which to measure serial cortisol values, and the tests may be performed at home. Salivary cortisol obtained at midnight is a highly specific and sensitive test for hypercortisolism.

3. 24-Hour urinary free cortisol excretion— This value is elevated. It is considered the most useful initial test to document hypercortisolism, although midnight salivary cortisol is considered a reasonable and more practical alternative. The urinary free cortisol/creatinine ratio is usually measured to correct for incomplete 24 hour collections.

4. Response to dexamethasone suppression testing— Suppression of adrenal function by a small dose (0.5–1.0 mg) of dexamethasone is seen in obese children who may have elevated urinary free cortisol excretion, but not in children with an ACTH-secreting tumor or adrenal tumor. Larger doses (4–16 mg/d in four divided doses) of dexamethasone cause suppression of adrenal activity when the disease is due to ACTH hypersecretion by a pituitary tumor, whereas hypercortisolism due to adrenal adenomas or adrenal carcinomas is rarely suppressed.

5. CRH test— The CRH stimulation test, in conjunction with petrosal sinus sampling, is effective in distinguishing pituitary and ectopic sources of ACTH excess and for lateralization of pituitary sources prior to surgery.

C. Imaging

Pituitary imaging may demonstrate a pituitary adenoma. Adrenal imaging by CT scan may demonstrate adenoma or bilateral hyperplasia. Radionuclide studies of the adrenals may be useful in complex cases. Osteoporosis, evident first in the spine and pelvis, with compression fractures may occur in advanced cases. Skeletal maturation is usually delayed.

 Differential Diagnosis

Children with exogenous obesity accompanied by striae and hypertension are often suspected of having Cushing syndrome. The child’s height, growth rate, and skeletal maturation are helpful in differentiating the two. Children with Cushing syndrome have a poor growth rate, relatively short stature, and delayed skeletal maturation, while those with exogenous obesity usually have a normal or slightly increased growth rate, normal to tall stature, and advanced skeletal maturation. The color of the striae (purplish in Cushing syndrome, pink in obesity) and the distribution of the obesity may assist in differentiation. The urinary-free cortisol excretion (in milligrams per gram of creatinine) may be mildly elevated in obesity, but midnight salivary cortisol is normal, and cortisol secretion is suppressed by a relatively small dose of dexamethasone (see “Response to dexamethasone suppression testing”).

 Treatment

In all cases of primary adrenal hyperfunction due to tumor, surgical removal is indicated if possible. Glucocorticoids should be administered parenterally in pharmacologic doses during and after surgery until the patient is stable. Supplemental oral glucocorticoids, potassium, salt, and mineralocorticoids may be necessary until the suppressed contralateral adrenal gland recovers, sometimes over a period of several months. The use of mitotane, a DDT derivative that is toxic to the adrenal cortex, and aminoglutethimide, an inhibitor of steroid synthesis, have been suggested, but their efficacy in children with adrenal tumors has not been determined. Pituitary microadenomas may respond to pituitary surgery or irradiation.

 Prognosis

If the tumor is malignant, the prognosis is poor if it cannot be completely removed. If it is benign, cure is to be expected following proper preparation and surgery.

Mancini T, Porcelli T, Giustina A: Treatment of Cushing disease: overview and recent findings. Ther Clin Risk Manag 2010 Oct 21; 6:505–516 [PMID: 21063461].

Nieman LK et al: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93(5):1526–1540 [PMID: 18334580].

Savage MO et al: Work-up and management of paediatric Cushing’s syndrome. Curr Opin Endocrinol Diabetes Obes 2008;15(4):346–351 [PMID: 18594275].

Primary hyperaldosteronism may be caused by an adrenal adenoma or adrenal hyperplasia. It is characterized by paresthesias, tetany, weakness, nocturnal enuresis, periodic paralysis, low serum potassium and elevated serum sodium levels, hypertension, metabolic alkalosis, and production of large volume, alkaline urine with low specific gravity. The specific gravity does not respond to vasopressin. Glucose tolerance test is frequently abnormal. Plasma and urinary aldosterone are elevated. In contrast to renal disease or Bartter syndrome, plasma renin activity is suppressed, creating a high aldosterone-renin ratio. In patients with adrenal tumor, ACTH may further increase the excretion of aldosterone. Marked improvement after the administration of an aldosterone antagonist such as spironolactone may be of diagnostic value.

Primary aldosteronism is rare in pediatrics. However, there are three recognized genetic causes (types I–III). Type I occurs due to inheritance of a hybrid of the genes encoding 11β-hydroxylase and aldosterone synthase. Type III was recently described and results from mutations in the KCNJ5 gene encoding a K⁺ channel. Somatic mutations of this gene are also seen in later onset hyperaldosteronism. The genetic cause for type II is unknown.

Treatment is with glucocorticoids (glucocorticoid remediable hyperaldosteronism or familial hyperaldosteronism type I), spironolactone (familial hyperaldosteronism type II), or subtotal or total adrenalectomy for hyperplasia, and surgical removal if a tumor is present.

Rossi GP, Seccia TM, Pessina AC: Primary aldosteronism—part I: prevalence, screening, and selection of cases for adrenal vein sampling. J Nephrol 2008;21(4):447–454 [PMID: 18651532].

Rossi GP, Seccia TM, Pessina AC: Primary aldosteronism—part II: subtype differentiation and treatment. J Nephrol 2008;21(4):455–462 [PMID: 18651533].

Stowasser M: Primary aldosteronism in 2011: towards a better understanding of causation and consequences. Nat Rev Endocrinol 2011 Dec 13;8(2):70–72 [PMID: 22158200].

Glucocorticoids are used for their anti-inflammatory and immunosuppressive properties in a variety of conditions in childhood. Pharmacologic doses are necessary to achieve these effects, and side effects are common. Numerous synthetic preparations possessing variable ratios of glucocorticoid to mineralocorticoid activity are available (Table 34–11).

Actions

Glucocorticoids exert a direct or permissive effect on virtually every tissue of the body; major known effects include the following:

1. Gluconeogenesis in the liver

2. Stimulation of fat breakdown (lipolysis) and redistribution of body fat

3. Catabolism of protein with an increase in nitrogen and phosphorus excretion

4. Decrease in lymphoid and thymic tissue and a decreased cellular response to inflammation and hypersensitivity

5. Alteration of CNS excitation

6. Retardation of connective tissue mitosis and migration; decreased wound healing

7. Improved capillary tone and increased vascular compartment volume and pressure

 Side Effects of Therapy

When prolonged use of pharmacologic doses of glucocorticoids is necessary, clinical manifestations of Cushing syndrome are common. Side effects may occur with the use of synthetic exogenous agents by any route, including inhalation and topical administration, or with the use of ACTH. Use of a larger dose of glucocorticoids given once every 48 hours (alternate-day therapy) lessens the incidence and severity of some of the side effects (Table 34–12).

 Tapering of Pharmacologic Doses of Steroids

Prolonged use of pharmacologic doses of glucocorticoids causes suppression of ACTH secretion and consequent adrenal atrophy. The abrupt discontinuation of glucocorticoids may result in adrenal insufficiency. ACTH secretion generally does not restart until the administered steroid has been given in subphysiologic doses (< 6 mg/m²/d orally) for several weeks.

If pharmacologic glucocorticoid therapy has been given for less than 10–14 days, the drug can be discontinued abruptly (if the condition for which it was prescribed allows) because adrenal suppression will be short-lived. However, it is advisable to educate the patient and family about the signs and symptoms of adrenal insufficiency in case problems arise.

If tapering is necessary in treating the condition for which the glucocorticoid is prescribed, a reduction of 25%–50% every 2–7 days is sufficiently rapid to permit observation of clinical symptomatology. An alternate-day schedule (single dose given every 48 hours) will allow for a 50% decrease in the total 2-day dosage while providing the desired pharmacologic effect. If tapering is not required for the underlying disease, the dosage can be rapidly decreased safely to the physiologic range. Although a rapid decrease in dose to the physiologic range will not lead to frank adrenal insufficiency (because adequate exogenous cortisol is being provided), some patients may experience a steroid withdrawal syndrome, characterized by malaise, insomnia, fatigue, and loss of appetite. These symptoms may necessitate a two- or three-step decrease in dose to the physiologic range.

Once a physiologic equivalent dose (8–10 mg/m²/d hydrocortisone or equivalent) is achieved and the patient’s underlying disease is stable, the dose can be decreased to 4–5 mg/m²/d given only in the morning. This will allow the adrenal axis to recover. After this dose has been given for 4–6 weeks, assessment of endogenous adrenal activity is estimated by obtaining fasting plasma cortisol concentrations between 7 and 8 AM prior to the morning steroid dose. When an alternate-day schedule is followed, plasma cortisol is measured the morning before treatment. Plasma cortisol concentration in the physiologic range (> 10 mg/dL) indicates return of basal physiologic adrenal rhythm. Exogenous steroids may then be discontinued safely, although it is advisable to continue giving stress doses of glucocorticoids when appropriate until recovery of the response to stress has been documented.

After basal physiologic adrenal function returns, the adrenal reserve or capacity to respond to stress and infection can be estimated by the low-dose ACTH stimulation test, in which 1 mcg of synthetic ACTH (cosyntropin) is administered intravenously. Plasma cortisol is measured prior to (zero time) and at 45–60 minutes after the infusion. A plasma cortisol concentration greater than 18 mg/dL at 60 minutes indicates a satisfactory adrenal reserve.

Even if the results of testing are normal, patients who have received prolonged treatment with glucocorticoids may develop signs and symptoms of adrenal insufficiency during acute stress, infection, or surgery for months to years after treatment has been stopped. Careful monitoring, and the use of stress doses of glucocorticoids, should be considered during severe illnesses and surgery.

Allen DB: Effects of inhaled steroids on growth, bone metabolism, and adrenal function. Adv Pediatr 2006;53:101–110 [PMID: 17089864].

Gulliver T, Eid N: Effects of glucocorticoids on the hypothalamic-pituitary-adrenal axis in children and adults. Immunol Allergy Clin North Am 2005;25:541 [PMID: 16054542].

Wildi-Runge S et al: A search for variables predicting cortisol response to low-dose corticotropin stimulation following supraphysiological doses of glucocorticoids. J Pediatr 2013 Feb (Epub ahead of print) [PMID: 23414662].

Zöllner EW: Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled corticosteroids: Part 1. Which test should be used? Pediatr Allergy Immunol 2007;18(5): 401–409 [PMID: 17561933].

Zöllner EW: Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled corticosteroids (part 2)—the risk as determined by gold standard adrenal function tests: a systematic review. Pediatr Allergy Immunol 2007;18(6):469–474 [PMID: 17680905].

Pheochromocytoma is an uncommon tumor, but up to 10% of reported cases occur in pediatric patients. The tumor can be located wherever chromaffin tissue (adrenal medulla, sympathetic ganglia, or carotid body) is present, possibly from decreased apoptosis of neural crest cells during development. It may be multiple, recurrent, and sometimes malignant. Familial forms include pheochromocytomas associated with the dominantly inherited neurofibromatosis type 1, MEN type 2, and von Hippel-Lindau syndromes, as well as mutations of the succinate dehydrogenase genes. Neuroblastomas, ganglioneuromas, and other neural crest tumors, as well as carcinoid tumors, may secrete pressor amines and mimic pheochromocytoma.

The symptoms of pheochromocytoma are generally caused by excessive secretion of epinephrine or norepinephrine and most commonly include headache, sweating, tachycardia, and hypertension. Other symptoms are anxiety, dizziness, weakness, nausea and vomiting, diarrhea, dilated pupils, blurred vision, abdominal and precordial pain, and vasomotor instability (flushing and postural hypotension). Sustained symptoms may lead to cardiac, renal, optic, or cerebral damage.

Laboratory diagnosis is possible in more than 90% of cases. Serum and urine catecholamines are elevated, but abnormalities may be limited to periods of symptomatology or paroxysm. Plasma-free metanephrine level (phenoxybenzamine, tricyclic antidepressants, and β-adrenoreceptor blockers can create false-positive results) is the most sensitive test and the gold standard for diagnosis. Levels three times the normal range are diagnostic. Intermediate values may require additional testing, with urinary vanillylmandelic acid and urinary total metanephrines providing the highest specificity. Provocative tests using histamine, tyramine, or glucagon and the phentolamine tests may be abnormal but are dangerous and are rarely necessary. After demonstrating a tumor biochemically, imaging methods including CT or MRI are used to localize the tumor. When available, functional ligands such as (123)I-MIBG, [¹⁸F]DA positron emission tomography scanning, and somatostatin receptor scintigraphy (with either [¹²³I]Tyr3-octreotide or [¹¹¹In] DTPA-octreotide) are useful in further diagnostic evaluation.

Laparoscopic tumor removal is the treatment of choice; however, the procedure must be undertaken with great caution and with the patient properly stabilized. Oral phenoxybenzamine or intravenous phentolamine is used preoperatively. Profound hypotension may occur as the tumor is removed but may be controlled with an infusion of norepinephrine, which may have to be continued for 1–2 days.

Unless irreversible secondary vascular changes have occurred, complete relief of symptoms is to be expected after recovery from removal of a benign tumor. However, prognosis is poor in patients with metastases, which occur more commonly with large, extra-adrenal pheochromocytomas.

Waguespack SG et al: A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 2010;95(5):2023–2037 [PMID: 20215394].