Pediatric Residency Training Program
Ronald A. Nagel M.D.
Lee Todd Miller M.D.
- Short Stature
- General Concepts
- Definition.Short stature is defined as height that is two standard deviations (SDs) below the mean (i.e., below the third percentile).
- Normal variant short staturedescribes a child whose height is below the third percentile but is growing with a normal growth velocity.
- Pathologic short staturedescribes a child whose height is below the third percentile (often more than 3 SDs below the mean) but is growing with a suboptimal growth velocity.
- Key point: It is critical to evaluate growth rate and not just absolute heightwhen evaluating short stature.
- In the first 2 years of life, a normal downward shift in the height percentile may reflect genetic short stature.
- Key pearl:Children who grow 2 inches per year (5 cm per year) between 3 years of age and puberty usually do not have an endocrinopathy or underlying pathologic disorder.
- All patients with short stature who are more than 3 SDs below the mean or who have a growth velocity less than 5 cm per year are considered to have a pathologic growth disorder until proven otherwise.
- Determining the targeted mid-parental height (MPH)may be helpful in distinguishing a patient with normal variant short stature from pathologic short stature (Figure 6-1).
- Most children, when they have completed their growth, are within ±2 SDs, or 4 inches, of their MPH.
- A major discrepancy between a child's present growth percentile and the targeted MPH percentile suggests a pathologic state.
- Perinatal history.Assess for prematurity or intrauterine growth retardation (IUGR). A history of hypoglycemia, prolonged jaundice, cryptorchidism, or microphallus suggestshypopituitarism.
- Chronic diseasessuch as renal failure, central nervous system (CNS) disease, severe asthma with frequent and prolonged steroid use, sickle cell anemia, and inflammatory bowel disease may manifest short stature.
Figure 6-1. Determination of mid-parental height (MPH). Most patients, when they have completed their growth, will be within ±2 standard deviations, or 4 inches, of the MPH. For example, if a boy has a father who is 5 feet 9 inches in height and a mother who is 5 feet in height, then the MPH is 5 feet 7 inches ± 4 inches.
- Chronic use of drugs, such as steroids, or stimulants for attention deficit/hyperactivity disorder that result in significant appetite suppression and poor weight gain may lead to short stature.
- Family history, especially parental growth and pubertal histories, are important.To evaluate for constitutional delay short stature and familial short stature (see section D.1), ask whether the family history is positive for “late growth spurts” or “late bloomers” in high school or college and the age of maternal menarche.
- Social historyis critical because children who live in neglected or hostile environments may exhibit short stature because of psychosocial deprivation.
- Review of systemsshould include questions about cold intolerance, constipation (hypothyroidism), abdominal pain, diarrhea or bloody stools (inflammatory bowel disease), and headaches and vomiting (brain tumor).
- Dental history.Delayed dental eruption may suggest a delayed bone age.
- Physical Examination
- Accurate height and weightshould be plotted on a U.S. National Center for Health Statistics (NCHS) growth chart, along with previous growth points to assess the child's growth pattern.
- Measure the patient's upper-to-lower (U/L) body segment ratio.
- Lower segment= pubic symphysis to the heel
- Upper segment= total height minus lower segment
- Normal ratios:
- Birth = 1.7
- 3 years of age = 1.3
- > 7 years of age = 1.0
- Abnormal U/L ratiosuggests disproportionate short stature (see section D.2.b).
- Thorough physical examination should include a funduscopic examination, assessment of thyroid size, evaluation for stigmata of genetic syndromes (e.g., web neck, shield chest, and short fourth metacarpals are
suggestive of Turner syndrome; see Chapter 5, section III.C.1), scoliosis screening, and Tanner staging (see Chapter 3, section I).
- Categorization of Short Stature (Figure 6-2)
- Normal variant short stature.The two most common categories of normal variant short stature (children whose height falls below the third percentile with normal growth velocity) are familial (or genetic) short stature and constitutional growth delay with delayed puberty.
- Familial (or genetic) short statureis defined as a height at least 2 SDs below the mean with a short MPH but with a normal bone age, a normal onset of puberty, and a minimum growth of 2 inches (or 5 cm) per year.
- Constitutional short statureis defined as a height at least 2 SDs below the mean with a history of delayed puberty in either or both parents, a delayed bone age and late onset of puberty, and a minimum growth of 2 inches (or 5 cm) per year.
- Pathologic short stature.Pathologic short stature (children whose heights fall more than 3 SDs below the mean with abnormal growth velocity (i.e., growth velocity less than 2 inches or 5 cm per year) may be categorized as proportionate or disproportionate.
- Proportionate short statureis defined as short stature with a normal U/L ratio (see section I.C.2.c). It is important to distinguish between prenatal onset and postnatal onset.
- Causes of prenatal onset proportionateshort stature include:
- Environmental exposures(e.g., in utero exposure to tobacco and alcohol)
Figure 6-2. Differential diagnosis of short stature.
- Chromosome disorders(e.g., Down syndrome, Turner syndrome)
- Genetic syndromes(e.g., Russell-Silver syndrome, Prader-Willi syndrome; see Chapter 5, sections III.A.13 and III.A.2, respectively)
- Viral infectionearly in pregnancy (e.g., cytomegalovirus, rubella)
- Causes of postnatal onset proportionateshort stature
- Psychosocial causes (e.g., neglect, child abuse)
- Organ system diseases, including gastrointestinal diseases (inflammatory bowel disease), cardiac diseases (cyanotic congenital heart disease), renal diseases (renal failure, renal tubular acidosis), chronic lung diseases (cystic fibrosis, asthma), and endocrinopathies (hypothyroidism, growth hormone deficiency, and cortisol excess; see alsosection I.F)
- Disproportionate short statureis defined as short stature in patients are who very short-legged with an increased U/L ratio, suggesting rickets or a skeletal dysplasia.
- Consider ricketsfor patients with frontal bossing, bowed legs, low serum phosphorus level, and high serum alkaline phosphatase (see section X.C).
- Consider some form of skeletal dysplasia(e.g., achondroplasia) for patients who are short with short limbs (see Chapter 5, section III.D).
- Evaluation of Pathologic Short Stature
- Laboratory studies
- Complete blood count (CBC), erythrocyte sedimentation rate (ESR), thyroxine (T4), serum electrolytes including calcium and phosphorus, and serum creatinine and bicarbonate levels should be obtained.
- Insulin growth factor (IGF-1) is an indirect test for growth hormone deficiency. Random growth hormone level should not be measured; most growth hormone is released during stage IV non-rapid eye movement sleep.
- Chromosome analysis in girls to evaluate for Turner syndrome
- Radiographic studies
- Bone agedetermination (anterior-posterior [AP] film of the left hand and wrist to assess the characteristics of the epiphyses or growth plates) is very helpful to compare with chronologic age (Table 6-1).
- AP and lateral skull radiographs are necessary to assess the pituitary gland (distortion of the sella turcica and suprasellar calcification suggest craniopharyngioma).
- Key pearl:Patients with poor growth velocity with normal screening laboratory results but low IGF-1 and delayed bone age should have a workup for growth hormone deficiency.
Table 6-1. Using Bone Age in the Differential Diagnosis of Short Stature
Bone Age = Chronologic Age
Bone Age < Chronologic Age
Familial short stature
Constitutional short stature
Intrauterine growth retardation
Growth hormone deficiency
- Endocrinopathies that Cause Short Stature
- Growth hormone (GH) deficiencyis uncommon.
- Clinical features.A history of prolonged neonatal jaundice, hypoglycemia, cherubic facies, central obesity, microphallus, cryptorchidism, and midline defects (e.g., cleft palate) may be present. The growth curve demonstrates poor growth velocity (less than 2 inches or 5 cm per year).
- Causesinclude brain tumors (pearl: craniopharyngioma must be considered in any child older than 5 years of age who is not growing 2 inches per year), prior CNS irradiation, CNS vascular malformations, autoimmune diseases, trauma, and congenital midline defects. (Consider GH deficiency in patients with a single central maxillary incisor or with cleft palate.)
- Imaging studies.Patients have a delayed bone age. All patients with GH deficiency must have an MRI of the head to rule out a CNS lesion.
- Laboratory studies.Low IGF-1 levels, and a poor response on growth hormone stimulation testing (with L-dopa-Inderal, glucagon, or clonidine)
- Management.Treatment includes daily subcutaneous injections of recombinant growth hormone until a bone age determination shows that the patient has reached nearly maximal growth potential (by about 13–14 years of age in girls and 15–16 years of age in boys).
- Hypothyroidism.The most common cause of hypothyroidism is Hashimoto's thyroiditis (see section VIII.B.2.b). Patients will present with increased TSH, low T4, and positive antithyroid peroxidase antibodies.
- Hypercortisolism.The most common cause of hypercortisolism is iatrogenic as a result of prolonged use of steroids (see section IV.E.1). Patients present with a history of poor growth and increasing weight gain, purpuric stretch marks and a dorsal neck fat pad on examination, and delayed bone age.
- Turner syndrome(see also Chapter 5, section III.C.1). Female patients who are missing part or all of one of the X chromosomes may present with lack of puberty and poor growth velocity. Growth hormone treatment has been shown to improve the ultimate height of these patients.
- Disorders of Puberty
- Normal Puberty (see also Chapter 3, section I.A.2)
- In the prepubescent state, sex steroids (testosterone and estradiol) are depressed by sensitive negative feedback at the level of the hypothalamus.
- Puberty begins when there is a reduction in this hypothalamic inhibition, resulting in activation of the hypothalamic-pituitary-gonadal axis (HPGA).
- The HPGA releases gonadotropin-releasing hormone (GnRH) from the hypothalamus, which binds to receptors in the pituitary gland and causes the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
- Female puberty.Different stages of pubertal development are defined as follows. It is important, however, to be aware that the age of onset and subsequent course of hormonal and physical changes during puberty are variable:
- Onset is between 7 and 13 years of age.
- Thelarcheis the onset of breast development as a result of the release of estrogen, and adrenarche is the onset of pubic or axillary hair development as a result of the release of adrenal androgens. Breast buds are usually the first sign of puberty, although in 15% of girls, pubic hair develops first.
- Menarcheis the onset of the menstrual cycle. Menstruation begins at 9–15 years of age, with a mean onset of 12.5 years of age.
- FSHstimulates the ovaries to produce ovarian follicles, which in turn produce estrogen.
- LHis responsible for the positive feedback in the middle of the menstrual cycle resulting in the release of an egg.
- Tanner staging.See Chapter 3, section I.A.2.c.(2).
- Male puberty
- Onset is between 9 and 14 years of age.
- Testicular enlargementis usually the first sign of puberty (≥ 4 mL as measured with an orchidometer).
- Seventy-five percent of the testicular volume is the seminiferous tubules.
- FSHin boys stimulates the seminiferous tubules in the testes to produce sperm.
- LHin boys stimulates the testicular Leydig cells to produce androgens, which in turn are responsible for penile enlargement and the growth of axillary, facial, and pubic hair.
- Tanner staging. See Chapter 3, section I.A.2.c.(1).
- African American children develop secondary sexual characteristics earlier than do most other children.
- Moderate to severe obesity is associated with sexual precocity.
- Precocious Puberty
- Girls:presence of breast development or pubic hair before 7 years of age or menarche before 9 years of age
- Boys:presence of testicular changes, penile enlargement, or pubic or axillary hair before 9 years of age
- Premature thelarche
- Definition.There is visible or palpable breast tissue only, with no other secondary sex characteristics. The growth pattern should be normal, and no pubic hair should be apparent.
- Epidemiology.This very common and benign condition usually presents in the first 2 years of life.
- Etiology.This condition is caused by a transient activation of the HPGA, resulting in transient ovarian follicular stimulation and a release of low levels of estrogen.
- No workup is necessary and no treatment is indicated, unless there is pubic hair development or a rapid growth spurt.
- Premature adrenarche
- Definition.Early onset of pubic or axillary hair occurs without the development of breast tissue or enlarged testes.
- Epidemiology.This condition is more common in girls than in boys.
- Classic presentationoccurs after 5 years of age, with the onset of pubic hair growth, axillary hair growth, and apocrine odor. No breast tissue is noted, and there is no clitoromegaly. Growth is normal without advancement of bone age.
- No treatment is indicated.
- Isosexual precocious puberty or central precocious puberty (CPP)
- Definition.The early onset of gonadotropin-mediated (i.e., mediated by FSH and LH) puberty is a normal state, except that the hypothalamus has been activated earlier than usual.
- Epidemiology. Girlshave a higher incidence of isosexual precocious puberty than boys.
- Clinical features
- In girls, physical examination shows breast development, pubic hair, and rapid growth.
- In boys, physical examination shows testicular enlargement, pubic hair, and rapid growth.
- In girls, most cases are idiopathic.
- In boys, sexual precocity tends to be organic, and all cases need evaluation with an MRI of the head.
- CNS abnormalities that may cause isosexual precocious puberty includehydrocephalus, CNS infections, cerebral palsy, benign hypothalamic hamartomas, malignant tumors such as astrocytomas and gliomas, and severe head trauma.
- Hypothyroidismmay also present with isosexual precocious puberty, but in this case there is poor growth and a delayed bone age (unlike all other causes of sexual precocity).
- FSH, LH, and sex steroidsare elevated in the pubertal range.
- The GnRH stimulation testis an ideal test to demonstrate premature activation of the hypothalamus.
- By injecting synthetic GnRH into a patient, the LH response, and to a lesser degree the FSH response, can be used as an assessment of the activation of the HPGA. In response to synthetic GnRH, patients with CPP have a dramatic increase in LHsecretion when compared with baseline levels.
- On the other hand, prepubertal patients whose HPGA has not yet been activated, and patients with peripheral precocious puberty in which peripherally produced sex steroids suppress pituitary gonadotropin secretion, would be expected to have a flat response(i.e., no increase in LH secretion) on injection of synthetic GnRH.
- An MRI of the headshould be performed in all boys and in very young girls with any neurologic symptoms (e.g., headaches or seizures) or with very rapid pubertal changes.
- Peripheral precocious puberty (PPP) or heterosexual gonadotropin-independent puberty
- Definition.Precocious puberty that is independent of the HPGA (i.e., caused by the peripheral production of male or female sex steroids and not FSH- or LH-mediated). The hallmark of PPP is a flat response on GnRH stimulation testing because the HPGA has not been activated.
- Clinical features
- Boyspresent with either feminization (gynecomastia) or with premature onset of pubic hair. Note that there is usually no testicular enlargement because these patients do not have an increase in FSH, which would stimulate seminiferous tubule enlargement (see exceptions in section II.B.2.d.(3)(c)).
- Girlspresent with virilization or breast development.
- Etiology.Causes may differ in boys and girls, but in general include exposure to exogenous sex steroids (found in some skin lotions or foods), gonadal tumors, adrenal tumors, and nonclassic congenital adrenal hyperplasia (CAH; see section IV.C.4.a.(3)). All of these causes are independent of the HPGA.
- In boys, consider adrenal tumors, Leydig cell tumors (presenting with asymmetric testicular enlargement), nonclassic CAH, βhuman chorionic gonadotropin (β-HCG)-producing tumors, McCune-Albright syndrome, and testotoxicosis.
- In girls, consider adrenal tumors, virilizing ovarian tumors (arrhenoblastomas), feminizing ovarian tumors (juvenile granulosa tumors), nonclassic CAH, and McCune-Albright syndrome.
- Specific causes of PPP in males that result in testicular enlargement
- McCune-Albright syndromeis characterized by bony changes (polyostotic fibrous dysplasia), skin findings (irregularly bordered hyperpigmented macules, or “coast of Maine” café-au-lait spots), and endocrinopathies (PPP or hyperthyroidism). Patients often have enlarged gonads but their secretion of sex steroids is independent of the HPGA.
- Testotoxicosisis a rare disease in which the testes enlarge bilaterally independent of the HPGA.
iii. β-HCG–secreting tumors are unique to boys. These tumors are found in the chest, pineal gland, gonad, or liver (hepatoblastoma). Because the β-HCG molecule crossreacts with LH, it too can bind to LH receptors and enlarge the testes slightly, stimulating Leydig cells and secreting androgens.
- Evaluation.A GnRH stimulation test may be warranted in addition to the following:
- In boys, check serum FSH, LH, testosterone, and β-HCG levels.
- In girls, check serum FSH, LH, and estradiol levels.
- Perform CNS imaging studies depending on the suspected etiology.
- Management.Treatment depends on the underlying cause.
- Delayed Puberty
- Boys:No testicular enlargement by 14 years of age.
- Girls:No breast tissue by 13 years of age, or no menarche by 14 years of age.
- Classification.Two categories of disorders may result in delayed puberty.
- Hypogonadotropic hypogonadism.Because of inactivity of the hypothalamus and pituitary gland, these patients have a low FSH, low LH, and, in turn, low testosterone and low estradiol, with a prepubertal (flat) GnRH stimulation test.
- Hypergonadotropic hypogonadism.Because of end-organ dysfunction (i.e., gonadal failure), these patients have high FSH and high LH levels with low testosterone or low estradiol levels. There is no abnormality in the hypothalamus or pituitary gland.
- Etiology of hypogonadotropic hypogonadism
- Constitutional delay of puberty(i.e., immature hypothalamus or “late bloomers”) is much more common in boys than in girls. Often there is a family history in one parent (i.e., mother had late menarche or father had his growth spurt late in high school or in college). Constitutional delay of puberty is frequently associated with constitutional delay of growth (see section I.D.1.b for a description of growth pattern).
- Chronic diseasescan cause pubertal delay (e.g., inflammatory bowel disease, anorexia nervosa, renal failure, and heart failure).
- Hypopituitarismof any cause (e.g., brain tumors)
- Primary hypothyroidism
- Genetic syndromes
- Kallman syndrome.Isolated gonadotropin deficiency associated with anosmia (inability to smell)
- Prader-Willi syndrome(see Chapter 5, section III.A.2)
- Lawrence-Moon-Biedl syndrome.Obesity, retinitis pigmentosa, hypogonadism, and polysyndactyly
- Etiology of hypergonadotropic hypogonadism
- Chromosomal disorders
- In boys, consider Klinefelter syndrome (XXY;see Chapter 5, section III.C.3).
- In girls, consider Turner syndromeor gonadal dysgenesis (see Chapter 5, section III.C.1).
- Autoimmune disorders(e.g., hypogonadism in autoimmune oophoritis, which may also be associated with Hashimoto's thyroiditis or Addison's disease)
- Evaluation of delayed puberty.A CBC, ESR, T4, testosterone or estradiol, FSH, LH, prolactin level, and bone age are necessary.
III. Ambiguous Genitalia
- Normal Sexual Differentiation (Figure 6-3)
- During the first 7 weeks of gestation, the gonadal tissue remains undifferentiated. The final appearance of gonadal tissue is dependent on both genetic and hormonal influences.
- Male sexual differentiationis an active process, whereas female sexual differentiation develops when genetic and hormonal influences are absent.
- Male sexual differentiation
is initiated by the SRY gene located on the short arm of the Y chromosome. By 9 weeks gestation, the SRY gene differentiates the gonads into fetal testes, which subsequently produce testosterone and anti-müllerian hormone (AMH).
- Internal ducts.In the genetic XY male, testosterone made by fetal Leydig cells stimulates the development of the wolffian ducts (epididymis, vas deferens, and seminal vesicles), and anti-müllerian hormone made by fetal Sertoli cells inhibits the development of the müllerian structures (fallopian tubes, uterus, and upper one third of the vagina).
- External genitalia.The conversion of testosterone to dihydrotestosterone (DHT) by 5α-reductase occurs in the skin of the external genitalia. DHT is responsible for penile enlargement, scrotal fusion, and the entire masculinization of the external genitalia. By 12 weeks this process is complete, except for penile growth, which continues to term.
Figure 6-3. Normal sexual differentiation in utero. DHT = dihydrotestosterone.
- Female sexual differentiation
In the absence of the SRY gene, the gonads become ovaries.
- Internal ducts.Because there is no testicular tissue, there is no secretion of testosterone or of anti-müllerian hormone, resulting in the regression of the wolffian ducts and the development of the müllerian structures, respectively.
- External genitalia.The external genitalia do not virilize because there is a lack of testosterone and of DHT. This results in the development of the labia, the clitoris, and the lower two thirds of the vagina.
- Differential diagnosis of ambiguous genitalia in the undervirilized male
(i.e., a male pseudohermaphrodite, who is usually a genetic 46, XY with ambiguous genitalia and one or both testes palpable; Figure 6-4)
- Inborn error in testosterone synthesis.Several inherited enzyme deficiencies result in low testosterone levels (i.e., any enzyme deficiency in the pathway of androgen synthesis in Figure 6-5).
- Gonadal intersex(i.e., conditions in which the internal structures are a combination of both male and female structures). These include two rare conditions:
- Mixed gonadal dysgenesis (MGD).These patients have a karyotype with a 45, XO/46, XY mosaicism. Clinical presentation may be
variable; however, most patients present with ambiguous genitalia and a testis and vas deferens on one side and a “streak gonad” on the contralateral side. Fallopian tubes may also be present bilaterally despite the presence of a testis.
Figure 6-4. Differential diagnosis of ambiguous genitalia in an undervirilized male. 17–hydroxy pregnenolone
- True hermaphroditism.These patients have ambiguous genitalia with both ovarian and testicular gonadal tissue. Usually the karyotype is 46, XX, but it can be 46, XY.
- Partial androgen insensitivity.These patients have partial or incomplete peripheral androgen resistance resulting in defective androgen binding in the genital tissue (Note:Patients with testicular feminiza-
tion syndrome have complete androgen insensitivity and present as normal phenotypic females [normal external genitalia] but with a 46, XY karyotype; see Chapter 3, Table 3-6).
Figure 6-5. Steroid pathways in the adrenal cortex. A = 3β-hydroxysteroid dehydrogenase; B = 21-hydroxylase (21-αOH); C = 11β-hydroxylase (11β-OH); D = 5α-reductase;DHEA = dehydroepiandrosterone; DHT = dihydrotestosterone.
- Differential diagnosis of ambiguous genitalia in the virilized female
(i.e., a female pseudohermaphrodite, who is a genetic XX with ambiguous genitalia and no gonads palpable; Figure 6-6).
- CAH caused by 21-hydroxylase deficiency is the most common cause of female pseudohermaphroditism(see section IV.B). 11β-Hydroxylase (11β-OH) deficiency and 3β-hydroxysteroid dehydrogenase deficiency are other causes of CAH.
- Virilizing drugused by mother during pregnancy
- Virilizing tumorin mother during pregnancy
- Evaluation of the patient with ambiguous genitalia
- Careful history.Maternal history of drugs or virilization, family history of androgen insensitivity, CAH, or consanguinity
- Physical examination.Presence or absence of gonads, labioscrotal swelling, bifid scrotum, labial fusion, urogenital sinus, or hypospadias. (Pearl: Increased blood pressure suggests CAH with 11β-OH deficiency, and decreased blood pressure suggests adrenal insufficiency; see sections IV.B.1.a and IV.C.3.b.)
- Chromosome studies
- Radiographic studiesinclude pelvic ultrasound and genitogram to define the internal genitourinary anatomy.
- Laboratory studies
- Male pseudohermaphrodites.DHT and testosterone levels are warranted. If serum testosterone is low, further evaluation for an inborn error in androgen synthesis is indicated.
- Female pseudohermaphrodites.Serum electrolytes, testosterone level, and further studies to look for evidence of CAH (17-OH progesterone, dehydroepiandrosterone [DHEA], and Compound S levels) are indicated (see Figure 6-5 and section IV.C.4).
- Management.The focus is on gender assignment as soon as possible, with input from a pediatric urologist on surgical options. Hormonal therapy depends on etiology.
Figure 6-6. Differential diagnosis of ambiguous genitalia in a virilized female.
- Disorders of the Adrenal Gland
- General Principles of Adrenal Function
- The adrenal glandis composed of two parts, the adrenal cortex, which synthesizes a multitude of different steroid compounds, and the adrenal medulla, which produces catecholamines (i.e., epinephrine).
- Three major pathwaysin the adrenal cortex result in the production of mineralocorticoids (aldosterone), glucocorticoids (cortisol), and androgens (DHEA), as outlined in Figure 6-5.
- Glucocorticoid and androgen synthesisare regulated by a negative feedback loop by the hypothalamic-pituitary-adrenal axis via adrenocorticotropin hormone (ACTH).Mineralocorticoid synthesis, however, is controlled by the renin-angiotensin system and is independent of the pituitary gland and ACTH.
- Children may present with disorders of adrenal insufficiency and with disorders of glucocorticoid excess.
- Classification of Adrenal Insufficiency
- Primaryor secondary, each with different clinical manifestations
- Primary adrenal insufficiency
- This condition results from destruction of the adrenal cortex or from an enzyme deficiency (i.e., a problem at the level of the adrenal gland).
- Patients present with signs and symptoms of both cortisol deficiency(anorexia, weakness, hyponatremia, hypotension, and increased pigmentation over recently healed scars) and aldosterone deficiency (failure to thrive, salt craving, hyponatremia, and hyperkalemia).
- Examplesinclude Addison's disease, CAH, and adrenoleukodystrophy (rare, X-linked recessive disorder with neurologic deterioration).
- Secondary adrenal insufficiency
- This condition results from any process that interferes with the release of cortisol-releasing hormone (CRH) from the hypothalamus or ACTH from the pituitary (i.e., a problem at the hypothalamic or pituitary level).
- In contrast to primary adrenal insufficiency, serum potassium may be normal in secondary adrenal insufficiency because there is no aldosterone deficiencygiven an intact renin-angiotensin system.
- Examplesinclude pituitary tumors, craniopharyngioma, and Langerhans cell histiocytosis. However, the most common cause is iatrogenic; this occurs when the hypothalamic-pituitary axis has been suppressed by exposure to long-term dosages of glucocorticoids (usually longer than 2 weeks).
- Congenitalor acquired
- Congenital adrenal insufficiencyincludes CAH.
- Acquired adrenal insufficiencyincludes Addison's disease and patients taking chronic steroids resulting in adrenal suppression.
- Congenital Adrenal Hyperplasia (CAH)
- This autosomal recessivecongenital enzyme deficiency in the adrenal cortex is a classic example of primary adrenal insufficiency of childhood. CAH is also the most common cause of ambiguous genitalia when no gonads are palpable.
- The enzyme deficiency in patients with CAH may lead to underproduction of cortisol or aldosterone and a build-up of precursors that shunt into another pathway leading toincreased production of androgens(see Figure 6-5).
- Multiple enzyme deficienciesmay lead to CAH, and the clinical presentation varies depending on which enzyme is affected. The three main types include:
- 21-Hydroxylase deficiency(accounts for 90% of cases). Three different subtypes of 21-hydroxylase deficiency affect the clinical presentation.
- Classic salt-wasting CAH (i.e., both mineralocorticoid and glucocorticoid pathways are affected, resulting in both cortisol and aldosterone deficiency).Girls present with ambiguous genitalia, and at 1–2 weeks of life both boys and girls present with failure to thrive, vomiting, and electrolyte abnormalities.
- Simple virilizing CAH (i.e., only the glucocorticoid pathway is affected, resulting only in cortisol deficiency).Because there is no aldosterone deficiency, there are usually no electrolyte abnormalities. Girls present with ambiguous genitalia at birth, and boys present later in life (1–4 years of age) with tall stature, advanced bone age, pubic hair, and penile enlargement.
- Nonclassic CAH (i.e., late-onset with very mild cortisol deficiency and no mineralocorticoid involvement).These patients usually present at 4–5 years of age. Girls present with premature adrenarche, clitoromegaly, acne, rapid growth, hirsutism, and infertility. Boys present with premature adrenarche, rapid growth, and premature acne.
- 11β-Hydroxylase deficiency(accounts for 5% of cases). These patients present similarly to patients with the more common 21-hydroxylase deficiency, except that they arehypertensive and hypokalemic.
- 3β-Hydroxysteroid dehydrogenase deficiency(rare). These patients present with salt-wasting crises, glucocorticoid deficiency, and ambiguous genitalia as a result of an early block in all three adrenal cortex steroid pathways.
- Diagnostic workupvaries with the type of CAH (see Figure 6-5):
- Patients with 21-hydroxylase deficiencyhave increased 17-hydroxyprogesterone (17-OHP) levels.
- Patients with 11β-hydroxylase deficiencyhave increased levels of 11-deoxycortisol (also known as specific compound S).
- Patients with 3β-hydroxysteroid dehydrogenase deficiencyhave increased levels of DHEA and 17-hydroxypregnenolone.
- Cortisone is administered at a dose that sufficiently suppresses ACTH production so that androgen production decreases but is not excessive enough to interfere with proper growth.
- If patients are also aldosterone deficient, mineralocorticoid replacement (fluorocortisol) may be given at a dosage that normalizes the plasma renin activity (PRA).
- Frequent follow-up is essential, and growth velocity, physical examination, bone age, and laboratory tests (17-OHP, PRA) should be monitored carefully. Parents should be educated and warned about the importance of compliance with medicines and how febrile episodes, vomiting, and surgical operations may require additional steroid therapy to prevent adrenal shock.
- Acquired Adrenal Insufficiency
- Etiology. Causesare multiple.
- Chronic supraphysiologic steroid use(usually greater than 2 weeks)
- Addison's diseaseis adrenal insufficiency resulting from autoimmune destruction of the adrenal cortex by lymphocytic infiltration. Antibodies to the adrenal gland may be detected, and there may be other associated endocrinopathies, including Hashimoto's thyroiditis and type 1 diabetes mellitus (type I polyglandular syndrome) or hypoparathyroidism and chronic mucocutaneous candidiasis (type II polyglandular syndrome).
- Less common causesof acquired adrenal insufficiency are acute adrenal hemorrhage in the neonate and septicemia (especially associated with meningococcemia, known asWaterhouse-Friderichsen syndrome).
- A high index of suspicion is necessary because the symptoms may be very subtle and the conditions can be life-threatening.
- History of prior steroid use or autoimmune disorders should raise clinical suspicion.
- Random plasma cortisol levels are usually not helpful (although a cortisol level > 20 g/dL in the presence of stress excludes adrenal insufficiency).
- ACTH stimulation testis the test of choice and measures adrenal cortisol reserve by comparing the baseline cortisol level with the cortisol level 1 hour after ACTH injection. Normally, the cortisol level doubles in response to ACTH stimulation. If there is a blunted response, it usually indicates primary adrenal insufficiency.
- Adrenal crisis is a medical emergency!
- Prompt treatment requires intravenous fluidswith 5% dextrose in
normal saline to correct hypotension and hyponatremia and to prevent hypoglycemia.
- Parenteral steroidsare given until the patient is stabilized.
- Glucocorticoid Excess
- Clinical featuresinclude poor growth with delayed bone age, central obesity, moon facies, nuchal fad pad, easy bruisability, purplish (hemorrhagic) striae, hypertension, and glucose intolerance.
- Major causes of hypercortisolism
- Iatrogenic.The most common cause of glucocorticoid excess is iatrogenic, as seen in patients who have been treated with chronic steroids for chronic diseases such as asthma, inflammatory bowel disease, and juvenile rheumatoid arthritis.
- Cushing syndrome.This is excessive glucocorticoid production caused by benign or malignant adrenal tumors. Note that most adrenal tumors are virilizing, but on occasion they may also feminize.
- Cushing disease.This is excessive glucocorticoid production caused by excessive ACTH production by a pituitary tumor, such as a microadenoma.
- Laboratory evaluation and diagnosis
- Elevated free cortisol in 24-hour urine collection.
- Absence of the expected cortisol suppression seen in an overnight dexamethasone suppression test(i.e., dexamethasone given in the evening normally suppresses the following morning's physiologic rise in cortisol)
- Key pearl:Cortisol excess states may be confused with obesity. Hypercortisolism presents with growth impairment and delayed bone age, but obese patients have normal to fast growth and an advanced bone age.
- Diabetes Mellitus
- Diabetes mellitus (DM)is the second most common chronic disease of childhood, affecting 1 of 500 children.
- Two times more common in boysthan in girls
- Types of Diabetes
- Type 1—insulin deficiency (insulin-dependent)
- Type 2—insulin resistant (non–insulin-dependent)
- Type 1 Diabetes Mellitus (Type 1 DM)
Type 1 DM is likely multifactorial with genetic, environmental, and autoimmune factors.
- Genetic factors
- There are strong genetic influences, but inheritance has not been found to fit into classic Mendelian patterns (autosomal or X-linked).
- Approximately 95% of patients with type 1 DM have HLA haplotype DR3or DR4.
- Monozygotic twins have a 50% concordance rate, whereas dizygotic twins have only a 30% concordance rate.
- Environmental triggers
- Viral infectionshave been implicated, including enteroviruses (coxsackie) and rubella.
- Whether the early introduction of cow's milk might trigger DM is controversial.
- Autoimmune factors.The autoimmune process begins with lymphocytic infiltration of the pancreas.
- Islet cell antibodies (ICA)are present in 85% of patients.
- ICAmay be detected in asymptomatic patients 10 years before the onset of clinical symptoms. Other immunologic markers may also be detected in patients long before the onset of clinical symptoms, including antibodies against insulin and against glutamic acid decarboxylase (GAD).
- Note that up to 10% of the general population may have ICA. Therefore, to develop type 1 DM, children must have a combination of ICA, environmental factors, and a genetic predisposition.
- Clinical Features
- The classic presentationincludes several weeks of polyuria, polydipsia, nocturia, and occasionally enuresis. As symptoms progress, weight loss, vomiting, and dehydration occur.
- Diabetic ketoacidosis (DKA)may be the initial presentation in 25% of patients (see section VIII). The younger the patient, the shorter the course of symptoms before DKA occurs.
- Girlswho have protracted cases of monilial vulvovaginitis may have early type 1 DM.
- Adolescentsmay present with type 1 DM during their pubertal growth spurt with hormones that are antagonistic to insulin action (specifically growth hormone and the sex steroids).
Patients must have hyperglycemia documented by a random blood sugar above 200 mg/dL with polyuria, polydipsia, weight loss, or nocturia.
- Types of insulininclude short-acting, intermediate-acting, long-acting, and very long-acting.
- Administrationin newly diagnosed patients may involve combining the above types of insulin.
- Insulin pumpsare now being used in children to achieve better glucose control and to improve lifestyle.
- Daily blood glucosemeasurements using a glucose meter before all meals and at bedtime.
- Glycosylated hemoglobin level, reflecting diabetic control for the past 2–3 months, should be checked every 3 months.
- Watch for hypoglycemia.All patients should have parenteral glucagon available in case of seizure or coma secondary to low blood sugar.
- Watch for “honeymoon” period.Within a few weeks after initial diagnosis, 75% of patients exhibit a temporary progressive reduction in their daily insulin requirements. This is because of a transient recovery of residual islet cell function, resulting in endogenous release of insulin in response to carbohydrate exposure. This honeymoon period may last anywhere from months to 1–2 years.
- Watch for Somogyi phenomenon.This occurs when the evening dose of insulin is too high, causing hypoglycemia in the early morning hours, resulting in the release of counter-regulatory hormones (epinephrine and glucagon) to counteract this insulin-induced hypoglycemia. The patient then has high blood glucose and ketones in the morning. The treatment is to actually lower the bedtime insulin dose and not to raise it.
- Diet.Follow the American Diabetic Association (ADA) diet.
- Education and close follow-upevery 3 months.
- Long-Term Complications
- Microvascular complicationsinclude diabetic retinopathy, nephropathy, and neuropathy.
- Macrovascular complications are usually seen in adulthoodand include atherosclerotic disease, hypertension, heart disease, and stroke.
- DKAwhen ill or noncompliant
VII. Type 2 Diabetes Mellitus (Type 2 DM)
- Occurs in 2–3% of all children with diabetes.
- In the last decade there has been a 10-fold increase in the incidence of type 2 DM in children due to an increase in obesity.
- Very strong hereditary component (stronger for type 2 than for type 1)
- The cause is likely a combination of peripheral tissue resistance to insulin and progressive decline in insulin secretion, both of which result in a hyperglycemic state.
- Clinical Features
The clinical presentation is variable.
- Asymptomatic (50%) to mild DKA. Serious DKA is uncommonbecause type 2 DM is more of an insulin resistance than insulin deficiency.
- Acanthosis nigricans(velvety and hyperpigmented skin of the neck and axillary folds) is common.
- Oral hypoglycemic agentsmay be used if blood sugar levels are not very high.
- Insulin therapymay be required for those patients who have high blood sugar or who fail oral agents.
VIII. Diabetic Ketoacidosis (DKA)
Hyperglycemia usually greater than 300 mg/dL with ketonuria and a serum bicarbonate level <15 mmol/L or a serum pH < 7.30.
- Insulin deficiencycreates a state of diminished glucose substrate at the cellular level, despite the high serum levels of glucose. The body's need for substrate to make energy therefore results in gluconeogenesis.
- Hyperglycemiaresulting from this insulin deficiency leads to an osmotic diuresis with polyuria and eventual dehydration.
- Counter-regulatory stress hormones(i.e., glucagon, epinephrine, cortisol, and growth hormone) are released and contribute to fat breakdown (lipolysis).
- Glucagonstimulates conversion of free fatty acids into ketone bodies (acetone, acetoacetate, andβ-hydroxybutyrate).
- The counter-regulatory stress hormones, in the face of insulin deficiency, lead to fat lipolysis and ketone formation and eventually DKA.
- Clinical Features
- Patients with mild DKAmay present with vomiting, polyuria, polydipsia, and mild to moderate dehydration.
- Patients with severe DKAmay present with severe dehydration, severe abdominal pain that may mimic appendicitis, rapid and deep (Kussmaul) respirations, and coma.
- It is the presence of ketones that gives the patient with DKA “fruity breath.” Ketones also contribute to coma in severe DKA.
- Laboratory Findings
- Anion gap metabolic acidosis
- Hyperglycemia and glucosuria
- Ketonemia and ketonuria
- Hyperkalemiacaused by metabolic acidosis (potassium moves out of the cells in the face of acidosis) or normokalemia
- Fluid and electrolyte therapyand replacement of the depleted intravascular volume using isotonic saline should begin immediately.
- A gradual decline in osmolalityis critical to minimize the risks of cerebral edema, which is a very significant cause of morbidity and mortality in the treatment of DKA.
- Potassium repletion(once urine output has been established) using potassium acetate and potassium phosphate is very important because all patients are potassium depleted, even with a normal serum potassium. Potassium acetate is helpful in managing the patient's metabolic acidosis. Potassium phosphate helps increase serum levels of 2, 3-diphosphate glycerate (2, 3-DPG), which in turn shifts the oxygen dissociation curve to the right and makes oxygen more readily available to the tissues.
- Regular insulin(usually a continuous infusion of 0.1 U/kg per hour) with careful monitoring of serum glucose levels to ensure a gradual drop in the serum glucose levels
- The combination of intravenous fluids and insulinshould reverse the ketogenesis, stop the hepatic production of glucose, shut down the release of counter-regulatory hormones, and enhance peripheral glucose uptake.
- Cerebral edema
- Usually occurs 6–12 hours into therapy and rarely after 24 hours
- Risk factors include patients younger than 5 years of age, initial drops in serum glucose levels faster than 100 mg/dL per hour, and fluid administration greater than 4 L/m2per 24 hours.
- Mortality rate may be as high as 70%.
- Severe hypokalemia
- Hypocalcemia, due to either excessive use of potassium phosphate or osmotic losses.
- Thyroid Disorders
- Thyroid Physiology
- Hypothalamic-pituitary-thyroid axisis regulated by a feedback loop between thyroxine (T4), triiodothyronine (T3), thyrotropin-releasing hormone (TRH), and thyroid-stimulating hormone (TSH).
- Both T4and T3 circulate bound to thyroid-binding proteins, including thyroid-binding globulin (TBG) and thyroid-binding prealbumin (TBPA).
- The free (unbound) formsof T4 and of T3 are the biologically active forms of each hormone.
- Clinical presentation
- Suboptimal growth velocity(less than 5 cm per year or 2 inches per year) with a delayed bone age
- Goitersometimes may be found on gland palpation.
- Myxedema, or “puffy skin,” dry skin, or, occasionally, orange-tinged skin
- Amenorrhea or oligomenorrhea in adolescent girls
- Causesare extensive.
- Congenital hypothyroidism
- Epidemiology.This condition is the most common metabolic disorder. It is evaluated on newborn screening and has an incidence of 1 in 4, 000 births.
- Thyroid dysgenesis. This is the most common cause (90%) of congenital hypothyroidism.Two thirds of affected patients have an absent thyroid gland (thyroid aplasia) or thyroid hypoplasia. One third have an ectopic thyroid gland, which may be found anywhere between the base of the tongue (foramen cecum) to the mid-chest.
- Thyroid dyshormonogenesis.This refers to multiple inborn errors of thyroid hormone synthesis, which account for about 10% of all cases of congenital hypothyroidism. These conditions are autosomal recessive and usually present with a goiter. Pendred syndrome, an organification defect, is the most common of these defects and is associated with sensorineural hearing loss.
- Use of propylthiouracil (PTU)during pregnancy for maternal Graves' disease may result in transient hypothyroidism in the newborn because PTU crosses the placenta and may temporarily block fetal thyroid hormone synthesis.
- Maternal autoimmune thyroid diseasemay also result in transient hypothyroidism, as maternal thyroid-blocking antibodies may cross the placenta and block TSH receptors on the newborn thyroid gland.
- Clinical features.Most newborns are asymptomatic at birth and have an unremarkable physical examination (T4 is not essential for fetal growth). However, thyroid hormone is essential for normal brain growth during the first 2 years of life, and with time, the following clinical features become more apparent if the patient goes untreated:
- Classic historical featuresinclude a history of prolonged jaundice and poor feeding.
- Classic symptomsinclude lethargy and constipation.
- Classic physical examination findingsinclude large anterior and posterior fontanelles, protruding tongue, umbilical hernia, myxedema, mottled skin, hypothermia, delayed neurodevelopment, and poor growth.
- Thyroid hormone replacement should begin immediately with L-thyroxine.
- If treatment is delayed until after the signs and symptoms of hypothyroidism appear, most patients will have suffered permanent neurologic sequelae.
- Hashimoto's disease (chronic lymphocytic thyroiditis [CLT]).This autoimmune disorder is characterized by lymphocytic infiltration of the thyroid gland, resulting in varying degrees of follicular fibrosis and atrophy and follicular hyperplasia.
- Most common cause of acquired hypothyroidism with or without a goiter
- More common in girls
- Etiology.Thyroid autoantibodies develop because of a disturbance in immunoregulation, resulting in a state of thyroid cell cytotoxicity or stimulation. There is often a genetic predisposition.
- Clinical features.Presentation is variable.
- Goiter, which is classically firm and pebbly in nature
- Short stature
- Transient hyperthyroidism (“Hashitoxicosis”) may occur in some patients.
- Management. Thyroid hormone replacement with L-thyroxineto normalize the TSH level.
- Diagnosis of hypothyroidism
- Neonatal screening testsfor congenital hypothyroidism (TSH is measured)
- Increased TSH, which is usually the first sign of thyroid failure
- Low T4level
- Antithyroid antibodies(especially thyroid antiperoxidase antibodies) as a marker for autoimmune thyroid disease
- Clinical features
- Eyeexamination may demonstrate lid lag and exophthalmos.
- Thyroid glandis enlarged and usually smooth in texture.
- Cardiac examinationdemonstrates tachycardia, and patients may complain of palpitations.
- Skinis warm and flushed. (Pearl: The presence of vitiligo or alopecia suggests the possible coexistence of other autoimmune polyendocrinopathies, including Addison's disease and diabetes mellitus.)
- CNSevaluation may be remarkable for nervousness and fine tremors with a history of fatigue and difficulty concentrating in school.
- Pubertalevaluation may be notable for delayed menarche and gynecomastia in boys.
- Graves' disease (diffuse toxic goiter).This autoimmune disorder is characterized by autonomous production of excessive thyroid hormone by the thyroid gland mediated by a TSH look-alike antibody.
- Epidemiology. Graves' disease is the most common cause of hyperthyroidismin childhood. Females predominate (M:F = 1:3).
- Strong genetic factors
- Thyroid-stimulating immunoglobulin (TSI), an IgG antibody, cross-reacts with TSH and binds to and stimulates the TSH receptors in the thyroid gland.
- Laboratory findings. Increased T3and T4 levels with suppressed TSH level in the presence of TSI.
- Antithyroid medications.The two most commonly used antithyroid medications are PTU and methimazole. Although both medications inhibit thyroid hormone synthesis, PTU also impairs the peripheral conversion of T4 to T3. These medications are usually the first-line treatment.
- Subtotal thyroidectomymay be considered if antithyroid medication fails.
- Radioactive iodineis often used in adolescents if noncompliance with medication is an issue. Its use eventually results in permanent hypothyroidism.
- Bone Mineral Disorders
- Physiology of calcium and vitamin D metabolism
- Bone.Both vitamin D and parathormone (PTH) release calcium and phosphorus from bone.
- Parathyroid gland
- PTHhelps maintain a normal serum calcium level by releasing calcium from the bone and reabsorbing calcium from the kidneys.
- PTHalso releases phosphorus from the bone and excretes phosphorus from the kidneys.
- PTHis responsible for calcium and bicarbonate reabsorption and phosphorus excretion.
- The enzyme 1β-hydroxylase vitamin Dmade in the kidney converts 25-(OH) vitamin D (made by the liver) into the active vitamin D metabolite 1, 25-(OH) vitamin D(stimulated by PTH).
- Gastrointestinal (GI) tract.The main source of calcium absorption is through the intestine, due to 1, 25-(OH) vitamin D, which is the most potent form of vitamin D.
- Hypocalcemia.Serum calcium less than 8.0 mg/dL, or ionized calcium less than 2.5 mg/dL.
- Pseudohypocalcemia.The factitious lowering of total calcium levels
as a result of low serum albumin levels, as seen in nephrotic syndrome. Therefore, all low total calcium levels should have an ionized calcium level measured to verify true hypocalcemia.
- Clinical features
- Tetany(neuromuscular hyperexcitability)
- Carpopedal spasm.Hypocalcemia causes hyperexcitability of peripheral motor nerves, resulting in painful spasms of the muscles of the wrists and ankles.
- Laryngospasm.Spasm of the laryngeal muscles
- Seizures.Younger patients with hypocalcemia tend to present with seizures or coma, whereas older patients exhibit more signs of neuromuscular hyperexcitability.
- Early neonatal hypocalcemia (younger than 4 days of age) is usually transient and may be associated with prematurity, IUGR, asphyxia, or infants of diabetic mothers. Hypomagnesemia may also result in hypocalcemia.
- Late neonatal hypocalcemia (older than 4 days of age)
- Hypoparathyroidism.Patients have low calcium and elevated phosphorus levels, usually caused by asymptomatic maternal hyperparathyroidism, in which the mother's high serum calcium crosses the placenta and suppresses the fetus's PTH. After delivery this creates a temporary state of hypocalcemic hypoparathyroidism.
- DiGeorge syndrome(see Chapter 5, section III.A.5)
- Hyperphosphatemialeads to hypocalcemia by binding to calcium. It may result from excessive phosphate intake (found in some infant formulas) or from uremia.
- Childhood hypocalcemia
- Hypoparathyroidism (parathyroid failure).This condition may be genetic (ring chromosome 16 or 18), autoimmune, or related to DiGeorge syndrome (see Chapter 5, section III.A.5) as above.
- Pseudohypoparathyroidism (parathyroid resistance).This rare autosomal dominant disorder results in PTH resistance. Patients present with short stature, short metacarpals, developmental delay, and elevated PTH levels.
- Hypomagnesemia.A low magnesium level, as seen in some renal and malabsorptive diseases, may cause hypocalcemia because it interferes with PTH release.
- Vitamin D deficiencycan cause hypocalcemia with low phosphorus levels (see section X.C).
- Laboratory evaluation
- Serum ionized calcium and phosphorus
- Serum magnesium
- Electrocardiogramdemonstrating a prolonged QT interval may be found with hypocalcemia.
- PTH levelto distinguish between hypoparathyroidism (low PTH) and pseudohypoparathyroidism (increased PTH)
- Vitamin D level(in an older child) if both calcium and phosphorus levels are low
- Radiograph of wrists or kneesto evaluate for rickets (see section X.C)
- Mild asymptomatic hypocalcemia does not require treatment.
- In newborns with serum calcium levels < 7.5 mg/dL (or ionized calcium < 2.5 mg/dL) or in older children with serum calcium levels < 8.0 mg/dL, calcium should be corrected to prevent CNS hyperexcitability.
- Calcium supplementation
- Oral therapyis acceptable if there are no seizures or only moderate tetany.
- Intravenous calcium gluconateshould be given if patients are more symptomatic.
- 1, 25 Vitamin D analog (calcitriol)should be given to patients with chronic hypoparathyroidism.
- Definition.Rickets is a condition caused by vitamin D deficiency that results in deficient mineralization of growing bones with a normal bone matrix.
- Predisposing factors
- Exclusively breastfed infants with minimal sunshine exposure
- Fad diets
- Use of anticonvulsant medications (phenytoin, phenobarbital), which interfere with liver metabolism
- Renal or hepatic failure
- Vitamin D deficiency
- GI disordersassociated with fat malabsorption resulting in vitamin D deficiency (e.g., cystic fibrosis, celiac disease)
- Nutritional causes(rare in the United States because of vitamin D supplementation)
- Defective vitamin D metabolismfrom renal and hepatic failure may cause a deficiency in the important enzymes that synthesize 1, 25-(OH) vitamin D, resulting in renal osteodystrophy (see Chapter 11, section X.F). Anticonvulsants may also interfere with vitamin D metabolism through their effect on liver metabolism.
- Vitamin D–dependent rickets
- This autosomal recessive condition is very rare.
- Enzyme deficiencyin the kidneys of 1β-hydroxylase vitamin D results in the lack of 1, 25-(OH) vitamin D.
- Patients present with increased PTH, low vitamin D levels, low calcium, low phosphorus, and increased alkaline phosphatase.
- Vitamin D–resistant rickets (familial hypophosphatemia)
- Most common form of rickets in the United States today
- X-linked dominantdisorder
- Caused by a renal tubular phosphorus leak, resulting in a low serum phosphorus level
- Patients present with ricketsin the face of normal calcium and low phosphorus.
- Patients develop typical bowing of the legs, but never tetany.
- Treatmentincludes phosphate supplements and 1, 25 vitamin D analogs.
- Oncogenous ricketsis a phosphate-deficient form of rickets caused by a bone or soft tissue tumor. It should be considered in patients who present with bone pain or a myopathy.
- Clinical features
- Rickets usually occurs during the first 2 years of lifeand in adolescence, when bone growth is most rapid.
- Rickets usually involves the wrists, knees, and ribs(where the growth velocity is the fastest), presenting with a knobby appearance.
- Weight-bearing bones become bowedonce the patient begins ambulating.
- Short stature
- “Rachitic rosary”or prominent costochondral junctions
- Craniotabesor thinning of the outer skull create a “Ping-Pong ball sensation” on palpation.
- Frontal bossingand delayed suture closure
- Radiographic findings. Wrist radiographsshow earliest changes of rickets with the distal end of the metaphysis appearing widened, frayed, and cupped, instead of showing a well-demarcated zone. There is also widening of the space between the epiphysis and the end of the metaphysis.
- Laboratory findings.A low serum phosphorus, low to normal serum calcium, elevated alkaline phosphatase, and elevated PTH levels are present.
- Management.Treatment depends on etiology.
- Diabetes Insipidus (DI)
Inability to maximally concentrate urine because of either low levels of antidiuretic hormone (ADH) or renal unresponsiveness to ADH.
ADH is an octapeptide synthesized in the hypothalamic nuclei and transported via axons to the posterior pituitary. The action of ADH is to increase permeability of the renal collecting ducts to water, leading to increased water reabsorption. It is regulated by changes in volume, serum osmolality, and posture.
- Central DI = ADH-deficient
- Nephrogenic DI = ADH-resistant(kidney does not respond to ADH)
- Etiology of Central DI
- Autoimmune.Antibodies target ADH-producing cells.
- 2. Traumaand hypoxic ischemic brain injury
- Hypothalamic tumors(e.g., craniopharyngioma, glioma, germinoma)
- Langerhans cell histiocytosis.Twenty-five percent of patients develop DI.
- Granulomatous disease(e.g., sarcoidosis, tuberculosis)
- Vascular(e.g., aneurysms)
- Genetic(autosomal dominant inheritance)
- Etiology of Nephrogenic DI
Inherited as an X-linked recessive disorder
- Clinical Features
Children present with nocturia, enuresis, poor weight gain, polydipsia, and polyuria.
- Evaluation and Diagnosis
- If thirst mechanisms are intact and child has access to water, then serum electrolytes will be normal. Otherwise, patients present with hypernatremic dehydrationwith aninappropriately dilute urine in the face of increased serum sodium and increased serum osmolality.
- An early morning urine specimen with a specific gravity > 1.018 rules out the diagnosis of DI.
- Water deprivation testin the hospital may be used to diagnose DI. A rising serum osmolality in the presence of persistent urine output and an inappropriately low urine osmolality is diagnostic. If, at the end of the test, the patient does not respond to administered ADH, then the patient has nephrogenic DI.
- In an MRI of the head, hyperintense signal normally found in the posterior pituitary is missing.
- A bone scanmay be indicated to rule out Langerhans cell histiocytosis.
The drug of choice for central DI is DDAVP (synthetic ADH).
- General Principles
- Definition.Serum glucose less than 40 mg/dL, or whole blood glucose less than 45 mg/dL.
- It is important to recognize hypoglycemia early, especially in newborns and young infants, when the brain is dependent on glucose for proper neurodevelopment.
- The symptoms of hypoglycemiaare age-dependent and vary in each patient.
- Newborns or infantsmay have varied symptoms that include lethargy, myoclonic jerks, cyanosis, apnea, or seizures.
- Older childrenmay have symptoms similar to adults, including tachycardia, diaphoresis, tremors, headaches, or seizures.
- Neonatal Hypoglycemia
This condition may be transient (most common) or persistent (less common).
- Transient neonatal hypoglycemiais usually detected by screening protocols established for high-risk infants.
- High-risk conditions associated with inadequate substrateinclude prematurity, a history of perinatal asphyxia or fetal distress, and small-for-gestational age (SGA) and large-for-gestational age (LGA) infants.
- High-risk conditions associated with inappropriate hyperinsulinisminclude SGA infants and infants of diabetic mothers.
- Persistent neonatal hypoglycemiais defined as hypoglycemia that persists for longer than 3 days. The differential diagnosis of persistent neonatal hypoglycemia includes:
- Hyperinsulinism, which may be caused by:
- Islet cell hyperplasia (nesidioblastosis)
- Beckwith-Wiedemann syndrome:Patients are LGA and present with visceromegaly, hemihypertrophy, macroglossia, umbilical hernias, and distinctive ear creases.
- Hereditary defects in carbohydrate metabolism(e.g., glycogen storage disease type I and galactosemia) or amino acid metabolism (e.g., maple syrup urine disease, methylmalonic acidemia and tyrosinemia; see Chapter 5, sections V and VI, and Table 5-5).
- Hormone deficiencies, including growth hormone deficiency and cortisol deficiency. (Pearl: Congenital hypopituitarism should be suspected in the neonate who presents with hypoglycemia, microphallus, and midline defects such as a cleft palate.)
- Hypoglycemia in Infancy and Childhood
Hypoglycemia is relatively uncommon in older infants and children, but the differential diagnosis is extensive and includes the following:
- Ketotic hypoglycemiais the most common cause of hypoglycemia in children 1–6 years of age. This is defined as hypoglycemia occuring late in the morning in the presence of ketonuria and a low insulin level. This appears to be an inability to adapt to a fasting state. Typically these children are thin and become hypoglycemic after intercurrent infection.
- Ingestionsmust always be considered in the differential diagnosis of hypoglycemia in the older child, especially in adolescents.
- Alcoholmetabolism in the liver can deplete essential cofactors needed for adequate gluconeogenesis, resulting in hypoglycemia (especially when the child is in the fasting state).
- Oral hypoglycemic agents
- Inborn errors of metabolism
- Hyperinsulinism, as described in section XII.B.2.a
- A 7-year-old boy is brought to the office for a routine health care maintenance visit. The nurse brings to your attention that he has grown only 1 inch during the past year. A review of his growth curve during the past 2 years shows that his height percentile has fallen from the 75th to the 40th percentile. His father is 66 inches tall, and his mother is 65 inches tall. He has recently had some early morning vomiting and headache. However, physical examination is unremarkable. A bone age study reveals a growth delay of just over 2.5 years. Complete blood count, erythrocyte sedimentation rate, and thyroid studies are all normal. The most likely cause of this patient's short stature is which of the following?
(A) Genetic short stature
(b) Constitutional growth delay
(D) Skeletal dysplasia
(E) Cushing disease
- You are called to the delivery room to evaluate a newborn infant with ambiguous genitalia. The mother had an amniocentesis showing a fetus with an XX genotype. Physical examination of the neonate indicates no palpable gonads, a small phallic structure, and labial fusion with a urogenital opening. Which of the following is the most likely diagnosis?
(b) Partial androgen insensitivity
(c) Congenital adrenal hyperplasia caused by 21-hydroxylase deficiency
(D) 5α-Reductase deficiency
- An obese 12-year-old child is suspected of having the diagnosis of type 2 diabetes mellitus (DM). Which of the following statements regarding this suspected diagnosis is correct?
(A) This patient is likely to present with diabetic ketoacidosis during adolescence.
(b) Approximately 95% of patients with type 2 DM have HLA haplotypes DR3 or DR4.
(c) This patient is likely to have had islet cell antibodies before the onset of clinical symptoms.
(D) Type 2 DM has a very strong hereditary component (even stronger than in type 1 DM).
(E) In the last decade, there has been a decline in the incidence of type 2 DM, given greater public awareness of healthy eating habits.
- A 13-year-old girl is brought to the office by her mother because of poor attention span and deteriorating grades. She is also fidgety and cannot sit still. Her mother is also concerned because her daughter has lost 5 pounds during the past 2 months. Physical examination shows a blood pressure of 130/75 mm Hg, a heart rate of 115 beats/min, and thyromegaly. You suspect Graves' disease. Which of the following statements regarding the suspected diagnosis is correct?
(A) Thyroid-stimulating immunoglobulins (TSI) are usually present and bind to thyrotropin (TSH) receptors.
(b) Girls with Graves' disease have an increased likelihood of developing precocious puberty.
(c) Subtotal thyroidotomy is the most appropriate initial management.
(D) This disease is more common in males.
(E) Radioactive iodine treatment is ineffective.
- You have been following an 8-year-old child in your office for the past several years and have noted that during the past year, his height has remained below the third percentile. You are concerned about his short stature and decide to begin a workup. Your workup includes a bone age determination. The patient's bone age is discovered to be 3 years younger than his chronologic age. Which of the following diagnoses should be considered?
(A) Genetic short stature
(b) Skeletal dysplasias
(c) Intrauterine growth retardation
(D) Turner syndrome
(E) Growth hormone deficiency
- You are called to the pediatric intensive care unit to evaluate a 4-year old girl with new onset type 1 diabetes mellitus who is in diabetic ketoacidosis (DKA). The nurse reports that she was alert and talking but suddenlyhas become obtunded and listless. Which of the following conditions is the likely cause of her change in mental status?
(b) Cerebral edema
The response options for statements 7–11 are the same. You will be required to select one answer for each statement in the set.
(A) Premature adrenarche
(b) Premature thelarche
(c) Central precocious puberty
(D) Peripheral precocious puberty
(E) Normal, no pubertal disorder
For each patient, select the most likely pubertal disorder.
- A 13-month-old girl has a several month history of breast growth with Tanner stage 2 breast development on examination, but has no pubic hair. Her growth consistently follows the 75% growth curve.
- A 7-year-old boy presents with pubic hair, acne, and rapid growth. His bone age evaluation reveals that his bones demonstrate advanced growth to the equivalent of a 10-yearold boy. Testicular examination shows prepubertal size testes.
- A 5-year-old girl has a 1-year history of breast development and pubic hair. She is Tanner stage 3 on breast examination and Tanner stage 2 on pubic hair examination. Today she had her first menses. Bone age determination reveals her bone appearance is 5 years advanced, to that of a 10-year-old girl.
- A 6-year-old girl has a strong apocrine odor, mild axillary hair, and Tanner stage 3 pubic hair. No clitoromegaly or breast development is seen. Bone age determination reveals her bone appearance is 2 years advanced, to that of an 8-year-old girl.
- A 5-year-old girl is referred for vaginal bleeding. Physical examination shows breast development, multiple café-au-lait spots, and thyromegaly, and cystic bony changes are apparent on radiography of her legs.
The response options for statements 12–15 are the same. You will be required to select one answer for each statement in the set.
(c) Beckwith-Wiedemann syndrome
(D) Glycogen storage disease
(E) Ketotic hypoglycemia
For each patient, select the most likely diagnosis.
- A 4-year-old thin boy with a fever and vomiting went to sleep without dinner and has a hypoglycemic seizure at 8:00 AM.
- A male newborn has a glucose of 15 mg/dL at 6 hours of age. Physical examination reveals a cleft palate, microphallus, and undescended testes.
- A newborn who has had hypoglycemia for 1 week is nondysmorphic and requires a high rate of dextrose infusion to maintain blood sugar. The insulin level is inappropriately high.
- A large-for-gestational age infant has hepatomegaly, macroglossia, moderate umbilical hernia, and hypoglycemia.
Answers and Explanations
- The answer is C[I.F.1.b]. The decreased rate of growth in the face of early morning emesis should make one suspect a mass lesion within the central nervous system. The workup should begin with a skull radiograph followed by a cranial magnetic resonance imaging (MRI) scan. Both genetic short stature and constitutional growth delay are excluded from the diagnosis because patients with these conditions grow at a normal rate, at least 2 inches per year. Skeletal dysplasia may be ruled out because the delayed bone age is inconsistent with such a condition. Cushing disease may cause poor growth and bone age delay, but this rare disease is not associated with headaches and morning emesis.
- The answer is C[III.D, III.E, and III.F]. Congenital adrenal hyperplasia (CAH) as a result of 21-hydroxylase deficiency is the most common form of female pseudohermaphrodism. The chromosomal analysis revealing XX chromosomes and the lack of gonads immediately exclude a male pseudohermaphrodite, such as that caused by partial androgen insensitivity, and inborn errors in testosterone synthesis, as in 5α-reductase deficiency. A true hermaphrodite is a possibility, but CAH is more common. Hypopituitarism in a newborn with an XX genotype would not present with ambiguous genitalia.
- The answer is D[VII.A and VII.B]. Type 2 diabetes mellitus (DM) occurs in 2–3% of all children with diabetes mellitus, with a very significant increase in incidence during the last decade. There is a much stronger hereditary component in type 2 DM than in type 1 DM, and the etiology is likely a combination of peripheral tissue resistance to insulin and a progressive decline in insulin secretion. The clinical presentation of type 2 DM may be quite variable; however, the majority of patients do not present with diabetic ketoacidosis because type 2 DM reflects more of an insulin resistance than an insulin deficiency, and patients are not likely to present with insulin autoantibodies. Approximately 95% of patients with type 1 DM will have HLA haplotypes DR3 or DR4. Patients are often asymptomatic, with only glucosuria, and physical examination may be significant for obesity and acanthosis nigricans (velvety and hyperpigmented skin of the neck and axillary folds).
- The answer is A[IX.C.2]. In patients with Graves' disease, thyroid-stimulating immunoglobulins are usually present because this is an autoimmune process and these antibodies are the cause of the thyrotoxic state. Girls with hyperthyroidism are more likely to have delayed menarche than to have precocious puberty. Both Graves' disease and Hashimoto's thyroiditis are examples of autoimmune disorders that are more common in females. First-line therapy is antithyroid medication. Surgery or radioactive iodine is effective and should be considered if medical treatment fails or is not tolerated. Radioactive iodine may also be considered for adolescents if noncompliance with medications is an issue.
- The answer is E[I.E.2.a, I.F.1, and Table 6-1]. Bone age determination may be very helpful when compared with the patient's chronologic age in the evaluation of short stature. Because of slowed growth velocity, patients with growth hormone deficiency would be expected to have their bone age less than their chronologic age, as would patients with constitutional growth delay, hypothyroidism, and hypercortisolism. Patients with genetic short stature, skeletal dysplasias, intrauterine growth retardation, and Turner syndrome would all be expected to have their bone age approximately the same as their chronologic age.
- The correct answer is B[VIII.F]. When treating diabetic ketoacidosis, especially in children younger than 5 years of age, the diagnosis of cerebral edema must be entertained if there is a sudden change in mental status. Risk factors for the development of cerebral edema include drops in serum glucose levels faster than 100 mg/dL per hour and excessive fluid administration. Changes in mental status can also result from hypoglycemia, hypocalcemia, and hypokalemia. If dextrose is not added to the insulin drip when the blood sugar drops below 250 mg/dL, the child may experience a sudden drop in glucose and exhibit lethargy, seizures, or coma. Hypocalcemia is caused by excessive phosphorus usage or osmotic losses and can cause a seizure or change in mental status. Hypokalemia can result in an arrhythmia that, in turn, may result in hypotension and cardiac arrest. Stroke is a complication of long-standing poorly controlled DM.
7, 8, 9, 10, and 11. The answers are B, D, C, A, and D, respectively [II.B]. Most cases of sexual precocity are benign. Premature thelarche (question 7) is a transient state of isolated early breast development as is found in a girl younger than 7 years of age. Premature adrenarche is the early onset of pubic or axillary hair (question 10). Individuals with these conditions present with pubic hair and an apocrine odor but no breast development or very advanced bone age. Neither premature thelarche nor premature adrenarche are associated with activation of the hypothalamic-pituitary-gonadal axis.
12, 13, 14, and 15. The answers are E, B, A, and C, respectively [XII.B and XII.C]. Ketotic hypoglycemia is the most common cause of a low blood sugar in children. Patients are often thin, and symptoms develop after a prolonged fast. Congenital hypopituitarism should be considered in any newborn with a midline defect (e.g., cleft palate), hypoglycemia, and microphallus. Newborns with hypoglycemia persisting for longer than 4 days require further evaluation, and in these cases, hyperinsulinemia as a result of nesidioblastosis (beta cell hyperplasia) and Beckwith-Wiedemann syndrome should be considered. A newborn with nesidioblastosis will have no dysmorphic features but will have persistent low blood sugar owing to the high amounts of circulating insulin. Beckwith-Wiedemann syndrome is characterized at birth by large-for-gestational age, macroglossia, umbilical hernia, and hyperinsulinemic hypoglycemia.