Rudolph's Pediatrics, 22nd Ed.

CHAPTER 523. Endocrine Abnormalities Causing Growth Impairment

Edward O. Reiter

Most children with deficient pituitary function secrete inadequate amounts of growth hormone (GH); therefore, the term hypopituitarism is used interchangeably with growth hormone deficiency (GHD). Children who have diabetes insipidus caused by isolated deficiency of antidiuretic hormone (discussed in Chapter 525) and those uncommon children who have isolated gonadotropin deficiency (Kallmann syndrome; see Chapter 541) are exceptions. They have normal GH secretion but pituitary dysfunction of posterior and anterior pituitary lobes, respectively. GHD is the most common endocrinologic cause of the insulin-like growth factor deficiency (IGFD) syndrome.

Deficiency of GH can occur alone (isolated GHD) or in conjunction with overt deficiency of one or more other pituitary hormones (the term panhypopituitarism refers to multiple pituitary hormone deficiencies). Although there are exceptions, patients with multiple pituitary hormonal deficiencies tend to have more severe GHD.

GROWTH HORMONE DEFICIENCY (HYPOPITUITARISM)

EPIDEMIOLOGY

The best estimate of incidence of GHD in the US population is often cited as being about 1:3480. However, acquired, idiopathic, isolated GHD may be overdiagnosed. Growth hormone (GH)-treated patients with GHD (as defined by a stimulated GH level of < 10 ng/mL) account for about 60% of all treated patients of whom 78% have “idiopathic” GHD and 22% have “acquired” or “organic” (neoplasms, trauma, inflammation, miscellaneous) causes of GHD.

Around 300 patients with inherited abnormalities of the GH receptor have been identified. Potentially, a larger group of individuals with heterozygous abnormalities of the GH receptor will be added to this group with abnormalities such as defects of GH receptor signaling (JAK-STAT) and defects of the insulin-like growth factor I (IGF-I) gene.

DIFFERENTIAL DIAGNOSIS OF GROWTH HORMONE DEFICIENCY (HYPOPITUITARISM)

The causes of hypopituitarism include disorders of the pituitary gland and hypothalamic disorders that impair the release of growth hormone-releasing hormone (GHRH), as listed in Table 523-1.

Hypothalamic Dysfunction

Idiopathic hypopituitarism with growth failure due to growth hormone deficiency (GHD) may appear at the end of the first year after birth. This disorder has been postulated to be due to brith complications because as many as 70% of children with idiopathic hypopituitarism have histories of some form of perinatal insult, such as hypoxia from maternal bleeding, breech delivery, or asphyxia during the birth process. However, in at least 30% of these patients, abnormalities of the pituitary stalk, an ectopic posterior pituitary gland, or anterior pituitary hypoplasia are demonstrated with imaging studies. Therefore, it seems more likely that the perinatal difficulties in GHD children are a consequence, rather than a cause, of the hypopituitarism. These children are able to secrete growth hormone (GH) in response to the injection of growth hormone-releasing hormone (GHRH), and can secrete thyroid-stimulating hormone (TSH) in response to thyrotropin-releasing hormone (TRH). Deficiency of GH may also be associated with a variety of midline central nervous system and facial developmental defects, including holoprosencephaly, cleft lip, and cleft palate. Hypopituitarism also can occur in association with hypotelorism or single upper central incisor.

Septooptic dysplasia is a form of midfacial central nervous system hypoplasia in which GH deficiency and other pituitary hormone deficiencies are associated with small optic disc, nystagmus, blindness, and often absence or underdevelopment of the septum pellucidum. There is an increased incidence in offspring of young mothers, in first-born children, in areas of high unemployment, and in babies exposed to intrauterine medications, smoking, alcohol, and diabetes. Mutations of HESX1, a paired-like homeodomain gene expressed early in pituitary and forebrain development, are associated with familial forms of septooptic dysplasia.

Table 523-1. Causes of Growth Hormone Deficiency Leading to Insulin-like Growth Factor Type I Deficiency Syndrome

Hypothalamic Disorders: Growth Hormone-Releasing Hormone Deficiency

Developmental abnormalities

Infundibular dysgenesis (anterior pituitary hypoplasia, stalk attenuation or absence, ectopic posterior pituitary); often associated with birth trauma and other forms of perinatal insult

Midline central nervous system and facial developmental defects: septooptic dysplasia, holoprosencephaly, cleft lip or palate, single upper central incisor

Infection

Histiocytosis

Hypothalamic tumor

Craniopharyngioma

Hamartoma

Neurofibroma

Glioma

Germinoma

Psychosocial dwarfism

Idiopathic disorder

Disorders of the Pituitary Gland

Aplasia, hypoplasia

Genetic syndromes: deletion of the growth hormone gene, familial panhypopituitarism and familial isolated growth hormone deficiency

Intrasellar tumor: craniopharyngioma, adenoma

Nontumorous destruction: Infarction associated with trauma, infection, or irradiation of the head

Genetic Causes of Growth Hormone Deficiency

Inherited genetic defects are associated with growth hormone deficiency (GHD) and hypopituitarism (Table 523-2); as many as 3% to 30% of children with GHD have an affected parent, sibling, or child. A variety of coding defects for transcription factors led to a failure of development of the pituitary cells.

Table 523-2. Genetic Defects of the Growth Hormone-Insulin-like Growth Factor Axis Resulting in Insulin-like Growth Factor Deficiency

Abnormalities of human PROP1 result in multiple pituitary hormone deficiencies (MPHDs), characterized by variable and often age-dependent degrees of deficiency of growth hormone (GH), prolactin, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), leuteinizing hormone (LH), and, occasionally, adrenocorticotrophic hormone (ACTH). Gonadotropin abnormalities are particularly variable such that approximately 30% of patients have spontaneous pubertal development, including menarche, before ultimately developing hypogonadotropic hypogonadism. Pituitary size varies among patients and through life so that it may be very large and then involute leaving an empty sella. ACTH deficiency may not develop until the fourth or fifth decade of life.  Large-scale screening of patients with MPHDs has found 54% with PROP1 mutations, but there appears to be substantial geographic variation in associated genetic defects.

Specific mutations, especially deletions, in the gene encoding GH, some with abnormalities that produce a bioinactive GH, have been described. No examples of mutations of the gene encoding growth hormone-releasing hormone (GHRH) have been identified, but multiple kindreds with homozygous mutations of the GHRH-receptor gene have been identified; these patients have marked short stature, but lack other features of GHD, such as microphallus, truncal obesity, and hypoglycemia.

Cranial Irradiation

There are as many as 4000 pediatric cancer survivors who have growth hormone deficiency (GHD) resulting from a broad range of cancer treatments. Following cranial irradiation, GHD may evolve over years; thus, diagnosis may require serial testing. Some patients with auxology suggestive of GHD may have insulin-like growth factor I (IGF-I) and/or insulin-like growth factor binding protein 3 (IGFBP-3) levels below the normal range on repeated tests, but growth hormone (GH) responses in provocation tests remain above the “cut-off” level. Such children do not have classical GHD, but nonetheless may have an abnormality of the GH/IGF axis and may benefit from GH treatment.

Radiation may impair both hypothalamic and pituitary function; however, in the dosing range usually given to children with malignancy, hypothalamic damage is more common. Low doses typically cause isolated GHD, and higher doses may cause multiple pituitary deficiencies. The majority of long-term survivors develop GHD with the adverse effect of radiotherapy directly related to the biologically effective dose to the hypothalamus. Within 5 years of radiation, nearly 100% of children receiving ≥ 30 Gy over 3 weeks to the hypothalamic-pituitary axis have subnormal GH responses to provocative tests, whereas GHD may not become apparent for a decade or more after lower doses (18-24 Gy). Even when serum GH responses to provocative testing are normal, spontaneous GH secretion may be blunted at x-ray doses as low as 18 to 24 GY.

Poor linear growth from decreased GH secretion may be exacerbated by the impact of radiation itself, with inadequate pubertal acceleration of spinal growth. Surprisingly, cranial radiation can also result in precocious puberty, especially in children irradiated at young ages, causing early epiphyseal fusion. Sexual precocity appears to occur more frequently with low doses of radiation, and gonadotropin deficiency is likely at high doses. Treatment with gonadotropin-releasing hormone (GnRH) analogs may be necessary to suppress the hypothalamic-pituitary gonadal axis in an attempt to attain normal final height.

Bone marrow transplantation (BMT) for patients with inborn errors of metabolism, aplastic anemias, and malignancies requires preparative regimens that include total lymphoid or total body radiation, often with chemotherapy, and sometimes including cranial radiation. In children who had cranial radiation followed by high-dose chemotherapy and total body radiation as preparative regimens, growth failure is almost inevitable 2 to 5 years after BMT.

Neoplasms

Craniopharyngiomas are the most common neoplastic cause of pituitary insufficiency in children. This tumor is a congenital malformation present at birth and gradually grows over the ensuing years. About 75% of craniopharyngiomas arise in the suprasellar region, the remainder resembling pituitary adenomas. Most often, symptoms of headaches, vomiting, visual disturbances, symptoms of diabetes insipidus, and a change in sensorium result from the central nervous system involvement by the tumor. Fifty percent to 80% of patients have abnormalities of at least one anterior pituitary hormone at diagnosis. Many children or adolescents have evidence of growth arrest that may have begun near infancy and/or pubertal delay.  Hypothalamic gliomas, often associated with neurofibromatosis, and germinomas can cause pituitary insufficiency and many of the neurologic signs of craniopharyngioma. Microadenoma of the pituitary can occur with Cushing syndrome (see Chapter 535) and can cause hypopituitarism by compressing adjacent normal pituitary tissue. Following transsphenoidal resection, those with a macroadenoma have about a 50% incidence of hypopituitarism, whereas those with microadenomas have normal pituitary function; long-term cure rates are 55% to 65% for both tumor sizes.

Other Acquired Conditions

Decreased growth and impaired pubertal maturation may be seen in up to 60% of children and adolescents who have suffered mild to severe head injury. Growth hormone (GH) secretory defects are seen in psychosocial dwarfism, and extreme form of “failure to thrive” due to emotional deprivation. After the children spend a brief period in a supportive environment, pituitary function improves remarkably, and linear growth is accelerated. Empty sella syndrome is an uncommon disorder among children. It occurs when the diaphragma sellae does not surround the pituitary stalk tightly. The result is herniation of the arachnoid into the pituitary fossa and compression of normal pituitary tissue onto the walls of the sella turcica. The sella turcica can be expanded, and intrasellar hypodensity may be apparent by CT. Many patients with empty sella syndrome have no symptoms or signs of pituitary dysfunction but some do have associated pituitary hypofunction. The prevalence of empty sella syndrome increases among patients with pituitary adenoma. Localized (hypothalamus, pituitary) or generalized proliferation of mononuclear macrophages (histiocytes) characterizes Langerhans cell histiocytosis, a diverse disorder occurring at all ages, with peak incidence at ages 1 to 4 years (see Chapter 463). Approximately 50% to 75% of patients with one of these disorders, Hand-Schüller-Christian, have diabetes insipidus, But growth hormone deficiency (GHD) is rare.

Table 523-3. Clinical Features of Growth Hormone Deficiency or Growth Hormone Insensitivity

Growth and development

Birth weight: near normal

Birth length: may be slightly decreased

Postnatal growth: severe growth failure

Bone age: delayed, but may be advanced relative to height age

Genitalia: micropenis in childhood; normal for body size in adults

Puberty: delayed 3-7 years

Sexual function and fertility: normal

Craniofacies

Hair: sparse before age 7 years

Forehead: prominent; frontal bossing

Skull: normal head circumference; craniofacial disproportion due to small facies

Facies: small

Nasal bridge: hypoplastic

Orbits: shallow

Dentition: delayed eruption

Sclerae: blue

Voice: high pitched

Musculoskeletal/metabolic/miscellaneous

Hypoglycemia: in infants and children; fasting symptoms in some adults

Walking and motor milestones: delayed

Hips: dysplasia; avascular necrosis of femoral head

Elbow: limited extensibility

Skin: thin, prematurely aged

Osteopenia

CLINICAL PRESENTATION

The clinical presentation of hypopituitarism with growth hormone deficiency (GHD) varies, depending on the age at presentation. Typical features are shown in Table 523-3. In the newborn, diagnosis can be challenging. The presence of micropenis in a male newborn should always lead to an evaluation of the growth hormone (GH)/insulin-like growth factor (IGF) axis. Head MRI is essential when the diagnosis is suspected because it will identify developmental abnormalities of the hypothalamic-pituitary area, and the results are available sooner than other laboratory data. A GH level must be measured in the presence of neonatal hypoglycemia occurring in the absence of a metabolic disorder such as hyperammonemia or carnitine deficiency syndromes (see Chapter 545). A level of less than 20 ng/mL (in contrast to 10 ng/mL in older children) in a polyclonal radioimmunoassay (RIA) suggests neonatal GHD. An insulin-like growth factor binding protein 3 (IGFBP-3) level is of value for the diagnosis of neonatal GHD, but insulin-like growth factor I (IGF-I) levels are rarely helpful.

Most patients with idiopathic hypopituitarism without neonatal findings manifest poor growth by the end of the first year of life. Growth rates are slow during childhood, with rates of less than 3 to 4 cm/year being common. Onset of growth failure after a period of normal growth suggests the presence of an intrasellar or suprasellar tumor, or some other acquired defect. Among patients with early-onset disease, episodes of hypoglycemia are common, usually after periods of fasting, before breakfast, or during illnesses. There is a 10% incidence of hypoglycemic seizures and a 20% incidence of hypoglycemia without clinical findings. Children with hypopituitarism tend to be overweight for height and have prominent subcutaneous deposits of abdominal fat (Fig. 523-1). Many affected patients do not undergo puberty at the appropriate age because of concurrent gonadotropin deficiency. Because adrenal secretion of mineralocorticoids is not dependent on pituitary adrenocorticotrophic hormone (ACTH), children with hypopituitarism rarely have an electrolyte imbalance. Most children show no clinical signs of thyroid hormone deficiency, although serum thyroxine concentrations may be less than normal. Diabetes insipidus is rare among patients with idiopathic hypopituitarism. When present, it suggests the presence of a tumor or another structural hypothalamic lesion (eg, septo-optic dysplasia or infundibular dysgenesis).

TREATMENT OF HYPOPITUITARISM

Therapy for hypopituitarism includes replacement of all deficient hormones. Growth hormone (GH) therapy is described in detail later in this chapter. Most children with hypopituitarism do not have clinical hypothyroidism, but in those who do, growth responses may be attenuated. Some, however, may have serum T4 concentrations less than normal. Others may have a decline in serum T4 level once GH therapy is started. This may attenuate the growth response. Replacement doses of levothyroxine are indicated with the goal of achieving free T4 levels in the upper part of the normal range. Clinical signs of hypoadrenalism are uncommon among children with hypopituitarism, so administration of glucocorticoids is not generally indicated unless the patient has syncope, postural hypotension, attacks of hypoglycemia, or laboratory evidence of pituitary-adrenal axis hypofunction. Because glucocorticoid excess attenuates growth, the dose is usually limited to 5 to 10 mg cortisol per square meter of body surface area per day by mouth. Four to six times this dosage is needed during periods of stress. Diabetes insipidus often occurs after operations on the region of the pituitary gland and hypothalamus. Management using desmopressin is discussed in Chapter 525. Long-acting testosterone enanthate is administered intramuscularly to boys with hypopituitarism who have no signs of puberty by 14 years of age; beginning with a dosage of 50 mg a month, the dosage is gradually increased over several years to 200 mg every 2 weeks. This androgen often markedly enhances the growth response to GH. Girls who need estrogen replacement are given conjugated oral estrogens (0.3–0.6 mg daily) or transdermal estradiol (eg, Vivelle dots). After 9 to 12 months of continuous estrogen therapy, cycling with a synthetic progestin is begun, and the dosage of estradiol is gradually increased.

FIGURE 523-1. Children with growth hormone deficiency (GHD) have an immature appearance in addition to short stature. Patients A and B are typical of most growth hormone (GH)-deficient patients, being overweight for height with folds of ripply fat, particularly on the trunk. Because growth of the cranium is determined primarily by the growth of the brain, whereas growth of the face is dependent on GH, the calvarium is often large relative to the face. Patient C had a small penis and impaired response to exogenous gonadotropins, suggesting gonadotropin deficiency. Patient D is quite thin.

Treatment of Growth Hormone Deficiency in Hypopituitarism

The growth response to growth hormone (GH) of children with hypopituitarism is a function of the logarithm of the GH dose. The currently used starting dose is 0.03 to 0.05 mg/kg/d given subcutaneously on a daily basis, with the mean American dose being 0.3 mg/kg/week. Children with growth hormone deficiency (GHD) typically increase their growth rate from 3 to 4 cm/year before treatment to a mean of 8.0 to 11.0 cm/year during the first year of therapy. As treatment continues, growth rate declines somewhat, so that after 3 to 4 years of therapy, it may be average for age and maturational status. In general, children with the most profound GHD respond best to GH.

The best results of treatment are achieved by children who are treated earlier and never have the psychologic consequences of short stature. Growth response is inversely correlated with age of treatment onset.  Although the development of recombinant GH has solved the problem of supply experienced in the pituitary GH era, delays in diagnosis and initiation of therapy may still compromise adult height.

The use of higher doses of GH, the ability to treat until growth cessation, early initiation of treatment, progressive weight-related dose increments with attention to compliance with daily administration, and appropriate thyroid hormone and glucocorticoid replacement therapy are important factors in these adult height outcomes. As final height correlates with height at the onset of puberty in the GH-deficient patients, every effort must be made to enhance growth velocity during prepuberty. Attempts at modifying growth during pubertal years with robust GH dosing, slowing the pubertal process with gonadotropin-releasing hormone agonists, or blocking estrogen production with aromatase inhibitors to slow skeletal maturation have had modest success, but require further research prior to routine use.

Changes in levels of the GH-dependent peptides, IGF-I, and insulin-like growth factor binding protein 3 (IGFBP-3), acid labile subunit (ALS) as well as of leptin, correlate with growth responses. Measurement of these may give added information on the growth-promoting and fat-mobilizing actions of GH, as well as of the spectrum of childhood responsivity to exogenous GH. Specifically, modifying the GH dose based on frequent monitoring of IGF-I levels, combined with documentation of the growth response, seems reasonable and may enhance growth outcomes by greater individualization of the treatment program. Safety monitoring should include 6 to 12 monthly assessment of IGF-I and IGFBP-3 values, and perhaps annual measurement of fasting glucose/insulin ratios.

If a child does not respond to GH therapy, the diagnosis of GHD is reconsidered, and the possibility of a problem that impairs the GH response is considered. A suboptimal response can be due to (1) most important, by poor compliance; (2) improper preparation of GH for administration or incorrect injection techniques; (3) sub-clinical hypothyroidism; (4) coexisting systemic disease; (5) excessive glucocorticoid therapy; (6) prior radiation of the spine; (7) epiphyseal fusion; and (8) anti-GH antibodies. Although 10% to 20% of recipients of recombinant GH develop anti-GH antibodies, growth attenuation is rarely due to such antibodies. GH resistance syndromes involving abnormalities of structure or function of the GH receptor exist on an inherited or acquired basis and cause failure of IGF generation with consequent growth impairment. The most common situation in which GH-mediated IGF production is impaired is in malnutrition or chronic illness. In these settings, although the anabolic actions of GH may seem to have merit, the efficacy is extremely variable.

GH treatment of children has few side effects. Glucose intolerance among treated patients is extremely rare. Concern had been raised that GH treatment may predispose patients to leukemia, but no relation between GH and leukemia has been established. Slipped capital femoral epiphysis, pseudotumor cerebri, and gynecomastia are rare adverse effects of GH treatment. The latter two are reversible with cessation of therapy and then reinitiation of treatment with slowly progressive dosing.

GROWTH HORMONE THERAPY IN OTHER DISORDERS

The US Food and Drug Administration currently approves growth hormone (GH) treatment for children with Turner syndrome, chronic renal insufficiency, short children who were babies with intrauterine growth retardation, Prader-Willi syndrome, Noonan syndrome, and idiopathic short stature. It is certainly apparent that many children do not have the classic criteria of growth hormone deficiency (GHD), but they and other specific groups may benefit from GH therapy of their extreme short stature.

Cranial Radiation/Chemotherapy

Children that underwent cranial radiation with documented GHD and growth failure are candidates for exogenous GH treatment, there is no evidence for enhanced relapses of the primary neoplasm in patients treated with GH. Unfortunately, the response to GH is very variable. Spinal growth impairment, inadequate or delayed treatment, and sexual precocity may limit linear growth. Chemotherapy regimens by themselves may impair final adult height, although not nearly to the extent seen after radiation.

Renal Disease

Although growth hormone (GH) secretion and serum insulin-like growth factor I (IGF-I) and IGF-II levels usually are normal among these children, serum level of insulin-like growth factor binding proteins (IGFBPs) often are increased. Growth factor binding proteins (GFBPs) inhibit the action of IGF and, in turn, growth. In nephrotic syndrome, however, serum levels of IGF-I and IGFBP-3 are low because of urinary losses. Chronic glucocorticoid therapy can exacerbates growth retardation by diminishing GH release and blunting the action of IGF-I at growth plates. GH treatment of children with renal failure is effective in accelerating linear growth, likely by increasing the molar ratio of IGF peptides to IGFBPs and thereby overcoming the inhibitory action of IGFBPs.

Children with a History of Intrauterine Growth Retardation

Short children with a history of intrauterine growth retardation (IUGR) who are very short during early to middle childhood years are able to approximate the growth velocity of their peers with administration of growth hormone (GH) therapy. However, many questions regarding the long-term efficacy of GH therapy on final height remain. Younger, smaller, and lighter children grow best, with the greatest catch-up growth occurring during the prepubertal years. In a report from a long-term Dutch small for gestational age (SGA) treatment trial (mean duration of therapy being 8 years), mean height reached the parental target, with 91% of children within the normal range. More provocatively, intelligence quotient, behavior, and self-perception scores increased significantly and approximated those of normal Dutch children. The complexity of the metabolic derangements in the SGA population demands that long-term follow-up of treated children be undertaken to determine whether cardiovascular risk factors will also appear despite their earlier thin habitus.

Thalassemia

Growth hormone treatment increases growth, at least initially, in patients with thalassemia. In a long study (average duration 59 months) starting with young (7.2 years) patients, an increased growth velocity was maintained throughout the treatment period; when treatment was initiated at an older age (13.6 years), however, final height was not improved.

Cystic Fibrosis

The growth hormone (GH)-insulin-like growth factor (IGF) axis shows evidence for some degree of acquired GH insensitivity with lowered mean IGF-I and elevated GH levels.1-13 Short-term treatment of prepubertal children who have cystic fibrosis (CF) with GH results in an anabolic effect, with greater growth velocity, nitrogen retention, and increased protein and decreased fat stores.14-16 Pulmonary function improved in most patients. A 4-year longitudinal study using the National CF Foundation Registry found that improved nutrition status and growth were associated with a slower age-related decrement of pulmonary function.17 GH treatment may prove to have a role in CF therapy.18-23

Idiopathic Short Stature

Controlled studies have demonstrated clear gains of height among idiopathic short stature (ISS) children. A meta-analysis looking at an aggregate group of 1089 children suggested efficacy of treatment. Data from two large trials showed a cumulative gain of 7.3 cm in the group treated with 0.37 mg/kg/week over the placebo-treated children. Concerns had been raised that growth hormone (GH) treatment might accelerate pubertal onset and progression, resulting in failure to improve height standard deviation score (SDS) for bone age, thereby offsetting the positive responses observed during early years of GH treatment of ISS, but this has not been observed. Taken together, these data show that GH treatment of prepubertal children with ISS does increase growth velocity and final height. In two recent studies of GH-treated ISS children, no evidence of increased adverse events relative to other GH-treated groups was noted. In view of the current limitations of diagnostic testing to discriminate between GH deficiency and the less classical syndromes of primary insulin-like growth factor (IGF) deficiency, it is likely that some cases of “partial” GHD or GH insensitivity may not be diagnosed using traditional criteria. Further therapeutic trials of GH for ISS to adult height are required. Appropriate evaluation should include thorough analysis of the GH-IGF axis (with growth hormone-binding protein [GHBP] levels, serum IGF-I and insulin-like growth factor binding protein 3 [IGFBP-3] concentrations, and, in some cases, IGF responses to GH treatment), before labeling a short child as “normal.” Proper assessment of pretreatment growth velocity should be over a minimum of a 6-month period and preferably for 12 months.

Decisions concerning therapy should be individualized, with careful attention to the needs and expectations of the child and family. In the otherwise normal child with severe short stature (at least 2.25 standard deviations [SDs] below the mean for age) and a failure to show convincing evidence for spontaneous catch-up growth, a trial of GH therapy should be discussed with the patient and family. This discussion should include an assessment of normal growth patterns, familial growth patterns, and predicted pubertal and statural development. The inconveniences, discomforts, and potential risks of GH treatment should be fully described. It is the physician’s responsibility to ensure that expectations of the child and the parents are realistic in regard to short-term growth and ultimate height. Where appropriate, counseling and psychologic support should be provided. If a trial of GH therapy is desired, treatment should be for a minimum of 6 months with the US Food and Drug Administration (FDA)-approved dosage of 0.37 mg/kg/week, and therapy with GH should be continued beyond 6 months only if growth is accelerated (defined as an increase in the height velocity of at least 2 cm/year). Documentation of the efficacy of treatment requires continuous monitoring, both in terms of growth and in measurement of the GH-dependent peptides. Growth acceleration with GH treatment does not relieve the physician of seeking an underlying etiology for the child’s growth retardation. Appropriate studies should be repeated, when indicated. Treatment must be carefully monitored for side effects of GH treatment, and continued psychologic support should be provided for the child and family. This includes guiding the patient through puberty and providing posttreatment follow-up.

The use of biosynthetic IGF-I for treatment of children with ISS has been suggested, but should be viewed as experimental.

OTHER ENDOCRINE CAUSES OF GROWTH RETARDATION

Growth is usually retarded among children with hypothyroidism. Although growth failure depends on the age at onset, duration, and severity of disease, it often is profound and is frequently the most prominent manifestation of acquired hypothyroidism. Diagnosis and management of hypothyroidism is discussed further in Chapters 527 and 528.

Regardless of the source (endogenous adrenal production, as in Cushing syndrome, adrenal tumor, or exogenous administration), glucocorticoid excess interferes with chondro-genesis and with bone metabolism by inhibiting osteoblastic activity and enhancing bone resorption. The results are retarded skeletal growth. Cushing syndrome in children may not cause all clinical signs and symptoms associated with the disorder in adults and may present with growth arrest. Cushing syndrome is an unlikely diagnosis in children with obesity because exogenous obesity is associated with normal or even accelerated skeletal growth.

GROWTH HORMONE RESISTANCE

Another major category of the insulin-like growth factor (IGF) deficiency syndromes (Table 523-4) is that of resistance to the action of growth hormone (GH). Children with characteristics of GH deficiency accompanied by normal or elevated serum GH levels and decreased insulin-like growth factor I (IGF-I) level are said to have GH resistance and are in the group of patients with primary IGF deficiency syndrome. GH resistance or GH insensitivity can be caused by inherited or acquired abnormalities of the GH receptor, postreceptor defects of GH signaling mechanisms, or inherited errors of IGF-I biosynthesis. GH resistance can be acquired and appears to be a component of the pathophysiologic mechanism for growth failure associated with malnutrition and a variety of hepatic, renal, and other chronic diseases. The mechanisms of IGF insufficiency are not clearly defined. It can also be caused by acquisition of antibodies to GH.

Children with genetic defects in the GH receptor have clinical features identical to those of children with IGF deficiency caused by GHD (Table 523-3). Basal levels of serum GH are normal or elevated, whereas those of IGF-I, insulin-like growth factor II (IGF-II), and insulin-like growth factor binding protein 3 (IGFBP-3) are profoundly reduced. The hallmark of the diagnosis is the lack of response to GH treatment.  Measurement of serum GH-binding protein (GHBP) can be helpful in making the diagnosis because GHBP is a cleavage product of the extracellular portion of the GH receptor. Inability to detect GHBP in the serum thus suggests an absence of GH receptor. The presence of GHBP, however, does not exclude a disorder of the GH receptor.

Table 523-4. Insulin-like Growth Factor Deficiency Syndromes

Due to Failure of GH Action or Lack of IGF-I Availability (Primary IGF Deficiency)

Molecular (inherited) defects

Abnormalities of the GHR affecting GH binding

Abnormalities of the GHR affecting receptor dimerization

Abnormalities of the GHR affecting receptor anchoring

Abnormalities of the GHR affecting GH signal transduction

Intracellular post-GHR signaling defects

ALS mutations

IGF-I gene deletions

Inactivating mutations of the IGF-I gene (bioin-active IGF-I)

Acquired defects

Circulating antibodies to GH that inhibit GH action

Circulating antibodies to the GHR

Malnutrition/catabolic states

Liver disease

Inflammatory disease

Due to Decreased GH Production (Secondary IGF Deficiency)

GHD resulting from hypothalamic dysfunction

GHD resulting from pituitary dysfunction

GHD resulting from GH gene deletion

Inactivating mutations of the GH gene (bioinactive GH)

GH, growth hormone; IGF-I, insulin-like growth factor I; IGF, insulin-like growth factor; GHR, growth hormone receptor; ALS, acid labile subunit; GHD, growth hormone deficiency.

Several patients with abnormalities of IGF production or function have been reported, but only one with a defect in the gene for IGF-I has been described. This patient had a partial gene deletion, as well as sensorineural deafness, mental retardation, and microcephaly.