Growth Hormone Deficiency in Children

Growth hormone (GH) deficiency can occur in isolation or in association with generalized hypopituitarism. In both instances, growth hormone deficiency may be acquired or congenital (including hereditary genetic causes). Rarely, GH is not deficient, but the GH receptors are abnormal (GH insensitivity).

Isolated growth hormone deficiency is estimated to occur in 1/4,000 to 1/10,000 children. It is usually idiopathic, but about 25% of patients have an identifiable etiology. Congenital causes include abnormalities of the GH-releasing hormone receptor and of the GH1 gene and certain central nervous system (CNS) malformations. Acquired causes include therapeutic radiation of the CNS (high-dose radiation can cause generalized hypopituitarism), meningitis, histiocytosis, and brain injury. Radiation of the spine, either prophylactic or therapeutic, may further impair the growth potential of the vertebrae and further jeopardize height gain.

Generalized hypopituitarism may have genetic causes, involving hereditary or sporadic mutations that affect cells of the pituitary. In such cases, there also may be anomalies of other organ systems, particularly midline defects, such as cleft palate or septo-optic dysplasia (which involves absence of the septum pellucidum, optic nerve atrophy, and hypopituitarism). Generalized hypopituitarism also can be acquired from many types of lesions that affect the hypothalamus (impairing secretion of releasing hormones) or pituitary; examples include tumors (eg, most commonly craniopharyngioma), infections (eg, tuberculosis, toxoplasmosis, meningitis), and infiltrative disorders. The combination of lytic lesions of the bones or skull and (diabetes insipidus) suggests Langerhans cell histiocytosis.

Manifestations of growth hormone deficiency depend on the patient's age, the underlying etiology, and the specific hormone deficiencies.

Growth hormone deficiency itself typically manifests as growth failure, sometimes along with delay in tooth development. Height is below the third percentile, and growth velocity is < 6 cm/year before age 4 years, < 5 cm/year from age 4 to 8 years, and < 4 cm/year before puberty. Although of small stature, a child with hypopituitarism retains normal proportionality between upper and lower body segments. Skeletal maturation, assessed by bone age determination, is > 2 years behind chronologic age.

Other abnormalities may be present, depending on the underlying defect, and the child may have delayed or absent pubertal development. Weight gain may be out of proportion to growth, resulting in relative obesity. Neonates who have congenital defects of the pituitary or hypothalamus may have hypoglycemia (which also can occur in older children), hyperbilirubinemia, midline defects (eg, cleft palate), or micropenis, as well as manifestations of other endocrine deficiencies.

• Auxologic assessment (height and weight data recorded on a growth chart)

• Imaging studies

• Insulin-like growth factor 1 (IGF-1) levels and IGF binding protein type 3 (IGFBP-3) levels

• Usually confirmation by provocative testing

• Evaluation of other pituitary hormones and for other causes of poor growth

Current consensus guidelines for diagnosis of growth hormone deficiency require integration of growth criteria, medical history, laboratory testing, and imaging test results.

Growth is assessed; data for height and weight should be plotted on a growth chart (auxologic assessment) for all children. (For children 0 to 2 years, see World Health Organization [WHO] Growth Charts; for children 2 years and older, see Centers for Disease Control and Prevention [CDC] Growth Charts.)

Measurement of IGF-1 and IGFBP-3 levels begins the assessment of the GH/IGF-1 axis. IGF-1 levels reflect GH activity and serve as the principal mediator of the growth stimulating effects of GH. IGFBP-3 is the major carrier of IGF peptides. Levels of IGF-1 and IGFBP-3 are measured because GH levels are pulsatile, highly variable, and difficult to interpret.

IGF-1 levels vary by age and should be interpreted relative to bone age rather than to chronologic age. IGF-1 levels are lowest in infancy and early childhood (< 5 years) and thus do not reliably discriminate between normal and subnormal in these age groups. At puberty, IGF-1 levels rise and normal levels help exclude GH deficiency. Low IGF-1 levels in older children suggest GH deficiency; however, IGF-1 levels are low in conditions other than GH deficiency (eg, emotional deprivation, undernutrition, celiac disease, hypothyroidism), and these conditions must be excluded. However, IGFBP-3 levels, unlike IGF-1, are less affected by undernutrition and allow discrimination between normal and subnormal in younger children.

In children with low levels of IGF-1 and IGFBP-3, GH deficiency is usually confirmed by measuring GH levels. Because basal GH levels are typically low or undetectable (except after the onset of sleep), random GH levels are not useful and assessment of GH levels requires provocative testing. However, provocative testing is nonphysiologic, subject to laboratory variation, and poorly reproducible. Also, the definition of a normal response varies by age, sex, and testing center and is based on limited evidence. Treatment of GH deficiency should not be based solely on the results of provocative testing.

Imaging studies are done when growth is abnormal; bone age should be determined from an x-ray of the left hand (by convention). In GH deficiency, skeletal maturation is usually delayed to the same extent as height. With GH deficiency, evaluating the pituitary gland and hypothalamus with MRI is indicated to rule out calcifications, tumors, and structural anomalies.

Screening laboratory tests are done to look for other possible causes of poor growth, including

• Hypothyroidism (eg, thyroid-stimulating hormone, thyroxine)

• Renal disorders (eg, electrolytes, creatinine levels)

• Inflammatory and immune conditions (eg, tissue transglutaminase antibodies, C-reactive protein)

• Hematologic disorders (eg, complete blood count with differential)

Genetic testing for specific syndromes (eg, Turner syndrome) may be indicated by physical findings or if growth pattern differs significantly from family. If GH deficiency is highly suspected, additional tests of pituitary function are done (eg, ACTH, 8 AM serum cortisol level, LH, FSH, TSH, free serum thyroxine [free T4], and prolactin levels).

Provocative testing

Because GH responses are typically abnormal in patients with diminished thyroid function, provocative testing should be done in these patients only after adequate hormone replacement therapy.

The insulin tolerance test is the best provocative test for stimulating GH release but is rarely done because of the risks of hypoglycemia. Other provocative tests are less dangerous but also less reliable. These include tests using arginine infusion (500 mg/kg IV given over 30 minutes), clonidine (0.15 mg/m² orally [maximum 0.25 mg]), levodopa (10 mg/kg orally for children; 500 mg orally for adults), and glucagon (0.03 mg/kg IV [maximum 1 mg]). GH levels are measured at different times after drug administration depending on the drug.

Because no single test is 100% effective in eliciting GH release (1), 2 GH provocation tests are done (typically on the same day). GH levels generally peak 30 to 90 minutes after administration of insulin or the onset of arginine infusion, 30 to 120 minutes after levodopa, 60 to 90 minutes after clonidine, and 120 to 180 minutes after glucagon.

The GH response that is considered normal is somewhat arbitrary. Generally, any stimulated GH level > 10 ng/mL (> 10 mcg/L) is sufficient to rule out classic GH deficiency. GH deficiency may be considered for responses < 10 ng/mL (< 10 mcg/L)—some centers use a lower cutoff, eg, 7 ng/mL [7 mcg/L]) to 2 pharmacologic stimuli, but results must be interpreted in the context of auxologic data. Because of the arbitrary nature of thresholds for normal results on provocative GH tests, children with otherwise unexplained short stature and normal provocative GH test results may be considered to have GH deficiency if they meet most of the following criteria (2):

• Height > 2.25 standard deviations (SD) below the mean for age or > 2 SD below the midparental height

• Growth velocity < 25th percentile for bone age

• Bone age > 2 SD below the mean for age

• Low serum insulin-like growth factor 1 (IGF-1) and/or IGF binding protein type 3 (IGFBP-3) levels

• Other clinical features suggesting GH deficiency

Clinical Calculators

Height Potential: A Child's Target Height Based on Midparental Height

Because GH levels rise during puberty, many children who fail provocative GH stimulation testing before puberty may have normal results after puberty or when primed with gonadal steroids. To avoid unnecessary treatment of children with constitutional delay, sex steroid priming before provocative GH testing may be considered in prepubertal boys > 11 years of age and in prepubertal girls > 10 years of age with adult height prognosis within -2 standard deviations of the reference population mean. Priming protocols for both boys and girls suggest beta-estradiol 2 mg (1 mg for body weight < 20 kg) orally on each of the two nights before the test or, for boys, a depot formulation of testosterone 50 to 100 mg IM 1 week before the test (3).

Provocative testing may not detect subtle defects in the regulation of GH release. For example, in children with short stature secondary to GH secretory dysfunction, results of provocative testing for GH release are usually normal. However, serial measurements of GH levels over 12 to 24 hours indicate abnormally low 12- or 24-hour integrated GH secretion. However, this test is expensive and uncomfortable and thus is not the test of choice for GH deficiency.

If diminished GH release is confirmed, tests of secretion of other pituitary hormones and (if abnormal) hormones of their target peripheral endocrine glands along with pituitary imaging studies must be done if not done previously.

• Recombinant GH supplements

• Sometimes other pituitary hormone replacement

Recombinant GH is indicated for all children with short stature who have documented growth hormone deficiency. (See also the Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society's 2016 guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents.) Documented growth hormone deficiency is based on auxologic, biochemical, and sometimes radiologic findings.

Dosing of recombinant GH is usually from 0.03 to 0.05 mg/kg subcutaneously once a day. With therapy, height velocity often increases to 10 to 12 cm/year in the first year and, although it increases more slowly thereafter, remains above pretreatment rates. Therapy is continued until an acceptable height is reached or growth rate falls below 2.5 cm/year. Insulinalbuminhuman chorionic gonadotropin [hCG]). To date, trials with long-acting GH agents suggest treatment effects on height velocity that are similar to those seen with daily recombinant GH. IGF-1 levels may be more difficult to monitor than with daily GH and depend on formulation and timing of the last injection (1).

Adverse effects of GH therapy are few but include idiopathic intracranial hypertension (pseudotumor cerebri), slipped capital femoral epiphysis, and transient mild peripheral edema. Before the advent of recombinant GH, GH extracted from pituitary glands was used. This preparation rarely led to Creutzfeldt-Jakob disease 20 to 40 years after treatment. Pituitary-extracted GH was last used in the 1980s. Adverse effects resulting from new long-acting GH agents are thought to be similar to daily GH but need to be studied further given their different mechanisms.

It is controversial whether short children without evidence of an endocrine, metabolic, or other disease that explains the short stature should be treated with GH. These children are considered to have idiopathic short stature (ISS). ISS is defined as height 2 standard deviations (SD) below the mean for age, normal height velocity (near or at lower limit of normal), no biochemical evidence of a growth-restricting condition, and normal GH stimulation testing that excludes classic GH deficiency. Recombinant GH can be used to treat children with ISS who have a height 2.25 SD below the mean for age and a predicted adult height below the normal range (ie, < 150 cm for females and < 160 cm for males). Guidelines recommend against the routine use of GH for every child with ISS, and the decision to treat should be made on a case-by-case basis. Treatment responses are highly variable. With 5 years of treatment, some children may have a mean increase of about 5 cm in adult height, whereas other children may have no increase in adult height. A greater response to GH treatment may be expected in children with ISS based on height response in first year of treatment, age at the start of treatment (better response if treatment is started before age 9 in girls and before age 10 in boys), and change in IGF-1 level from baseline. For children who are treated, many experts recommend a trial of GH therapy for 6 to 12 months, continuing GH only if there is a doubling of or an increase of 3 cm/year over the pretreatment height velocity. Others object to this approach because it is expensive, is experimental, may lead to adverse effects, labels otherwise healthy children as abnormal, and raises ethical and psychosocial concerns that feed into the bias of “heightism.”

When other pituitary hormone deficiencies accompany growth hormone deficiency, additional hormone replacement is required. Cortisol (see Treatment of Addison Disease) and thyroid hormone (see Treatment of Hypothyroidism) should be replaced throughout childhood, adolescence, and adulthood when circulating levels of these hormones are low. Argininevasopressin). When puberty does not occur normally, treatment with gonadal sex steroids is indicated (see Treatment of Delayed Puberty).

GH therapy in children with short stature due to therapeutic radiation of the pituitary gland for cancer carries a theoretic risk of causing cancer recurrence. However, studies have not shown a greater-than-expected incidence of new cancers or a greater recurrence rate. GH replacement can probably be safely instituted at least 1 year after the successful completion of anticancer therapy.

The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

1. WHO: Growth charts for children 0 to 2 years

2. CDC: Growth charts for children 2 years and older

3. Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society: Guidelines for growth hormone and insulin-like growth factor-1 treatment in children and adolescents: Growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-1 deficiency (2016)