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Growth Hormone Deficiency in Children

(Pituitary Dwarfism)

by Andrew Calabria, MD

Growth hormone (GH) deficiency is the most common pituitary hormone deficiency in children and can be isolated or accompanied by deficiency of other pituitary hormones. GH deficiency typically results in abnormally slow growth and short stature with normal proportions. Diagnosis involves measurement of pituitary hormone levels and MRI to detect structural pituitary anomalies or brain tumors. Treatment usually involves specific hormone replacement and removal of any causative tumor.

Patients with GH deficiency associated with generalized hypopituitarism will also have deficiency of one or more other pituitary hormones (eg, follicle-stimulating hormone, luteinizing hormone, adrenocorticotropic hormone [ACTH], thyroid-stimulating hormone, antidiuretic hormone [ADH]).

Etiology

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

Isolated GH 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 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 or pituitary; examples include tumors(eg, most commonly craniopharyngioma), infections (eg, TB, toxoplasmosis, meningitis), and infiltrative disorders. The combination of lytic lesions of the bones or skull and diabetes insipidus suggests Langerhans cell histiocytosis (see Langerhans Cell Histiocytosis).

Symptoms and Signs

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

GH deficiency itself typically manifests as growth failure sometimes along with delay in tooth development. Height is below the 3rd percentile, and growth velocity is < 6 cm/yr before age 4 yr, < 5 cm/yr from age 4 to 8 yr, and < 4 cm/yr 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 yr 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), midline defects (eg, cleft palate), or micropenis, as well as manifestations of other endocrine deficiencies.

Diagnosis

  • Clinical evaluation, including growth criteria and other medical history

  • 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 GH deficiency require integration of growth criteria, medical history, laboratory testing, and imaging 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 yr, see WHO Growth Charts ; for children 2 yr and older, see CDC Growth Charts .)

Measurement of IGF-1 and IGFBP-3 levels begins the assessment of the GH/IGF-1 axis.

In mid to late childhood, IGF-1 levels, which reflect GH activity, are measured because GH levels are highly variable and difficult to interpret. Because IGF-1 levels rise at puberty, they should be interpreted relative to bone age rather than to chronologic age. Normal IGF-1 levels help exclude GH deficiency. However, IGF-1 levels are low in conditions other than GH deficiency, such as psychosocial deprivation, undernutrition, and hypothyroidism.

In infancy and early childhood, IGF-1 levels are normally low and thus do not reliably discriminate between normal and subnormal in these age groups. However, levels of IGFBP-3 (the major carrier of IGF peptides), 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 (see Provocative testing). However, provocative testing is nonphysiologic, subject to laboratory error, and poorly reproducible. Also, the definition of a normal response varies by age, sex, and testing center and is based on limited evidence.

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 sella turcica with CT or MRI is indicated to rule out calcifications and tumors; the sella turcica is abnormally small in 10 to 20% of patients.

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

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

  • Renal disorders (electrolytes, creatinine levels)

  • Inflammatory and immune conditions (eg, tissue transglutaminase antibodies, ESR)

  • Hematologic disorders (eg, CBC with differential)

Genetic testing for specific syndromes (eg, Turner syndrome—see 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, luteinizing hormone, follicle-stimulating hormone, and prolactin levels).

Pearls & Pitfalls

  • Unlike in many endocrine deficiencies in which hormone levels are diagnostic, random GH levels are of little use in diagnosing GH deficiency.

Provocative testing

Because GH responses are typically abnormal in patients with diminished thyroid or adrenal 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 it is risky. Other provocative tests are less dangerous but also less reliable. These include tests using arginine infusion (500 mg/kg IV given over 30 min), clonidine (0.15 mg/m 2 po [maximum 0.25 mg]), levodopa (10 mg/kg po for children; 500 mg po 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, two GH provocation tests are done (typically on the same day). GH levels generally peak 30 to 90 min after administration of insulin or the onset of arginine infusion, 30 to 120 min after levodopa, 60 to 90 min after clonidine, and 120 to 180 min after glucagon. The GH response that is considered normal is somewhat arbitrary. Generally, any stimulated GH level > 10 ng/mL is sufficient to rule out GH deficiency. GH deficiency may be considered for responses < 10 ng/mL (some centers use a lower cutoff, eg, 7 ng/mL) to two pharmacologic stimuli, but results must be interpreted in the context of auxologic data. 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.

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 h indicate abnormally low 12- or 24-h 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.

Treatment

  • Recombinant GH supplements

  • Sometimes other pituitary hormone replacement

Recombinant GH is indicated for all children with short stature who have documented GH deficiency. Dosing is usually from 0.03 to 0.05 mg/kg sc once/day. With therapy, height velocity often increases to 10 to 12 cm/yr 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/yr.

Adverse effects of GH therapy are few but include idiopathic intracranial hypertension (pseudotumor cerebri—see Idiopathic Intracranial Hypertension), slipped capital femoral epiphysis (see Slipped Capital Femoral Epiphysis (SCFE)), 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 yr after treatment (see Creutzfeldt-Jakob Disease (CJD)). Pituitary-extracted GH was last used in the 1980s.

It is controversial whether short children with clinical features of GH deficiency but with normal GH secretion and normal IGF-1 levels should be treated with GH. Many experts recommend a trial of GH therapy for 6 to 12 mo, continuing GH only if there is a doubling of or an increase of 3 cm/yr 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 GH deficiency, additional hormone replacement is required. Cortisol (see Addison Disease : Treatment) and thyroid hormone (see Subclinical Hyperthyroidism : Treatment) should be replaced throughout childhood, adolescence, and adulthood when circulating levels of these hormones are low. Diabetes insipidus typically requires lifelong treatment with desmopressin in tablet or intranasal form (see Central Diabetes Insipidus : Treatment). When puberty fails to occur normally, treatment with gonadal sex steroids is indicated (see Male Hypogonadism in Children : Treatment).

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 yr after the successful completion of anticancer therapy.

Key Points

  • Growth hormone (GH) deficiency can occur in isolation or in association with generalized hypopituitarism.

  • Causes include congenital (including genetic) disorders and a number of acquired disorders of the hypothalamus and/or pituitary.

  • GH deficiency causes short stature; numerous other manifestations may be present depending on the cause.

  • Diagnosis is based on a combination of clinical findings, imaging studies, and laboratory testing, usually including provocative tests of GH release.

  • Children with short stature and documented GH deficiency should receive recombinant GH; other manifestations of hypopituitarism are treated as needed.

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Drugs Mentioned In This Article

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  • R-GENE 10
  • CATAPRES
  • DDAVP, STIMATE

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