Basics
Description
- Growth hormone deficiency (GHD) is a rare cause of growth failure due to a lack of growth hormone action caused by a defect in GH synthesis (insufficient hormone), release, or signaling (decreased responsiveness to normal or high levels of hormone).
- GHD can be associated with other pituitary hormone deficiencies.
Epidemiology
- Prevalence in the United States is approximately 1:4,000.
- Males are more commonly diagnosed than females.
- 2 peak ages of diagnosis:
- Infancy (<1 year of age) usually because of associated hypoglycemia
- Childhood at >4 years of age, usually because of poor linear growth
Genetics
- Spontaneous
- Autosomal recessive (AR)
- Autosomal dominant (AD)
- X-linked forms
Pathophysiology
GH has a number of anabolic actions, but its principal one is increasing linear growth. This occurs predominantly due to direct GH action on the growth plate, although there are also some indirect GH actions on growth via stimulation of secretion of hepatic and growth plate insulin-like growth factor 1 (IGF-1).
Etiology
- Idiopathic: Although idiopathic GH deficiency is a relatively common diagnosis, it is a diagnosis of exclusion. Sometimes misdiagnosed in normally growing children
- Congenital
- Congenital malformation of the pituitary can be associated with the following:
- Holoprosencephaly
- Septo-optic dysplasia
- Midline defects: cleft lip, cleft palate, central maxillary incisor
- Ectopic posterior pituitary, small anterior pituitary, and/or hypoplastic infundibulum
- Genetic mutations
- Familial multiple anterior pituitary hormone deficiency (Pit-1, Prop-1)
- GH gene mutations (Type Ia, Ib, II, III)
- GH insensitivity
- Laron dwarfism, AR disorder classically caused by GH receptor mutations, presents with the phenotype of severe GH deficiency (severe short stature, hypoplastic nasal bridge, sparse hair, high-pitched voice, and delayed bone age).
- Postreceptor and second messenger defects such as IGF-1 gene deletion, IGF-1 receptor mutation, STAT5b mutation
- Acquired idiopathic
- CNS tumors: craniopharyngioma, germinoma, medulloblastoma, glioma, pinealoma
- Pituitary or hypothalamic irradiation
- Trauma: child abuse or closed head injury
- Surgical resection/damage of the pituitary gland/stalk
- Birth injury/perinatal insult
- Infection: viral encephalitis, bacterial or fungal infection, tuberculosis
- Vascular: pituitary infarction or aneurysm
- Infiltration affecting pituitary gland or sella turcica: histiocytosis, sarcoidosis
- Hypophysitis
- Psychosocial deprivation
Diagnosis
History
- Family history
- Parental heights
- Family history of short stature (women <4 feet 11 inches [150 cm] or men <5 feet 4 inches [163 cm]) indicates genetic shortness.
- Family history of delayed puberty "late bloomer" (growth after high school, menarche at ≥14 years): Constitutional delay of growth and development tends to occur in family members.
- Birth history
- Babies born small for gestational age. 10-15% will not show "catch-up growth," but are not typically GHD.
- Babies with congenital GHD may not be short at birth but will grow poorly over the next few years.
- Medication history: Look for overuse of corticosteroids, either systemic or inhaled. Ask about nonprescription drugs and health food store supplements.
- Past history of chronic illness (e.g., cyanotic cardiac disease, renal tubular acidosis, asthma, celiac disease, chronic anemia, etc.)
- Psychosocial history: Poor growth occurring at the time of a major stressful event may be due to psychosocial deprivation.
Physical Exam
- Measure accurate weight and height with wall-mounted stadiometer. Perform a sitting height and arm span if possible.
- Neurologic examination, including visual fields and funduscopic examination for evaluation of brain tumors
- Assess for signs of Turner syndrome:
- Cubitus valgus, low posterior hair line, abnormal dentition, abnormal ears, and/or shortened 4th metacarpals in girls suggest Turner syndrome.
- Turner syndrome is the most common pathologic cause of short stature in girls, and short stature may be the only manifestation.
- Midline facial defects such as submucous cleft, cleft lip, and palate are associated with hypopituitarism.
- Tanner stage
- Micropenis is associated with congenital hypopituitarism.
- Delayed puberty suggests constitutional delay but may also be indicative of panhypopituitarism.
- Cherubic facies with frontal bossing, thin hair, high-pitched voice, and relative truncal obesity with adiposity are seen in GHD.
Diagnostic Tests & Interpretation
Lab
- CBC with differential: anemia, malignancy, cell-based immunodeficiency, and inflammatory processes
- Sedimentation rate and CRP: inflammatory processes such as Crohn disease
- Hepatic and renal function tests: hepatic or renal disease
- Celiac screen
- Urinalysis including pH
- Thyroid function tests (thyroid-stimulating hormone [TSH] and either a T4 or a free T4)
- Chromosomes in females (to exclude Turner syndrome)
- IGF-1 and IGF-binding protein-3 (IGFBP-3) production is regulated directly by GH. However, there is a poor correlation with GH deficiency. IGF-1 values are low early in life and in conditions such as hypothyroidism, diabetes, renal failure, and undernutrition.
- GH-provocative testing (performed by an endocrinologist)
- A random GH level is of little value to diagnose GHD beyond the neonatal period.
- After neonatal period, GH is mostly secreted only in brief pulses during deep sleep (at night). However, false-positive results are common.
- NOTE: Using two GH provocation tests and strict GH cutoffs (<5.0 ng/mL), approximately 5% of normally growing children would be diagnosed as GH-deficient, whereas fully 20% of healthy GH-replete children can fail any one provocative test.
Imaging
- Bone age: radiography of left hand and wrist to assess skeletal maturation
- If provocative testing shows GH deficiency, obtain MRI with contrast of the pituitary and hypothalamus to look for central nervous system tumor or anomaly of the hypothalamus/pituitary.
Differential Diagnosis
- Abnormal body proportions:
- Skeletal dysplasia (e.g., hypochondroplasia, achondroplasia)
- Normal skeletal proportions with prenatal growth failure (birth weight <10th percentile):
- Small for gestational age
- Congenital infection
- Maternal drug use (tobacco, alcohol etc.)
- Chromosomal short stature (Turner, Down syndrome, etc.)
- Syndromes (Noonan, Prader Willi, Russell Silver syndrome, etc.)
- Normal skeletal proportions with postnatal growth failure (birth weight >10th percentile):
- Constitutional delay of growth and adolescence
- Familial short stature
- Malnutrition
- Renal failure
- Inflammatory bowel disease
- Celiac disease
- Congenital heart disease
- Hypothyroidism
- Hypercortisolism
- Metabolic disorders
- Rickets
- Psychosocial deprivation
Alert
- Children with constitutional growth delay or pubertal delay show poor growth when peers are going through their pubertal growth spurts, and have a delayed bone age, mimicking GH deficiency.
- GH-provocative testing may yield false-positive or false-negative results:
- 20% of normal children will fail at least 1 GH-provocative test.
- Obese but otherwise normal children are more likely to fail GH-provocative testing.
- When GH testing is done in a child at high risk for GHD or if the growth pattern is concerning, the predictive value of GH testing is markedly improved. Assessing growth velocity over a 6-12-month period is very useful.
- Malnutrition can cause low IGF-1.
- Psychosocial deprivation mimics GHD. Such deprived patients may have low growth factors and respond poorly to GH-provocative testing.
Treatment
Medication
- Recombinant human growth hormone (rhGH) was approved by FDA for use in 1985 by SQ injection daily.
- Duration of therapy (in children and adolescents)
- Until growth velocity drops to 2.5 cm/year
- When puberty is complete
- GH-deficient adults may benefit from lifelong rhGH therapy due to its effects on body composition, lipids, bone density, and general sense of well-being.
- Before adult GH is initiated, adult patients should undergo repeat GH-provocative testing in all instances, as GH testing can normalize even with known central structural lesions.
Alert
- rhGH is associated with idiopathic intracranial hypertension (pseudotumor cerebri). This side effect is usually transient and often reverses without cessation of therapy.
- rhGH is usually not given in cancer patients until 1 year has elapsed without recurrence.
- Carefully evaluate any limp or hip or knee pain in patients on rhGH therapy because these symptoms may be associated with slipped capital femoral epiphysis (SCFE); SCFE necessitates orthopedic consultation.
Ongoing Care
Follow-up Recommendations
Every 3 months by an endocrinologist
- When to expect improvement:
- Immediate effect on hypoglycemia
- Growth velocity improves within 3-6 months
- Signs to watch for:
- Pseudotumor cerebri (headache, vision problems)
- SCFE
- Scoliosis
- In adults, edema and carpal tunnel syndrome, but uncommon in children
- The risk of malignancy is generally NOT increased in children receiving GH therapy, although there may be a small increased risk of a secondary malignancy in those already who have previously survived a malignancy.
Prognosis
Response to GH therapy is excellent in truly GH-deficient patients. Those who are not GH-deficient have a variable but generally positive growth response. The main cause of poor growth in all children receiving GH therapy, however, is noncompliance. In one national study, 66% of patients missed at least one injection per week, and this affected growth.
Complications
- Short stature
- Lack of self-esteem because of short stature
- Delay in pubertal changes (sexual characteristics and growth spurt) due to delayed bone age
- Hypoglycemia (in the newborn period)
- Osteopenia
Additional Reading
- Clayton PE, Cohen P, Tanaka T, et al. Diagnosis of growth hormone deficiency in childhood. On behalf of the Growth Hormone Research Society. Horm Res. 2000;53(Suppl 3):30. [View Abstract]
- Cutfield WS, Derraik JGB, Gunn AJ, et al. Non-compliance with growth hormone treatment in children is common and impairs linear growth. PLoS One. 2011;6(1):e16223. [View Abstract]
- Pitukcheewanont P, Desrosiers P, Steelman J, et al. Issues and trends in pediatric growth hormone therapy-an update from the GH Monitor observational registry. Pediatr Endocrinol Rev. 2008;5(Suppl 2):702-707. [View Abstract]
- Richmond E, Rogol AD. Current indications for growth hormone therapy for children and adolescents. Endocr Dev. 2010;18:92-108. [View Abstract]
- Wit JM, Kiess W, Mullis P. Genetic evaluation of short stature. Best Pract Res Clin Endocrinol Metab. 2011;25(1):1-17. [View Abstract]
Codes
ICD09
- 253.3 Pituitary dwarfism
- 759.2 Anomalies of other endocrine glands
ICD10
- E23.0 Hypopituitarism
- Q89.2 Congenital malformations of other endocrine glands
SNOMED
- 397827003 Growth hormone deficiency (disorder)
- 237688008 idiopathic growth hormone deficiency (disorder)
FAQ
- Q: Does GH improve the body composition in patients with GH deficiency?
- A: Not only is growth impressive in these patients, but there is a normalization of body composition with a loss of fat and increased muscle mass due to the lipolytic and anabolic effects of growth hormone therapy.
- Q: Will GH use cause long-term safety issues?
- A: Although a study from France suggested increased long-term mortality, several similar studies have refuted this observation. Currently, there is no credible evidence suggesting there are long-term safety issues with GH treatment.