AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Many European paintings, particularly those of the Spanish Court, portray people with extremely short stature who may have had growth hormone deficiency (GHD). During the 1800s, General Tom Thumb and his wife, Lavinia Warren, exploited their short stature as part of the Barnum and Bailey Circus. The couple may have had GHD, although such a diagnosis was not recognized until the early 1900s.

In the 1950s, growth hormone (GH) isolated from the pituitaries of humans and anthropoid apes was discovered to stimulate growth in children who had GHD. From 1958-1985, a limited supply of cadaver-derived pituitary GH was used to treat 8000 children who had GHD in the US. In 1985, these preparations of cadaver-derived pituitary GH were implicated in several cases of Creutzfeldt-Jakob disease (CJD), and the Food and Drug Administration (FDA) ceased distribution of the cadaver-derived GH. In an analysis of patients treated with cadaver-derived GH, Mills et al have reported 26 subjects who died from Creutzfeldt-Jacob disease.

Since 1985, recombinant–deoxyribonucleic acid (DNA)-produced human GH has assured a safe and unlimited supply for uninterrupted therapy at doses adequate to restore normal growth. GHD may be isolated (isolated GHD) or associated with other pituitary deficiencies. Multiple pituitary hormone deficiency involving GHD is caused by genetic defects in pituitary stem cells or by anatomic problems that may be congenital or acquired (eg, from tumor, trauma, radiation, infection).

Pathophysiology

Pituitary GH secretion is stimulated by GH-releasing hormone (GHRH) from the hypothalamus and possibly by another signal, which may be stimulated by certain GH-releasing peptides (GHRPs). Receptors for the GHRPs have been identified, and the natural ligand for these receptors has been determined to be ghrelin. Somatostatin secreted by the hypothalamus inhibits GH secretion. When GH pulses are secreted into the systemic circulation, insulinlike growth factor 1 (IGF-1) is released, either locally or at the site of growing bone. GH binds to a specific GH-binding protein (GHBP) and circulates. This GHBP is the extracellular portion of the GH receptor. IGF-1 binds to one of several IGF-binding proteins (IGFBPs) and circulates almost entirely (>99%) in the bound state. IGFBP-3 accounts for most of the IGF-I binding and this binding protein depends directly on GH.

GHD may result from disruption of the GH axis in the higher brain, hypothalamus, or pituitary. This dysfunction can be congenital or acquired.

In 1992, a patient was described with a mutation in a transcription factor (POUF-1, also known as PIT-1), which resulted in familial GHD. As many as 14 different mutations have been described. In addition to GHD, affected individuals have had prolactin deficiencies and variable TSH deficiencies. Imaging of the pituitary gland usually shows a hypoplastic or ectopic posterior pituitary.

GHD with other hypopituitarism associated with inactivating mutations of the PROP1 (Prophet of PIT-1) transcription factor gene have been documented in reports. Patients with this mutation usually do not produce LH or FSH, and thus, do not progress into puberty spontaneously. They may also have TSH deficiency. Imaging of the pituitary gland of patients with PROP1 mutations may show either a small anterior pituitary or an intrapituitary mass.

Congenital GHD may be associated with an abnormal pituitary gland (seen on MRI) or may be part of a syndrome such as septooptic dysplasia (SOD) (de Morsier syndrome), which may include other pituitary deficiencies, optic nerve hypoplasia, and absence of the septum pellucidum; it occurs with an incidence of about 1 in 50,000 births. SOD may be associated with a mutation in the gene for another transcription factor, HESX1.

Acquired GHD may result from trauma, infections (eg, encephalitis, meningitis), cranial irradiation (somatotrophs appear to be the most radiation-sensitive cells in the pituitary), and other systemic diseases (particularly histiocytosis). While most instances of isolated GHD are idiopathic, specific etiologies cause most GHD associated with other pituitary deficiencies. A reported 12-86% of children with apparent isolated GHD have sellar developmental defects.

Frequency

United States

A study of 80,000 Salt Lake City, Utah, school children reported 555 children were below the third height percentile and had growth rates less than 5 cm/year; of these children, 33 had GHD, an incidence rate of 1 case per 3,500 children. Of more than 20,000 children receiving GH in the National Cooperative Growth Study (a database of patients receiving GH therapy), approximately 25% of the GH-deficient patients had an organic etiology. These etiologies included the following:

• CNS tumor, including craniopharyngioma - 47%
• CNS malformation - 15%
• Septooptic dysplasia - 14%
• Leukemia - 9%
• CNS radiation - 9%
• CNS trauma - 3%
• Histiocytosis - 2%
• CNS infection - 1%

International

Frequency of isolated GHD has been reported to range from 1 case per 1,800 children in Sri Lanka (a probable overestimate due to liberal diagnostic criteria) to 1 case per 30,000 children in Newcastle, UK (a probable underestimate due to its reliance on referral rates to a growth clinic).

Mortality/Morbidity

Mortality in children with GHD is due almost entirely to other pituitary hormone deficiencies. These children have an increased relative risk of death in adulthood from cardiovascular causes resulting from altered body composition and dyslipidemia.

• Most morbidity in children with GHD relates to short stature. Average adult height for untreated patients with severe isolated GHD is 143 cm in men and 130 cm in women. Approximately 5% of children with GHD also have episodes of hypoglycemia, particularly in infancy, which resolve with GH therapy.
• Adults with untreated GHD have altered body composition (eg, excess body fat, lower lean body mass), decreased bone mineralization, cardiovascular risk factors (in particular, altered blood lipids), and decreased exercise tolerance. In addition, these patients may be socially isolated.

Race

Although no racial difference in the incidence of GHD is apparent, the rate at which patients receive GH therapy appears to differ by race. Among nearly 9000 patients with idiopathic GHD in a large North American database of GH-treated patients, 85% are white, only 6% are black, and 2% are of Asian descent. An almost identical distribution is seen for patients with organic GHD. The racial difference may reflect a possible ascertainment bias, a notion supported by the observation that patients from other racial groups are shorter than their white counterparts at diagnosis.

Sex

The sex distribution of patients with idiopathic GHD in the National Cooperative Growth Study is 73% male and 27% female. Among patients with organic GHD, in which no sex difference should be present, the ratio is 62% male to 38% female.

When GHD is diagnosed as part of septooptic dysplasia, sex distribution is nearly equal (male-to-female ratio is 1.3:1). Referral bias may explain this distribution (ie, greater concern for short stature in boys). This referral bias is absent when reasons other than stature exist for making the diagnosis, eg, in patients with septooptic dysplasia. However, close examination of the Utah study data shows twice the number of boys than girls in the group with heights less than the third height percentile and with growth rates less than 5 cm/year. Further, the group diagnosed with GHD had about 3 times the number of boys as girls. Given the approximately equal number of boys and girls in the Utah school system, the observed difference may not be due to referral bias.

Age

Although most cases of idiopathic GHD are thought present at birth, diagnosis often is delayed until concern is raised about short stature. Diagnosis of GHD is made during 2 broad age peaks. The first age peak occurs at 5 years, a time when children begin school and the height of short children probably is compared to that of their peers. The second age peak occurs in girls aged 10-13 years and boys aged 12-16 years. This second peak possibly relates to the delay in puberty associated with GHD. Children with GHD may seem to grow at a slower rate than their peers, because their peers are in the midst of the pubertal growth spurt, while children with GHD have not yet entered this phase.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Short stature history should focus on the following issues:

• Birth weight and length: Intrauterine growth retardation is an issue in the differential diagnosis and should be apparent from the birth history.
• Height of parents
• • Calculation of the sex-adjusted midparental height, also termed the "target height," helps evaluate a child's genetic potential.
  • For boys, calculate the sex-adjusted midparental height by adding 2.5 in or 6.5 cm from the mean of the parents' heights. For girls, subtract 2.5 in or 6.5 cm from the mean of the parents' heights.
  • This sex-adjusted midparental height represents the statistically most probable adult height for the child, based on parental contribution.
• Timing of puberty in parents
• • Constitutional delay in growth and maturation may have a family history. Most mothers can remember their age at menarche (average age is 12-12.5 y).
  • Although pubertal age is more difficult to establish for fathers because no precise landmark exists, recall generally is good for development later than other boys, for always looking younger than peers, for continuing to grow after high school, and for delayed beard appearance.
• Previous growth points
• • The child's growth pattern is an important part of the workup for short stature. Previous growth data may be obtained from physicians' offices, schools, or heights plotted on a door at home.
  • If the growth rate is normal (about 2 in/y [5 cm/y] from age 3 y to puberty), the child's short stature most likely is caused by a normal variant, such as familial short stature or constitutional delay in growth and maturation. If the growth rate is slow, a pathological cause for short stature is more likely.
• General health of child: Exclusion of chronic disease as the cause of short stature is imperative.
• Nutritional history: Malnutrition is the most common cause of short stature worldwide.

Physical

The following items should be targeted in a workup of short stature.

• Accurately measure and record height and weight.
• • The best way to evaluate height or weight measurements is to plot the points on a growth chart. A growth chart depicts the child's growth over time, allows comparison of the height or weight to other children, and graphically depicts changes in growth or growth velocity.
  • While weight is not difficult to determine, height measurement requires care. The following points help provide accurate measurements:
    • Children should be either barefoot or in stocking feet upon measurement. The heels, buttocks, and shoulders should be in contact with the wall or the measuring device.
    • Have the child stand with feet slightly spread but with heels together.
    • Instruct the child to look straight ahead. This positions the head in the Frankfort horizontal plane (ie, the plane represented in the profile by a line between the lowest point on the margin of the orbit and the highest point on the margin of the auditory meatus).
    • Instruct the child to hold a deep breath at the time of measurement.
    • Use proper equipment. The ideal device for height measurement is a wall-mounted stadiometer with an arm that moves vertically. The arm is placed on the head; the height can be read from a counter or from a ruler on the wall. If a stadiometer is unavailable, good height measurements may be obtained from a yardstick (or meterstick) attached to the wall, combined with a device creating a right angle with the wall and the child's head. Floppy-arm devices mounted on weight scales are inherently inaccurate and frequently yield poor measurements. A child's height can be determined using this device, but accurate measurement requires even more attention.
    • For precise height determinations, measure the child 2-3 times and calculate the mean. If the first 2 measurements agree, consider them accurate.
    • Measure the child at the same time of day to minimize diurnal variation in height.
• Proportionality: Inspect the child for proportionality of limbs and trunk. The following measurements may be taken if disproportionality is suspected:
• • Arm span: Measure outstretched arms from fingertip to fingertip. The arm span should approximate the height, although this depends on genetic background. In comparisons of people of Asian, European, and African heritage, Asians have proportionally shorter arms, Europeans have intermediate arm length, and Africans have significantly longer arms.
  • Lower segment (LS): Measure from the symphysis pubis to the floor.
  • Upper segment (US): Calculate by subtracting the lower segment measurement from the height.
  • US/LS ratio: Calculate by dividing US by LS. For people of European origin, the US/LS ratio at birth is approximately 1.7:1 and decreases to 1:1 at age 10 years, a ratio that lasts throughout adulthood. In comparisons of people of Asian, European, and African heritage, Asians have proportionally shorter legs (and therefore larger US/LS ratios), Europeans have intermediate length legs, and Africans have significantly longer legs.
• Pubertal status
• • Calculate stage of puberty using the Tanner staging system (see Bibliography).
  • Constitutional and many other pathological causes of short stature, including GHD, delay puberty.
• Evidence of specific syndromes: Many syndromes include short stature as follows:
• • Turner syndrome
  • Noonan syndrome
  • Russell-Silver syndrome

Causes

• Most instances of GHD are idiopathic.
• Organic
• • Brain tumors, especially craniopharyngioma
  • CNS surgery
  • CNS radiation
  • Anatomical abnormalities (eg, septooptic dysplasia, empty sella syndrome signified by ectopic bright spot on MRI)
• Genetic GHD

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Familial (genetic) short stature
Constitutional delay of growth
Short stature accompanying systemic disease
Short stature as part of a genetic syndrome
Short stature related to endocrinopathy (eg, hypothyroidism, Cushing syndrome)
Short stature related to a metabolic abnormality (ie, renal tubular acidosis, poorly controlled diabetes mellitus)
Short stature from abuse and neglect

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Thyroxine and thyroid-stimulating hormone: Hypothyroidism should be excluded as a cause of growth failure and short stature.
• Serum electrolytes: A low bicarbonate level may indicate renal tubular acidosis, which can result in growth failure. Abnormal electrolytes may indicate renal failure.
• CBC and sedimentation rate: These studies may be helpful if inflammatory bowel disease is suspected.
• IGF-1 and IGFBP-3
• • Both IGF-1 and IGFBP-3 are GH-dependent.
  • Low values of IGF-1 and IGFBP-3 suggest GHD. A low value alone is not diagnostic, however, because IGFs are sensitive to other factors such as nutritional state and chronic systemic disease.
• Karyotype
• • Girls with otherwise unexplained short stature should have a karyotype study to rule out Turner syndrome.
  • Although many girls with Turner syndrome are diagnosed from signs on physical examination, the only recognizable feature of many girls with the condition is short stature.
  • In particular, girls with mosaic karyotypes or karyotypes with isochromosomes tend to exhibit fewer signs specific to Turner syndrome.
  • Many girls with Turner syndrome, and particularly those with mosaic karyotypes and karyotypes other than 45,X, do not demonstrate the striking stigmata associated with Turner syndrome.

Imaging Studies

• MRI of the head
• • Patients diagnosed with GHD should undergo an MRI of the head to exclude a brain tumor (eg, craniopharyngioma).
  • Approximately 15% of patients with GHD have an abnormality of the pituitary gland (eg, ectopic bright spot, empty or small sella).

Other Tests

• Bone age determination
• • Comparison of a left hand and wrist radiograph to standards can be used to estimate skeletal maturation.
  • With familial short stature, bone age is comparable to chronological age. Bone age usually is delayed in children with constitutional growth delay, malnutrition, and endocrine causes of short stature (eg, hypothyroidism, cortisol excess, GHD).
  • Bone age also allows determination of growth potential as adult stature may be estimated from the Bayley-Pinneau tables.
• GH provocative testing
• • GH response to insulin is the most reliable test for GHD.
  • Before accepting GHD diagnosis, many insurance companies require a documented failure to demonstrate a GH response (with a GH level >10 ng/mL) after presentation of 2 provocative stimuli.
  • Provocative stimuli include insulin-induced hypoglycemia, arginine, levodopa (L-dopa), clonidine, and glucagon.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Although GH normally is secreted in multiple peaks during the day and mostly at night, a single daily injection of recombinant GH can provide physiologic replacement. In order for GH replacement to be effective, other pituitary deficiencies should be treated. Response to GH therapy is measured (q3-6mo) by sequential height determinations and by occasional bone age determinations.

Consultations

Pediatric endocrinologists see almost all children with GHD.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

GH replacement is used to treat GHD.

Drug Category: Growth hormones

Used for physiologic replacement.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Most pediatric endocrinologists see patients receiving GH therapy 2-4 times per year.
• • The most important reasons for follow-up are to monitor growth progress and to adjust GH dosage. Growth rate usually increases most during the first year of treatment, with an average increase of 8-10 cm/year (often called "catch-up" growth). Progressive growth slows over the next several years (ie, waning effect). A growth rate appearing to slow more than expected should prompt investigation for a medical cause (eg, hypothyroidism) or another diagnosis (eg, inflammatory bowel disease).
  • Follow-up also may be needed to assure patient compliance with the GH injections.

Complications

• Although few patients experience adverse events from GH therapy, the following complications have been recognized:
• • Carbohydrate metabolism: GH has an anti-insulin effect, and carbohydrate metabolism has been monitored in many clinical studies of GH therapy. A review of large databases containing more than 35,000 patients on GH and more than 75,000 patients with years of exposure indicates no greater incidence of type 1 diabetes than would be expected in the general population of age-matched children. A recent study of an increased incidence of type 2 diabetes in children undergoing GH therapy with risk factors for diabetes suggests that GH may cause earlier expression of this condition.
  • Benign intracranial hypertension (pseudotumor cerebri): A clear association exists between intracranial hypertension and GH therapy. The incidence appears to be about 0.001 (21 cases reported out of 19,000 patients receiving GH, or 50,000 patient-years). Usually, severe headache symptoms (occasionally with vomiting) develop during the first 4 months of therapy. The risk of this complication increased in children receiving GH for chronic renal insufficiency. In most cases, cessation of GH therapy resolved the intracranial hypertension; the GH then could be restarted at a lower dose and titrated slowly back to the usual dose.
  • Fluid homeostasis: GH affects fluid homeostasis, which may lead to edema and even carpal tunnel syndrome. These problems are more common in adults receiving GH. When these occurrences become sufficiently serious to require action, stopping the GH provides resolution. Restarting the GH at a lower dose and titrating it slowly back to the usual dose usually is possible.
  • Skeletal and joint problems: Children receiving GH therapy are more susceptible to slipped capital femoral epiphysis (SCFE). Yet children with GHD, hypothyroidism, or renal disease seem to have increased risk for SCFE, even without GH therapy. When a child receiving GH therapy complains of hip or knee pain, a careful physical examination is vital, and, if warranted, a hip X-ray study. Scoliosis progression is another skeletal-related complication of GH therapy. Scoliosis relates to the rapid growth that occurs with therapy and is not a direct effect of the GH. Patients with scoliosis who are treated with GH should have their scoliosis monitored during therapy.
  • Prepubertal gynecomastia: Although adolescent gynecomastia is common, prepubertal gynecomastia occurs less frequently. Such cases have been reported in association with GH therapy, although whether the gynecomastia is related to the GH is unclear. Prepubertal gynecomastia is a benign condition that resolves without sequelae.
  • Leukemia: Several worldwide databases have been examined in response to sporadic reports of leukemia in patients undergoing GH therapy. When patients with other risk factors (eg, previous history of leukemia, radiation, chemotherapy) are excluded, no increased risk of leukemia has been demonstrated. No evidence exists of an association between GH therapy and leukemia in otherwise healthy children.

Prognosis

• Since recombinant–DNA-derived GH became available, most children with GHD reach normal adult stature. Duration of therapy has the most consistent correlation with growth response to GH. Initiate GH therapy as early as possible and continue therapy through adolescence to ensure the best chance of achieving height potential.

Patient Education

• Instruct patients and/or their families in SC injection technique.
• For excellent patient education resources, visit eMedicine's Growth Hormone Deficiency Center. Also, see eMedicine's patient education articles Growth Hormone Deficiency, Growth Hormone Deficiency in Children, Understanding Growth Hormone Deficiency Medications, and Growth Hormone Deficiency FAQs.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize a CNS tumor (eg, craniopharyngioma) as the cause of GHD.
• Failure to diagnose other pituitary deficiencies in addition to GH.
• Failure to recognize slipped caput femoral epiphysis, either before or after initiating GH replacement therapy.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Blethen SL, Compton P, Lippe BM. Factors predicting the response to growth hormone (GH) therapy in prepubertal children with GH deficiency. J Clin Endocrinol Metab. Mar 1993;76(3):574-9. [Medline].
• Blethen SL, Allen DB, Graves D. Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J Clin Endocrinol Metab. May 1996;81(5):1704-10. [Medline].
• Cheng JC, Leung SS, Lau J. Anthropometric measurements and body proportions among Chinese children. Clin Orthop. Feb 1996;(323):22-30. [Medline].
• Frasier SD, Costin G, Lippe BM. A dose-response curve for human growth hormone. J Clin Endocrinol Metab. Dec 1981;53(6):1213-7. [Medline].
• Frasier SD. A preview of growth hormone stimulation tests in children. Pediatrics. Jun 1974;53(6):929-37. [Medline].
• Frindik JP, Kemp SF, Pihoker C. Effective use of magnetic resonance imaging in the assessment of children with possible growth hormone deficiency. Endocrine Practice. 1996;2:8-12.
• Frindik JP, Baptista J. Adult height in growth hormone deficiency: historical perspective and examples from the national cooperative growth study. Pediatrics. Oct 1999;104(4 Pt 2):1000-4. [Medline].
• Hintz RL. The prismatic case of Creutzfeldt-Jakob disease associated with pituitary growth hormone treatment. J Clin Endocrinol Metab. Aug 1995;80(8):2298-301. [Medline].
• Kemp SF. Growth hormone therapeutic practice: dosing issues. The Endocrinologist. 1996;6:231-7.
• Lindsay R, Feldkamp M, Harris D. Utah Growth Study: growth standards and the prevalence of growth hormone deficiency. J Pediatr. Jul 1994;125(1):29-35. [Medline].
• Mills JL, Schonberger LB, Wysowski DK. Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients. J Pediatr. Apr 2004;144(4):430-6. [Medline].
• Rabin MS. Treatment of a pituitary dwarf with human growth hormone. J Clin Endrocrinol Metab. 1958;18:901-3.
• Rainbow LA, Rees SA, Shaikh MG. Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia. Clin Endocrinol (Oxf). Feb 2005;62(2):163-8. [Medline].
• Reiter EO, Martha PM Jr. Pharmacological testing of growth hormone secretion. Horm Res. 1990;33(2-4):121-6; discussion 126-7. [Medline].
• Root AW, Kemp SF, Rundle AC. Effect of long-term recombinant growth hormone therapy in children--the National Cooperative Growth Study. J Pediatr Endocrinol Metab. 1998;11:403-12.
• Rosenbloom AL, Knuth C, Shulman D. Growth hormone therapy by daily injection in patients previously treated for growth hormone deficiency. South Med J. 1980;83:653-5.
• Rosenfeld RG, Albertsson-Wikland K, Cassorla F. Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited. J Clin Endocrinol Metab. May 1995;80(5):1532-40. [Medline].
• Rosenfeld RG, Wilson DM, Lee PD. Insulin-like growth factors I and II in evaluation of growth retardation. J Pediatr. Sep 1986;109(3):428-33. [Medline].
• Siklar Z, Tuna C, Dallar Y, Tanyer G. Zinc deficiency: a contributing factor of short stature in growth hormone deficient children. J Trop Pediatr. Jun 2003;49(3):187-8. [Medline].
• Tanner JM, Whitehouse RH, Hughes PC. Effect of human growth hormone treatment for 1 to 7 years on growth of 100 children, with growth hormone deficiency, low birthweight, inherited smallness, Turner''s syndrome, and other complaints. Arch Dis Child. Dec 1971;46(250):745-82. [Medline].

Article Last Updated: Apr 19, 2006