Pediatric Growth Hormone Deficiency

Updated: Dec 09, 2022
  • Author: Vaneeta Bamba, MD; Chief Editor: Robert P Hoffman, MD  more...
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Overview

Practice Essentials

Presentation

History

The history in patients with suspected growth hormone deficiency (GHD) 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

Timing of puberty in parents

Previous growth points

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:

Height and weight measurement

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.

Although weight is not difficult to determine, height measurement requires care.

Proportionality: Inspect the child for proportionality of limbs and trunk.

Pubertal status

Evidence of specific syndromes: Many syndromes include short stature as follows:

Turner syndrome

Noonan syndrome

Russell-Silver syndrome

Workup

Laboratory Studies

Laboratory studies in growth hormone deficiency (GHD) include the following:

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 count and sedimentation rate: These studies may be helpful if inflammatory bowel disease is suspected.

Insulinlike growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3)

Karyotype

Celiac panel: Celiac disease may present with growth failure without specific GI complaints

Imaging Studies

Bone age: Radiograph of left hand and wrist is compared to standards and can be used to estimate skeletal maturation.

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

Other Tests

Growth hormone response to insulin is the most reliable test for growth hormone deficiency.

Management

Medical Care

The current practice is a subcutaneous injection of growth hormone and daily administration is now commonly used. Long acting agents are currently still in the investigative phases. 

Although growth hormone is normally secreted in multiple peaks during the day and mostly at night, a single daily injection of recombinant growth hormone can provide physiologic replacement. In order for growth hormone replacement to be effective, other pituitary deficiencies should be treated. Response to growth hormone therapy is measured (every 3-6 mo) by sequential height determinations and by occasional bone age determinations.

See PresentationWorkup, Treatment and Medication for more detail.

Patient education

Instruct patients and families regarding subcutaneous injection technique.

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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 growth hormone deficiency, although such a diagnosis was not recognized until the early 1900s.

In the 1950s, growth hormone isolated from the pituitaries of humans and anthropoid apes was discovered to stimulate growth in children who had growth hormone deficiency. In the United States, human-derived growth hormone was produced and distributed by the National Institute of Health's (NIH’s) National Pituitary Agency. From 1958-1985, a limited supply of this cadaver-derived pituitary growth hormone was used to treat 8000 children who had growth hormone deficiency in the United States. The preparation was in short supply, resulting in lower-than-ideal dosing and frequent drug holidays. Potential recipients were required to participate in a research protocol; in order to ration the cadaveric growth hormone, the diagnosis of growth hormone deficiency required that the patient have a specific peak growth hormone level in response to provocative stimuli. This requirement gradually increased in response to a better supply of cadaveric growth hormone, starting at 5 ng/mL, then 7 ng/mL, and finally 10 ng/mL in the early 1980s.

In 1985, these preparations of cadaver-derived pituitary growth hormone were implicated in several cases of Creutzfeldt-Jakob disease (CJD), and the Food and Drug Administration (FDA) ceased distribution of the cadaver-derived growth hormone. In an analysis of patients treated with cadaver-derived growth hormone, Mills et al have reported 26 subjects in the United States who died from CJD out of 7700 who had received cadaver-derived growth hormone. [1] As of 2013, there have been 29 cases reported in the United States and 226 deaths associated with cadaveric growth hormone worldwide. [2]

Since 1985, recombinant DNA–produced human growth hormone has assured a safe and unlimited supply for uninterrupted therapy at doses adequate to restore normal growth. Growth hormone deficiency may be isolated (isolated growth hormone deficiency) or associated with other pituitary deficiencies. Multiple pituitary hormone deficiency involving growth hormone deficiency 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).

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Pathophysiology

Pituitary growth hormone secretion is stimulated by growth hormone–releasing hormone (GHRH) from the hypothalamus and possibly by another signal, which may be stimulated by certain growth hormone–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 growth hormone secretion. When growth hormone pulses are secreted into the systemic circulation, insulinlike growth factor 1 (IGF-1) is released, either locally or at the site of growing bone. Growth hormone binds to a specific growth hormone–binding protein (GHBP) and circulates. This GHBP is the extracellular portion of the growth hormone 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 directly depends on growth hormone.

Growth hormone deficiency may result from disruption of the growth hormone axis in the higher brain, hypothalamus, or pituitary. This dysfunction can be congenital or acquired.

A mutation in a transcription factor (POUF-1, also known as PIT-1) is known to result in familial growth hormone deficiency. [3] As many as 14 different mutations have been described. In addition to growth hormone deficiency, affected individuals have had prolactin deficiencies and variable thyroid-stimulating hormone (TSH) deficiencies. Imaging of the pituitary gland usually reveals a hypoplastic or ectopic posterior pituitary.

Growth hormone deficiency 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 luteinizing hormone (LH) or follicle-stimulating hormone (FSH), and thus, do not spontaneously progress into puberty. 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 growth hormone deficiency 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 growth hormone deficiency 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). Although most instances of isolated growth hormone deficiency are idiopathic, specific etiologies cause most growth hormone deficiency associated with other pituitary deficiencies. A reported 12-86% of children with apparent isolated growth hormone deficiency have sellar developmental defects.

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Etiology

Most instances of growth hormone deficiency are idiopathic. Other causes include the following:

  • Organic causes

    • Brain tumors, especially craniopharyngioma

    • CNS surgery

    • CNS radiation

    • Anatomical abnormalities (eg, septooptic dysplasia, empty sella syndrome signified by ectopic bright spot on MRI)

  • Genetic causes

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Epidemiology

United States statistics

A study of 80,000 children in Salt Lake City, Utah, reported that 555 children were below the third height percentile and had growth rates less than 5 cm/y; of these children, 33 had growth hormone deficiency, an incidence rate of 1 case per 3,500 children. Of more than 20,000 children receiving growth hormone in the National Cooperative Growth Study (a database of patients receiving growth hormone therapy), approximately 25% of the patients with growth hormone deficiency had an organic etiology. These etiologies included the following [4, 5, 6] :

  • CNS tumor, including craniopharyngioma - 47%

  • CNS malformation - 15%

  • SOD - 14%

  • Leukemia - 9%

  • CNS radiation - 9%

  • CNS trauma - 3%

  • Histiocytosis - 2%

  • CNS infection - 1%

International statistics

Frequency of isolated growth hormone deficiency 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, United Kingdom (a probable underestimate due to its reliance on referral rates to a growth clinic).

Race-, sex-, and age-related demographics

Race

Although no racial difference in the incidence of growth hormone deficiency is apparent, the rate at which patients receive growth hormone therapy appears to differ by race. Among nearly 9000 patients with idiopathic growth hormone deficiency in a large North American database of patients treated with growth hormone, 85% were White, only 6% were Black, and 2% were of Asian descent. [4, 5, 6] An almost identical distribution is seen for patients with organic growth hormone deficiency. 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 growth hormone deficiency in the National Cooperative Growth Study is 73% male and 27% female. [4, 5, 6] Among patients with organic growth hormone deficiency, in which no sex difference should be present, the ratio is 62% male to 38% female.

When growth hormone deficiency is diagnosed as part of SOD, 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 result in diagnosis (eg, in patients with SOD). However, close examination of the Utah study data reveals 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/y. [7] Furthermore, the group diagnosed with growth hormone deficiency 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.

However, several studies have tried to determine the point at which gender bias is introduced. Cuttler et al published results of a survey of pediatric endocrinologists that growth hormone treatment was 1.3 times more common in boys than in girls. [8] Furthermore, Grimberg et al examined a large worldwide database of children treated with growth hormone and found a male predominance of treated patients in Asia, the United States, Europe, Australia, and New Zealand, but not in the rest of the world. [9] These authors speculate that the bias may be introduced by parents and referring physicians and is a reflection of the culture in those countries in which the bias is observed.

Age

Although most cases of idiopathic growth hormone deficiency are thought present at birth, diagnosis is often delayed until concern is raised about short stature. Diagnosis of growth hormone deficiency 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 is probably compared with 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 growth hormone deficiency. Children with growth hormone deficiency may seem to grow at a slower rate than their peers because their peers are in the midst of the pubertal growth spurt, whereas children with growth hormone have not yet entered this phase.

Growth hormone deficiency is a congenital disease no matter when height deficit becomes clinically evident; children with growth hormone deficiency grow in disease-specific percentile channels, with a highly significantly reduced length and weight. This reveals that growth hormone is essential for adequate growth in infancy and early childhood. [10]

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Prognosis

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

Morbidity/mortality

Mortality in children with growth hormone (GH) deficiency is due almost entirely to other pituitary hormone deficiencies. [1]  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 GH deficiency relates to short stature. Average adult height for untreated patients with severe isolated GH deficiency is 143 cm in men and 130 cm in women. Approximately 5% of children with GH deficiency also have episodes of hypoglycemia, particularly in infancy, which resolve with GH therapy.

Overall, GH has been shown to be a safe hormone when used at recommended doses. There are excellent large databases for evaluation of possible safety signals that occur during treatment with GH. GH adverse events have been carefully documented in a review by Krysiak R et al. Most adverse events have been local injection site reactions, which rarely lead to discontinuation. Headache, nausea, and fever have been generally self-limiting and are well tolerated. Adverse events such as edema or carpal tunnel syndrome are seen more often in adults than children, and they may be the result of fluid retention caused by GH. Adverse events seen particularly in children have included transient idiopathic intracranial hypertension (also known as pseudotumor cerebri), gynecomastia, and slipped capital femoral epiphysis. The idiopathic intracranial hypertension resolved after discontinuation of GH and restarting at a low dose.

There have been concerns about cancer associated with GH administration, and these concerns have stemmed from several observations. First, acromegaly (a condition of GH excess) is known to increase the risk of colorectal cancer. Second, epidemiological studies have shown a relationship between tall statue and cancer risk, between insulinlike growth factor I (IGF-I) levels and the risk of prostate cancer, and an increase in breast cancer associated with levels of free IGF-I. One study has suggested that there may be reason for concern because of cases of Hodgkin disease and colorectal cancer found in long-term follow up of patients who had received human-derived GH. Although the incidence of these diseases was greater than the population at large, it was not outside the confidence ranges.

Further, follow up of patients receiving human-derived GH in the United States has not shown such a correlation. There has been recent concern from analysis of data in French children who were treated with GH between 1985 and 1996, and then followed until 1996 (the SAGhE study). [11]  A retrospective analysis of mortality in this population suggests the possibility of increased cardiovascular disease and bone tumors in adults who received GH as children. The cardiovascular disease was primarily attributed to subarachnoid or intracerebral hemorrhages. Overall cancer mortality rates were not higher than the general population, but bone tumor–related deaths were 5 times higher than expected. There appeared to be a dose relationship (risk was highest in patients receiving doses >50 mcg/d).

The study is flawed by not having a control group (data from those who took GH as children were compared to the population at large, which may not be an appropriate comparison). In addition, there was no apparent relationship with duration of GH therapy, which one would expect if the increase in mortality was actually related GH therapy, suggesting that the increase in mortality in this group could be more likely related to the reason they were short and taking GH, rather than an effect of the GH itself.

Similar data from Sweden, The Netherlands, and Belgium [12]  have shown no increase in mortality rates, and all of the deaths were attributable to accidents or suicide, further suggesting that the French data could be misleading. Clearly, what is most needed is long-term adult follow up of those patients who received GH as children

Adults with untreated GH deficiency 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.

Complications

Although few patients experience adverse events from growth hormone therapy, the following complications have been recognized:

  • Carbohydrate metabolism: Growth hormone has an anti-insulin effect, and carbohydrate metabolism has been monitored in many clinical studies of growth hormone therapy. A review of large databases containing more than 35,000 patients on growth hormone 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. One study of an increased incidence of type 2 diabetes in children undergoing growth hormone therapy with risk factors for diabetes suggests that growth hormone may cause earlier expression of this condition.

  • Benign intracranial hypertension (pseudotumor cerebri): A clear association between intracranial hypertension and growth hormone therapy is observed. The incidence appears to be about 0.001 (21 cases reported out of 19,000 patients receiving growth hormone, 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 growth hormone for chronic renal insufficiency. In most cases, cessation of growth hormone therapy resolved the intracranial hypertension; the growth hormone then could be restarted at a lower dose and slowly titrated back to the usual dose.

  • Fluid homeostasis: Growth hormone affects fluid homeostasis, which may lead to edema and even carpal tunnel syndrome. These problems are more common in adults receiving growth hormone. When these occurrences become sufficiently serious to require action, stopping the growth hormone provides resolution. Restarting the growth hormone at a lower dose and slowly titrating it back to the usual dose is usually possible.

  • Skeletal and joint problems: Children receiving growth hormone therapy are more susceptible to slipped capital femoral epiphysis (SCFE). Yet children with growth hormone deficiency (GHD), hypothyroidism, or renal disease seem to have increased risk for SCFE, even without growth hormone therapy. When a child receiving growth hormone therapy complains of hip or knee pain, a careful physical examination is vital, and, if warranted, hip radiography. Scoliosis progression is another skeletal-related complication of growth hormone therapy. Scoliosis relates to the rapid growth that occurs with therapy and is not a direct effect of the growth hormone. Patients with scoliosis who are treated with growth hormone 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 growth hormone therapy, although whether the gynecomastia is related to the growth hormone 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 growth hormone 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 suggests an association between growth hormone therapy and leukemia in otherwise healthy children.

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