eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Growth Hormone Deficiency

Author: Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
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Updated: Sep 15, 2008

Introduction

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. From 1958-1985, a limited supply of cadaver-derived pituitary growth hormone was used to treat 8000 children who had growth hormone deficiency in the United States. 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 who died from CJD.¹

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).

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.

In 1992, a patient was described with a mutation in a transcription factor (POUF-1, also known as PIT-1), which resulted in familial growth hormone deficiency.² 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.

Frequency

United States

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:^3,4,5

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

International

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).

Mortality/Morbidity

Mortality in children with growth hormone deficiency 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 growth hormone deficiency relates to short stature. Average adult height for untreated patients with severe isolated growth hormone deficiency is 143 cm in men and 130 cm in women. Approximately 5% of children with growth hormone deficiency also have episodes of hypoglycemia, particularly in infancy, which resolve with growth hormone therapy.
• Adults with untreated growth hormone 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.

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.^3,4,5 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.^3,4,5 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.⁶ 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 recent 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.⁷  Furthermore, Grimburg 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.⁸ 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.

Clinical

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 is recognized, recall is generally 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.

• 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. 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.⁹
  • Constitutional and many other pathological causes of short stature, including growth hormone deficiency (GHD), delayed puberty.
• Evidence of specific syndromes: Many syndromes include short stature as follows:
  • Turner syndrome
  • Noonan syndrome
  • Russell-Silver syndrome

Causes

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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