Short Stature: Endocrine Causes

Evaluation of the child with short stature

Definition

A child who is 2 standard deviations (SD) or more below the mean height for children of that sex and chronological age (and ideally of the same racial-ethnic group) is said to have short stature. A single measurement of height is much less reliable in assessing growth than is the trend over a period of time; the key finding is slowed growth that progressively deviates from a previously defined growth channel (or percentile) even if within 2 SD of the mean.

Linear growth measurements must be made with an appropriate apparatus and these measurements (along with those of weight and head circumference) plotted accurately on the appropriate growth chart (see detailed information on growth charts later in this text).

This topic will emphasize the presentation of and diagnostic approach to children with short stature.

Growth Charts

In a child with a growth disorder, examination of his or her growth pattern over time can provide important clues to the correct diagnosis. Accurate measurements, using age- and sex-specific growth charts, are mandatory to make sure that the child is growing at an appropriate rate. Care must be taken to plot the stature and weight based on the child’s actual chronological age (to the month). Length should be measured in infants until 2 years of age and standing height thereafter if possible (height being slightly less than length at any given time).

Height should be measured using a wall-mounted stadiometer while making sure that the child is shoeless, standing up straight, with his/her feet together and looking directly forward with the eyes and pinnae along the Frankfurt (auriculo-orbital) plane. Infant length should be measured from the crown of the head to the outstretched heel on a firm platform with a fixed head-plate, a moveable footplate, and a mounted ruler. Clinicians in the US historically have used growth charts provided by the Centers for Disease Control and Prevention (CDC).

The CDC growth charts represent a “growth reference” that shows how a large cross-section of US infants actually grew between 1970 and the early 1990s. They were based on data from infants whose feeding approximated the mix of practices of that time: ~50% were never breast-fed and ~33% were breast-fed to 3 months.

In April 2006, the World Health Organization (WHO) released new international growth charts for children aged 0 to 59 months. Similar to the 2000 CDC growth charts, these charts describe weight for age, length (or stature) for age, weight for length (or stature), and body mass index (BMI) for age. The measurements from birth to 2 years were accrued from 882 infants of high socio-economic status from multiple sites around the world who were exclusively/predominantly breast-fed for at least 4 months and who continued breast-feeding for at least 12 months. These infants were measured 21 times over 24 months.

These new charts, therefore, show how predominantly breast-fed infants “should grow” under ideal conditions and are considered growth standards. The 2006 WHO international growth charts, rather than the CDC growth charts, are thus recommended for children (in the US) <24 months of age. In the US, the CDC growth charts should continue to be used for the assessment of growth in children aged 2 to 19 years. The CDC and WHO growth charts are available at http://www.cdc.gov/growthcharts.

Premature infants should have their growth plotted on charts designed to account for their gestational age (i.e., until 24 months for weight, 40 months for length, and 18 months for head circumference). Disease-specific growth charts should be used, when available, for syndromic short stature to compare growth with data from other children with the same disorder (e.g., trisomy 21 [Down syndrome], Turner syndrome, Noonan syndrome, achondroplasia, etc.).

Normal Variants

Familial (genetic) short stature and constitutional short stature are common variations of normal growth. Children with familial short stature have a normal growth rate within their mid-parental target height (MPTH) range (see below), do not have bone age delay, puberty and the pubertal growth spurt occur at a normal age, and adult height is appropriate for the MPTH range. Constitutional delay of growth is suggested by deceleration of length/height in the first 3 years of life, a normal or near-normal height velocity during childhood (2-3 inches/year), significantly delayed bone age and pubertal development, and adult height within or slightly below the MPTH range.

Constitutional delay of growth is often familial (~50% of the time). Careful questioning of the parents about their childhood growth and pubertal patterns can be helpful. With familial as well as constitutional short stature, reassurance is often all that is needed, although boys with constitutional short stature may profit psychologically from a short course of low-dose testosterone treatment beginning around age 13 years.

Abnormal Growth

Children whose linear growth measurements are at the extremes of the growth curve, but associated with a normal rate of growth, are likely to be normal. Conversely, a slow growth rate, irrespective of the actual height percentile (even one that is within the normal range, i.e., > 3rd percentile), is more likely to be abnormal and warrants further evaluation. As noted previously, linear growth must be evaluated over time, preferably over a minimum of 3-6 months, in order to determine velocity and the need for merely ongoing observation or initiation of an evaluation.

Importantly, linear growth patterns must be viewed in the context of simultaneous weight-tracking, as concomitant weight slow-down vs. weight preservation provides a highly useful diagnostic fulcrum. Additional information can be gleaned from concomitant pubertal delay in the older child, along with dental delay at any age, as well as physical findings to suggest a specific diagnosis.

A useful starting-off point to guide the differential diagnosis is a bone age which is delayed in children with constitutional short stature and various systemic and endocrine causes of growth failure and typically more so in pathological situations. On the other hand, the bone age is usually not delayed when growth failure is caused by familial short stature or genetic syndromes.

How to determine if growth is normal

Physiology of Growth

Hormonal regulation of human growth involves the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis. There is also clearly a genetic contribution to human growth. This is discussed further under normal (parental growth and development history) and abnormal growth patterns (Turner syndrome and SHOX deficiency). GH is important in promoting somatic growth and in regulating body composition and muscle and bone metabolism. Some of these GH effects are direct actions whereas others, specifically linear growth, are mediated through IGF-I.

The original “somatomedin (alternatively termed IGF) hypothesis” postulated that somatic growth was controlled by pituitary GH and mediated by circulating IGF-I produced exclusively by the liver. The discovery in the late 1980’s that most tissues produce IGF-I, supporting a role of autocrine/paracrine IGF-I, led investigators to modify the original hypothesis to what is known today as the “dual effector” theory. Experiments using gene deletions and transgenic technologies have revealed new information that again has led investigators to revisit the hypothesis. These experimental studies in mice have shown that, while the liver is the principal source of IGF-I in the circulation, hepatic IGF-I is not required for postnatal growth. Extrapolating to humans, this finding indicates that autocrine/paracrine (local) IGF-I produced in cartilage itself, but not liver-derived (endocrine) IGF-I, may be the major determinant of postnatal somatic growth.

Growth Velocity

A newborn’s size is determined by its intra-uterine environment, which is influenced by maternal size, nutrition, general health, and social habits, such as smoking or drinking alcohol. Thus, an “overnourished” mother can have a heavier and longer baby and an “undernourished” mother can have a lighter and shorter baby than otherwise dictated by family growth genetics. The average weight of a newborn is 3.25 kilograms (7.25 pounds) and the average length is 50 centimeters (19.7 inches). After birth, the linear growth rate becomes more dependent on the infant’s genetic background.

Important physiological phenomena, known as catch-up and catch-down growth, occur in the first 18 months of life. In two-thirds of children, the growth rate percentile shifts after birth until the child reaches his or her genetically determined height percentile. Some children (born too small because of uterine fetal constraint) move upward (catch-up) on the growth chart because they have tall parents, whereas others (oversized at birth because of excessive maternal nutrition during the pregnancy) move downward (catch-down) on the growth chart because they have short parents. By 18 to 24 months of age, most children’s stature has shifted to their genetically determined percentiles. Thereafter, growth typically proceeds along the same percentile until the onset of puberty (see Table 1).

Table 1.n

Genetic Potential

Determination of the MPTH is a critical first step in the assessment of a child’s stature, and obtaining accurate parental height measurements is essential when determining the MPTH. A large proportion of parents who bring their children for a consultation with a pediatric endocrinologist make a significant error in reporting their own heights. Since parental height often determines the extent of a work-up and/or therapeutic intervention, it is the opinion of the authors that parents’ heights should be directly measured whenever possible.

The MPTH is a child’s projected adult height based on the heights of his or her parents. Sex-specific calculations are shown in Table 2. For both genders, 1.7 inches on either side of the calculated MPTH is ~1 SD while 3.3 inches on either side is ~2 SD. By calculating the percentile and range for the MPTH, it can be determined if a child is growing on a percentile that is within or outside this range.

Table 2.n

What Else Could the Patient Have?

Endocrine Causes of Short Stature

Hypothyroidism

What you should be alert for in the history

Hypothyroidism is a deficiency in thyroid hormone secretion by the thyroid gland, with a reduction in thyroid hormone action at the cellular level. The two major forms in children are:

• congenital primary hypothyroidism (occurring in ~1:1700 live births)

• acquired hypothyroidism due to diseases that have an onset any time after birth

Two major subcategories are:

• congenital hypothyroidism due to a damaged, defective, or absent thyroid gland, or acquired hypothyroidism most commonly the result of an autoimmune process (Hashimoto thyroiditis)

• hypothalamic or pituitary (central) hypothyroidism occurring in ~1:20,000-80,000 live births, usually occurring as a part of more global hypopituitarism

Characteristic findings

Typical features of infants with undiagnosed congenital hypothyroidism include a prolonged gestation, large size at birth, and umbilical hernia, and, over time, delayed stooling, prolonged indirect jaundice, poor feeding, hypothermia, decreased activity, noisy breathy, large tongue, large fontanels, hoarse cry, and developmental delay/mental retardation. Typical features of longstanding undiagnosed acquired hypothyroidism are goiter (unless there is complete gland destruction), slow height growth, relative weight excess (but not obesity), increased weight-to-height ratio, bradycardia, delayed dentition, sexual pseudo-precocity, myxedema, cool/dry skin, brittle nails, and delayed relaxation of deep tendon reflexes.

Expected results of diagnostic studies

Serum thyrotropin (TSH) concentration is the most sensitive screening test for primary hypothyroidism.

Diagnosis confirmation

Newborn filter paper screening includes testing for congenital hypothyroidism in all 50 states in the US, with most employing a primary TSH-based screening procedure. For presumptive positive results, confirmatory venous testing of TSH and free or total T4 is done. To diagnose acquired primary hypothyroidism, TSH screening may suffice, but, more than likely, a total or free T4 level will be required, along with anti-thyroid antibody testing to help confirm the most likely etiology of Hashimoto (chronic lymphocytic) thyroiditis.

GH Deficiency (GHD)

What you should be alert for in the history

GHD should be suspected in a slowly growing infant who presents with a central midline defect (cleft palate/lip, single central maxillary incisor, cardiac disease, holoprosencephaly, or microphallus). GHD should be suspected in any poorly growing child with a history of brain tumor, central nervous system (CNS) surgery, CNS radiation, or a CNS anatomical abnormality (optic nerve hypoplasia [septo-optic dysplasia], empty sella syndrome, Rathke cleft cyst, etc.).

Characteristic findings on physical examination

Infants with GHD may present with a midline defect (see above), wandering (searching) nystagmus (due to optic nerve hypoplasia), signs of hypoglycemia (seizures, tremor, pallor, weakness, vomiting, diarrhea, and/or delayed development), and/or hepatomegaly with transaminitis. Children with GHD may present with a cherubic (angel-like) appearance, increased weight-to-height ratio, and proportionate short stature. Older children with GHD may also present with delayed sexual development.

Expected results of diagnostic studies: IGF-I and IGF binding protein-3 (IGBBP-3) are GH-dependent with long half-lives and are, therefore, the most commonly used screening tests for GHD. However, a low value of IGF-I is not diagnostic as it is quite sensitive to other factors such as age, nutritional state, and chronic disease.

Diagnosis confirmation: A GH level < 10 ng/mL during spontaneous hypoglycemia is suggestive of GHD in an infant or a child. A GH response of < 10 ng/mL after two provocative stimuli (clonidine, glucagon, arginine, and insulin-induced hypoglycemia) used to define GHD in a child.

Prader-Willi syndrome (PWS)

What you should be alert for in the history

Prader-Willi syndrome (PWS) is a rare genetic disorder occurring in 1:10,000 to 1:25,000 individuals. It is caused either by a paternal deletion (>70%), uniparental maternal disomy (~25%), or an imprinting defect (<2%) leading to non-expression of paternal genes in the PWS region at 15q11-q13. Children with PWS typically present with early hypotonia or with polyphagia, obesity, and short stature after two years of age.

Characteristic findings on physical examination

Newborns with PWS are typically born SGA, have poorly developed genitalia (males), hypotonia, problems with sucking and swallowing, difficulty gaining weight, small hands and feet, and characteristic facies (almond-shaped eyes with a small down-turned mouth). As affected children become older, they develop an intense craving for food and will do almost anything to get it. This results in quite rapid weight gain typically starting around age 2 years and finally morbid obesity, leading to obstructive sleep apnea, right-sided heart failure, insulin-resistant diabetes, and early death. Many adolescents with PWS have hypogonadism (usually central) and short stature with decreased height velocity often due to GHD.

Expected results of diagnostic studies

Hyperglycemia, abnormal sleep studies, abnormal echocardiograms, low sex steroids, and low IGF-I and IGFBP-3 may be seen in patients with PWS.

Diagnosis confirmation

DNA methylation testing confirms or rules out PWS with > 99% accuracy. The imprinting pattern in region 15q11-113 is evaluated for both the paternal and maternal DNA alleles. In patients with PWS, there is only a maternal pattern, whether there is a deletion, uniparental disomy, or an imprinting defect (a paternal expression pattern results in Angelman syndrome). Fluorescent in situ hybridization (FISH) testing for PWS should be avoided as it only detects deletions and is more expensive than is DNA methylation. For the PWS patient with slow growth, formal GH testing is not required according to the FDA.

Severe Primary IGF-I Deficiency (IGFD)

What you should be alert for in the history

Severe short stature with heights ranging from -5 to -11 SD is typically present. Depending on the etiology (see below), affected individuals may have similarly affected relatives and be the products of consanguineous unions; have histories of neonatal hypoglycemia; have mental retardation; and have manifestations of immunodeficiency. Whether there truly exists an entity of isolated primary IGF-I deficiency as a cause of “idiopathic” short stature remains the subject of great debate.

Characteristic findings on physical examination

Height, according to criteria set forth by the FDA, must be shorter than < -3 SD. While there may be no other specific physical findings, this diagnosis must be suspected in the setting of microcephaly, certain dysmorphic features, and chronic pulmonary changes.

Expected results of diagnostic studies

By the criteria set forth by the FDA, the serum IGF-I level must be at least -3 SD or lower. Etiologies include:

• Laron dwarfism (GH resistance due to a mutation in the GH receptor gene) associated with many of the features of congenital GHD

• a genetic defect in an intermediate the post-GH receptor signaling cascade, e.g., Stat 5B (which also involves pathways of cytokine action)

• an IGF-I gene mutation (associated with small head size and mental retardation)

GH therapy will be ineffective while administration of IGF-I bypasses the various blocks and should foster growth. IGF-I therapy is also approved for use in patients with GH-1 gene deletions who completely lack endogenous GH and who mount potent neutralizing antibodies to exogenous GH.

Diagnosis confirmation

The diagnosis of severe primary IGF-I deficiency is made by meeting the above FDA criteria along with having normal or elevated serum GH levels; excluding secondary causes of IGF-I deficiency (including GHD, malnutrition, hypothyroidism, chromosome abnormalities, chronic diseases, and pituitary tumors); assuring that the child is not taking GH or glucocorticoids; and having the child followed by pediatric endocrinologist.

Cushing syndrome (CS)

What you should be alert for in the history

Endogenous CS is rare in childhood and adolescence. The condition is caused by prolonged exposure to excessive glucocorticoids which can be secreted endogenously or administered exogenously. As with adult CS, the most common cause is iatrogenic secondary to administration of supraphysiological doses of exogenous glucocorticoids. Non-iatrogenic pediatric CS is divided into ACTH-dependent and ACTH-independent forms. These causes can be further classified according to age of onset. For example, CS in infancy is usually associated with McCune-Albright syndrome, with adrenocortical tumors in children under four years of age, and with pituitary tumors (Cushing disease) in adolescents.

Characteristic findings on physical examination

Children with CS can present with a number of symptoms and signs. These can vary depending on the age of the child and cause of the CS. The key symptoms and clinical findings include weight gain, slow height growth, acne, striae, and hypertension. In comparison to adult CS, growth failure with associated weight gain is one of the most reliable indicators of hypercortisolemia in pediatric CS. Clinical features may occur gradually over a period of time and go unrecognized for years prior to diagnosis.

Expected results of diagnostic studies

Elevated levels of neutrophils, absent eosinophils, hyperglycemia, and hypokalemic metabolic alkalosis are suggestive of CS.

Diagnosis confirmation

No single laboratory test is perfect and usually several are needed. The three most common tests used to diagnose CS are the 24-hour urinary free cortisol-to-creatinine ratio; measurement of midnight serum cortisol or late-night salivary cortisol showing loss of diurnal variation; and the overnight, low-dose, and high-dose dexamethasone suppression tests.

Pseudohypoparathyroidism (PHP)

What you should be alert for in the history

PHP is a condition associated with primary resistance to parathyroid hormone (PTH). The pathogenesis of PHP has been linked to dysfunctional Gsα proteins. Short stature, obesity, skeletal abnormalities, and school difficulties suggest this diagnosis.

Characteristic findings on physical examination

Patients may present with features of hypocalcemia including carpopedal spasm, cramping, tetany, and seizures. Additional features include short stature (in some cases thought to be due to GHD resulting from resistance to GH-releasing hormone), obesity, developmental delay, calcification of the basal ganglia, and symptoms of mild hypothyroidism in patients who also have TSH resistance. There are three types of PHP:

• Type 1a (PTH resistance; skeletal abnormalities, including short fourth and sometimes other metacarpals; and a rounded facies, along with associated TSH resistance)

• Type 1b (lacks skeletal features, but is biochemically similar to Type 1a)

• Type 2 (similar to Type 1b, but has a different biochemical defect)

Expected results of diagnostic studies

PHP is characterized by hypocalcemia, hyperphosphatemia, elevated PTH, and, in some cases, mildly elevated TSH.

Diagnosis confirmation

Low total and ionized calcium confirm the hypocalcemic state. Serum phosphate levels are reciprocally elevated. Intact PTH (usually measured by immunoradiometric assay [IRMA]) is elevated.

Management and Treatment of the Disease

Hypothyroidism

Replacement with synthetic thyroxine is the treatment of choice. Such doses tend to be higher – ~100 mcg/m2/day – for primary hypothyroidism vs ~50 mcg/m2/day for central hypothyroidism. The ultimate adequacy of doing is determined by sequential thyroid function testing (free T4 and TSH).

GH Deficiency (GHD)

Recombinant GH was first approved in the US for treatment of children with severe GHD in 1985 at a dose up to 0.3 mg/kg/wk. Higher doses, up to 0.7 mg/kg/week, are approved for pubertal-aged children with GHD, but must be used very carefully. All GH preparations used today in clinical practice are manufactured by recombinant DNA technology. Recombinant human GH contains the identical 191-amino acid sequence as that of pituitary-derived human GH, and is, therefore, considered bio-identical therapy. GH safety in children with GHD has been well-studied with no association with malignancy (except for benign meningioma after medulloblastoma) and slightly increased risks of pseudotumor cerebri, type 2 diabetes, slipped capital femoral epiphysis, and worsening of pre-existing scoliosis. In point of fact, it is unclear if some of these side effects are related to the GH itself or to the rapid growth that it induces.

In a multi-national European study (Safety and Appropriateness of Growth hormone treatments in Europe [SAGhE]) of 6928 former GH-treated children (now >18 years old) with a history of either idiopathic isolated GH deficiency (n = 5162), GH neurosecretory dysfunction (n = 534), ISS (n = 871), or having been born SGA (n = 335) who started treatment with recombinant human GH between 1985 and 1996, mortality rates in a subset of French subjects were increased in this population of adults, especially in those who had received the highest doses (>0.35 mg/kg/wk or 50 mcg/kg/d).

On the basis of this preliminary report, the European Medicines Agency Committee for Medicinal Products for Human Use confirmed “no immediate danger,” but cautioned prescribers in Europe. This need for caution permeated to the United States, where those who prescribe GH for treating children with short stature for various indications were initially advised to inform the recipients of GH and their parents of the preliminary report from France.

However, in August of 2011, the Food and Drug Administration (FDA) identified a number of study design weaknesses that limited the ability to interpret the results and hence concluded that the evidence linking the use of GH and increased risk of death was inconclusive.

The initial suggestion of heightened mortality in GH-treated individuals, however, was not reproduced in a subsequent analysis of the entire SAGhE cohort. More recently, a possible association of GH treatment during childhood and subsequent stroke in young adulthood was raised in another partial analysis of the SAGhE cohort. Careful analysis of this report once again indicated a number of potential design flaws raising questions about the validity of this second report. This sentiment was echoed in a recent international workshop position paper on GH safety, but, quite appropriately, this body recommended continued vigilance and long-term follow-up of all GH-treated patients.

Prader-Willi syndrome (PWS)

GH was first approved for patients with PWS in 2000 at a dose of 0.24 mg/kg/wk. GH is now standard care in the US for children with growth failure secondary to PWS. Although GH treatment may help children with PWS in terms of body composition, strength, and agility, these are not approved indications. Concerns have arisen that patients with PWS may be at heightened risk for certain complications of GH treatment including sudden death due to respiratory/apnea issues, as well as be prone to insulin resistance/diabetes and worsening of existing scoliosis.

Furthermore, patients with PWS may also independently be at risk for ACTH/cortisol deficiency. It is recommended by most experts that a sleep study be conducted before initiating GH treatment in a child with PWS. At this time, there is no direct evidence of a causative link between GH treatment and the respiratory problems seen in patients with PWS, including sudden death. A follow-up sleep study after one year of GH treatment may also be indicated. Regardless, GH should only be prescribed in this population by an experienced endocrinologist.

Severe Primary IGF-I Deficiency (IGFD)

Mecasermin (recombinant human IGF-I) was approved by the FDA in 2005 at a dose of 120 mcg/kg subcutaneously twice daily. Dose initiation involves a standard upward titration protocol. Side effects of concern include hypoglycemia because of the insulin-like action of the drug as well as preferential growth-promoting action on lymphatic tissue, e.g., tonsils and adenoids.

Cushing syndrome (CS)

For endogenous CS, treatment involves surgical excision of an ACTH-producing pituitary tumor or an adrenal tumor. Iatrogenic CS requires discontinuation of or reduction in glucocorticoid dose.

Pseudohypoparathyroidism (PHP)

Normalizing serum calcium, phosphorus, and thyroid status are the only treatment options available and are accomplished with administration of calcium, phosphate binders, and calcitriol. These patients are still shorter-statured than age-matched controls, but may show benefit from GH treatment if GH-deficient.

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