Growth Failure 

Short stature may be the normal expression of genetic potential, in which case the growth rate is normal, or it may be the result of a condition that causes growth failure with a lower-than-normal growth rate.^[1] Growth failure is the term that describes a growth rate below the appropriate growth velocity for age (see image below).

A child is considered short if he or she has a height that is below the fifth percentile; alternatively, some define short stature as height less than 2 standard deviations below the mean, which is near the third percentile. Thus, 3-5% of all children are considered short. Many of these children actually have normal growth velocity. These short children include those with familial short stature or constitutional delay in growth and maturation. In order to maintain the same height percentile on the growth chart, growth velocity must be at least at the 25th percentile. When considering all children with short stature, only a few actually have a specific treatable diagnosis. Most of these are children with a slow growth velocity.

The most rapid phase of human growth is intrauterine. Following birth, a gradual decline in growth rate occurs over the first several years of life. The average length of an infant at birth is about 20 inches, the length at age 1 year is approximately 30 inches, the length at age 2 years is approximately 35 inches, and the length at age 3 years is approximately 38 inches. After age 3 years, linear growth proceeds at the relatively constant rate of 2 inches per year (5 cm/y) until puberty.

Normal growth is the result of the proper interaction of genetic, nutritional, metabolic, and endocrine factors. To a large extent, growth potential is determined by polygenic inheritance, which is reflected in the heights of parents and relatives. Secretion of growth hormone (GH) by the pituitary is stimulated by growth hormone–releasing hormone (GHRH) from the hypothalamus. Another signal, which is stimulated by certain growth hormone–releasing peptides (GHRPs), may be present; the receptor for the GHRPs has been identified, and a possible natural ligand for these receptors has been determined. Somatostatin secreted by the hypothalamus inhibits growth hormone secretion.

When growth hormone pulses are secreted into the systemic circulation, insulinlike growth factor (IGF)–1 is released, either locally or at the site of the growing bone. Growth hormone circulates bound to a specific binding protein (GHBP), which is the extracellular portion of the growth hormone receptor. IGF-1 circulates bound to one of several binding proteins (IGFBPs). The IGFBP that most depends on growth hormone is IGFBP-3.

A peptide hormone that stimulates growth hormone release, named ghrelin (from the word ghre, a root word in proto-Indo-European languages meaning grow), has been described. This hormone is unique in that it is a small polypeptide modified at the third amino acid (serine) by esterification of n-octanoic acid. Ghrelin appears to be made in the stomach and stimulates growth hormone secretion by binding with its own receptor, which had previously been known to bind synthetic GHRPs. Ghrelin may play a role in regulation of growth hormone at the hypothalamic level, permitting an adequate energy supply for maintenance, growth, and repair.

Frequency

United States

In 1994, Lindsay et al studied 114,881 school children in Utah.^[2] After 1 year, 79,495 of the original group were available for evaluation. Of these, 555 (0.7%) had heights that were below the third percentile and a growth rate that was less than 5 cm/y. When examined further, causes for short stature within this group of children included familial short stature (37%), constitutional delay (27%), a combination of familial short stature and constitutional delay (17%), other medical causes (10%), idiopathic short stature (5%), growth hormone deficiency (3%), Turner syndrome (3% of girls), and hypothyroidism (0.5%).

International

Several studies have been conducted to determine the frequency of various causes of short stature. In 1974, Lacey and Parkin evaluated children in Newcastle upon Tyne in England.^[3] They studied 2256 children, 111 of whom were below the third percentile in stature. Of the 98 children that they were able to examine, only 16 had evidence of organic disease causing their short stature. Diagnoses included Down syndrome, cystic fibrosis, chronic renal insufficiency, growth hormone deficiency, juvenile rheumatoid arthritis (treated with glucocorticoid), and Hurler syndrome.

Mortality/Morbidity

Short stature has been thought to have far-reaching effects on psychological well-being, including poor academic achievement (despite normal intelligence, healthy family dynamics, and high socioeconomic status) and behavioral problems (eg, anxiety, attention-seeking actions, poor social skills).

Morbidity related to the underlying cause of the growth failure may also be observed. Some studies involving children who have not been seen in a clinic that treats short stature (and, therefore, may represent a different patient population) have challenged the notion that short stature has psychological implications. At the present time, this issue is not completely resolved.

Mortality rates in children with growth failure relate to the underlying cause of the growth failure. Mortality is not related to growth failure itself; rather, it is related only to the cause of the growth failure.

Sex

The sex distribution of children treated with growth hormone is about 3 boys for every girl. Recent work in this area suggests that this is mostly due to a referral bias, either from parents themselves or from the referring physician.