SHORT STATUREGROWTHNormal growth is the final common pathway of many factors, including endocrine, environmental, nutritional, and genetic influences (see Chapter 5). A normal linear growth pattern is good evidence of overall health and can be considered a bioassay for the well-being of the whole child. The effects of certain hormones on growth and ultimate height are listed in Table 173-1. Just as various factors influence stature, stature itself influences psychological, social, and potentially eco-nomic well-being. Parental concern about the psychosocial consequences of abnormal stature often causes a family to seek medical attention.

Growth Hormone PhysiologyGrowth hormone (GH) secretion is pulsatile, stimulated by hypothalamic GH-releasing factor (GRF) and inhibited by GH release inhibitory factor (somatostatin, somatotropin release-inhibiting factor [SRIF]), which interact with their individual receptors on the somatotrope in a noncompet-itive manner. GH is also stimulated by ghrelin, produced in the stomach. GH circulates bound to a GH-binding protein (GHBP); GHBP abundance reflects the abundance of GH receptors. GH has direct effects on tissue and also causes pro-duction and secretion of insulin-like growth factor-1 (IGF-1) in many tissues. GH stimulates IGF-1 production in liver along with production of the acid-labile subunit and the IGF-bind-ing protein (IGF-BP3); this forms the complex that delivers IGF-1 to tissue.IGF-1 acts primarily as a paracrine and autocrine agent and is most closely associated with postnatal growth. When IGF-1 attaches to its membrane-bound receptor, second messengers are stimulated to change the physiology of the cell and pro-duce growth effects. IGF-1 production is influenced by disease states such as malnutrition, chronic renal and liver disease, hypothyroidism, or obesity.IGF-BP3 is measurable in clinical assays and is less influ-enced by nutrition and age than is IGF-1; measuring IGF-1 and IGF-BP3 is useful in evaluating GH adequacy, particularly in infancy and early childhood.Measurement of GrowthThe correct measurement of an infants length requires one adult to hold the infants head still and another adult to extend the feet with the soles perpendicular to the lower legs. A caliper-like device, such as an infantometer, or the movable plates on an infant scale are used so that the exact distance between the two calipers or plates can be determined. Marking the position of the head and feet of an infant lying on a sheet of paper on the examining table leads to inaccuracies and may miss true disorders of growth or create false concerns about a disorder of growth in a normal child. Accurate measurements of height (standing), or length (lying down), and weight should be plot-ted on the Centers for Disease Control and Prevention growth charts for the timely diagnosis of growth disorders (http://www.cdc.gov/growthcharts/).After 2 years of age, the height of a child should be mea-sured in the standing position. Children measured in the standing position should be barefoot against a hard surface. A Harpenden stadiometer or equivalent device is optimal for the measurement of stature. A decrease of roughly 1.25 cm in height measurement may occur when the child is measured in the standing position rather than in the lying position, leading to the inappropriate referral of many children who appear to be not growing to a subspecialist.

Measurement of the arm span is essential when the diagno-ses of Marfan or Klinefelter syndrome, short-limbed dwarfismor other dysmorphic conditions are considered. Arm span ismeasured as the distance between the tips of the fingers whenthe patient holds both arms outstretched horizontally whilestanding against a solid surface. The upper-to-lower segmentratio is the ratio of the upper segment (determined by sub-traction of the measurement from the symphysis pubis to thefloor [known as the lower segment] from the total height) tothe lower segment. This ratio changes with age. A normal term

infant has an upper-to-lower ratio of 1.7:1, a 1-year-old has a ratio of 1.4:1, and a 10-year-old has a ratio of 1:1. Condi-tions of hypogonadism, not commonly discerned or suspected until after the normal age for onset of puberty, lead to greatly decreased upper-to-lower ratio in an adult, whereas long-last-ing and untreated hypothyroidism leads to a high upper-to-lower ratio in the child.Endocrine Evaluation of Growth Hormone SecretionGH is a 191amino acid protein secreted by the pituitary gland under the control of GRF and SRIF (see Fig. 170-2). GH secretion is enhanced by -adrenergic stimulation, hypo-glycemia, starvation, exercise, early stages of sleep, and stress and inhibited by -adrenergic stimulation and hyperglycemia. Because concentrations of GH are low throughout the day, except for brief secretory peaks in the middle of the night or early morning, the daytime ascertainment of GH deficiency or sufficiency on the basis of a single determination of a ran-dom GH concentration is impossible. Adequacy of GH secre-tion may be determined by a stimulation test to measure peak GH secretion. A normal response is a vigorous secretory peak after stimulation; the lack of such a peak is consistent with GH deficiency. However there is a high false-positive rate (on any day, about 10% or more of normal children may not reach the normal GH peak after even two stimulatory tests). Indirect measurements of GH secretion, such as serum concentrations of IGF-1 and IGF-BP3, are considered better screens for GH deficiency.Decision-Making AlgorithmAvailable @ StudentConsult.comShThe factors responsible for postnatal growth are not the same as the factors that mediate fetal growth. Thyroid hor-mone is essential for normal postnatal growth, although a thy-roid hormonedeficient fetus achieves a normal birth length; similarly a GH-deficient fetus has a normal birth length, although in IGF-1 deficiency resulting from GH resistance (Laron dwarfism), fetuses are shorter than control subjects. Adequate thyroid hormone is necessary to allow the secretion ort Stature of GH. Hypothyroid patients may appear falsely to be GH defi-cient; with thyroid hormone repletion, GH secretion normal-izes. Gonadal steroids are important in the pubertal growth spurt. The effects of other hormones on growth are noted in Table 173-1.

ABNORMALITIES OF GROWTHShort Stature of Nonendocrine CausesShort stature is defined as subnormal height relative to other children of the same gender and age, taking family heights into consideration. It can be caused by numerous conditions (Table 173-2). The Centers for Disease Control and Pre-vention growth charts use the 3rd percentile of the growth curve as the demarcation of the lower limit. Growth failure denotes a slow growth rate regardless of stature. Ultimately a slow growth rate leads to short stature, but a disease process is detected sooner if the decreased growth rate is noted before the stature becomes short. Plotted on a growth chart, growth failure appears as a curve that crosses percentiles downward and is associated with a height velocity below the 5th percen-tile of height velocity for age (Fig. 173-1). A corrected mid-parental, or genetic target, height helps determine whether the child is growing well for the family (see Chapter 6). To determine a range of normal height for the family under con-sideration, the corrected midparental height is bracketed by 2 standard deviations (SDs), which, for the United States, is approximately 10 cm (4 in.). The presence of a height 3.5 SDs below the mean, a height velocity below the 5th percentile for age, or a height below the target height corrected for mid-parental height requires a diagnostic evaluation.Decision-Making AlgorithmAvailable @ StudentConsult.comShort Stature

Nutrition is the most important factor affecting growth on a worldwide basis (see Chapter 28). Failure to thrive may develop in the infant as a result of maternal deprivation (nutritional deficiency or aberrant psychosocial interaction) or as a result of organic illness (anorexia, nutrient losses through a form of malabsorption, or hypermetabolism causeddevelopment (see Fig. 173-1). Usually a family member had delayed growth or puberty but achieved a normal final height. The bone age is delayed, but the growth rate remains mostly within the lower limits of normal. Constitutional delay usually leads to a delay in secondary sexual development. Genetic or familial short stature (Table 173-3) refers to the stature of a child of short parents, who is expected to reach a lower than average height and yet normal for these parents. If the parents were malnourished as children, grew up in a zone of war, or suffered famine, the heights of the parents are less predictive. Although there are differences in height associated with eth-nicity, the most significant difference in stature between ethnic groups is the result of nutrition.Phenotypic features suggesting an underlying chromosomal disorder can occur in many syndromes. These syndromes can be suspected by attending to arm spans and upper-to-lower segment ratios. Genetic syndromes often combine obesity and decreased height, whereas otherwise normal obese children are usually taller than average and have advanced skeletal development and physical maturation (see Table 173-2). The Prader-Willi syn-drome includes fetal and infantile hypotonia, small hands and feet (acromicria), postnatal acquired obesity with an insatiable appetite, developmental delay, hypogonadism, almond-shaped eyes, and abnormalities of the snRNP (small nuclear ribonucleic particle) portion of the 15th chromosome at 15q11-q13. Most cases have deletion of the paternal sequence, but about 20% to 25% have uniparental disomy, in which both chromosomes 15 derive from the mother. Laurence-Moon-Bardet-Biedl syn-drome is characterized by retinitis pigmentosa, hypogonad-ism, and developmental delay with an autosomal dominant inheritance pattern. Laurence-Moon syndrome is associated with spastic paraplegia; Bardet-Biedl syndrome is associated with obesity and polydactyly. Pseudohypoparathyroidism leads to short stature and developmental delay with short fourth and fifth digits (Albright hereditary osteodystrophy phenotype), resistance to parathyroid hormone and resultant hypocalcemia, and elevated levels of serum phosphorus. Turner syndrome is characterized by a karyotype of 45XO or by a mosaic karyotype and clinically presents with short stature, shield chest, wide-spaced nipples, wide-carrying angle of the upper extremities, high-arched palate, gonadal failure, kidney dysplasias with normal function, and aortic arch abnormalities. Affected girls are often susceptible to autoimmune disorders.Short Stature Caused by Growth Hormone DeficiencyEtiology and EpidemiologyClassic congenital or idiopathic GH deficiency occurs in about 1 in 4000 to 1 in 10,000 children. Idiopathic GH defi-ciency, of unidentified specific etiology, is the most com-mon cause of both congenital and acquired GH deficiency. Less often GH deficiency is caused by anatomic defects of the pituitary gland, such as pituitary aplasia or other midline defects, with variable degrees of deficiency of other pituitary functions. Hereditary forms of GH deficiency that affect pitu-itary differentiation are the result of heterogeneous defects of the gene for GH, GRF, or GH receptor. Classic GH deficiency refers to very reduced to absent secretion of GH; numerous short children may have intermediate forms of decreased GH secretion. Acquired GH deficiency causing late-onset growth failure suggests the possibility of a tumor of the hypothalamus or pituitary causing compression of the area (see Tables 173-2 and 173-3).Decision-Making AlgorithmAvailable @ StudentConsult.comShort StatureClinical ManifestationsInfants with congenital GH deficiency achieve a normal or near-normal birth length and weight at term, but the growth rate slows after birth, most noticeably after age 2 to 3 years. These children become progressively shorter for age and tend to have an elevated weight-to-height ratio, appearing chubby and short. Careful measurements in the first year of life may suggest the diagnosis, but most patients elude diagnosis until several years of age. A patient with classic GH deficiency has the appearance of a cherub (a chubby, immature appear-ance), with a high-pitched voice resulting from an immature larynx. Unless severe hypoglycemia occurs or dysraphism (midline defects) of the head includes a central nervous sys- tem (CNS) defect that affects mentation, the patient has normal intellectual growth and age-appropriate speech. Male neonates with isolated GH deficiency with or without gonado- tropin deficiency may have a microphallus (a stretched penile length of