Normal Growth Patterns

Normal growth follows a predictable pattern. This pattern is depicted in widely used growth charts, which comprise sequential percentile curves showing the distribution of selected body measurements (usually length or height, weight, and weight for height or body mass index [BMI]) in children of a country. Growth is fastest during the fetal period; fetal size primarily relates to maternal health and nutrition. During infancy, the child’s genetic factors come into play. Growth gradually slows, with average increase in length of 25 cm over the first year of life and 10 cm over the second year. In this period, infants often cross length percentiles (channelize) to a percentile more in line with their genetic potential. After the second birthday, growth proceeds at a slow, relatively constant velocity of 4 to 6 cm/y, and shifting percentile channels is abnormal. Childhood growth is slowest just before the onset of puberty and then accelerates during adolescence, resulting in the pubertal “growth spurt” (average growth velocity of 10 cm/y). At the end of puberty, growth ceases as the epiphyses (growth plates) fuse.

Longitudinal Growth and Mediating Factors

Longitudinal growth occurs via chondrocyte proliferation and subsequent endochondral ossification in the growth plates of long bones (and vertebrae). The growth plate is a cartilaginous zone located between the metaphysis and epiphysis (secondary ossification zone at the end of the bone). Growth is a complex process regulated by multiple factors, including nutrition, hormones, and growth factors that act either locally within the growth plate or systemically.

Growth hormone (GH) is the most important growth-regulating hormone; its pulsatile secretion from the anterior pituitary somatotrophs is regulated by two hypothalamic peptide hormones, GH-releasing hormone (GHRH) and somatostatin, which, respectively, stimulate and inhibit its release (Figure 73-1). Circulating GH is bound to GH-binding protein (GHBP), which corresponds to the extracellular domain of the GH receptor. Many, although not all, of GH’s actions are mediated through insulin-like growth factor (IGF)-I (i.e., somatomedin-C). Serum IGF-I is produced principally in the liver in response to GH and circulates in the bloodstream bound to IGF-binding proteins (especially IGFBP-3) that control its bioavailability. IGF-I acts at target tissues by binding cell-surface IGF receptors and triggering multiple downstream effects that include cellular hypertrophy and proliferation. IGF-I and free fatty acids also inhibit GH secretion at the level of the pituitary and hypothalamus.

Figure 73-1 Growth hormone and insulinlike growth factor: systemic and metabolic effects.

Other systemic hormones that affect growth include insulin (the principal growth-promoting hormone in utero), androgens and estrogens (which induce the pubertal growth spurt and, in the case of estrogens, epiphyseal fusion), thyroid hormone (which has a permissive effect on GH secretion and exerts direct action at the growth plates), and glucocorticoids (which inhibit growth both centrally and at the growth plate).

Abnormal Growth

Abnormalities in growth can be caused by systemic illness, psychosocial deprivation, malnutrition, or abnormalities in the secretion or action of any of the aforementioned hormones and growth factors. Growth failure is defined as height velocity that is less than expected for a child’s age, sex, and pubertal stage or as the crossing downward of two or more major height percentiles (beyond 2 years of age). Growth failure always merits an evaluation. Normal height is a continuum; short stature is conventionally defined as a height that is below the child’s genetic potential (as determined by parental heights) or more than 2 standard deviations (SDs) below the mean for age and sex. Thus, approximately 2.5% of a population will be classified as short, including some healthy children. Because the average adult height differs considerably among different ethnic groups, the actual height that corresponds to short stature differs from population to population.

Familial Short Stature

FSS is the most common cause of short stature in otherwise well children. A child with FSS has a height that falls at the lower end of the population norm but that is consistent with the child’s genetic potential. Although in most cases FSS represents the cumulative effects of multiple growth-related genes, in some cases, FSS derives from transmission of an alteration or defect in a single gene (e.g., SHOX [short stature, homeobox-containing] gene; see below), particularly if height is significantly below the third percentile. Both parents’ heights are usually in the lower height percentiles, and the child’s growth pattern and predicted adult height are consistent with that of his or her parents (and often siblings). The hallmark is a normal growth velocity, such that the child’s growth curve is parallel to the standard population curve. In the absence of a family history of delayed puberty, the timing of puberty is usually average. The medical history, review of systems, and physical examination are typically unremarkable. The bone age is typically within the normal range, and laboratory workup results should be normal.

Constitutional Delay of Growth and Puberty

CDGP is the second most common cause of (transient) relative short stature in childhood. Children with CDGP usually have a normal birth length, begin crossing height percentiles by age 2 years, and settle in the lower percentiles, where they track until the onset of puberty in their peers, when they appear to drop further away from the growth curve. This growth pattern is associated with delayed puberty, which is defined as the absence of secondary sexual characteristics at an age beyond +2 SD for the population (see Chapter 67), that is, the absence of thelarche (breast development) in girls older than age 13 years, no signs of puberty in boys older than age 14 years, or no menarche in girls by 4 years after thelarche or by age 16 years (primary amenorrhea). CDGP represents the late end of the spectrum of pubertal development. Because children with CDGP enter puberty (and thus accelerate their growth velocity) later than most of their peers, they develop a transient relative height and sexual maturation gap relative to their age-matched peers. However, children with CDGP continue to grow after their peers cease growth, and thus they eventually attain an adult height within the normal range. Family history often reveals relatives with similarly delayed puberty (“late blooming”). There are no other abnormalities present other than short stature and delayed puberty. A detailed history and physical examination and thorough review of the child’s historical growth curve are essential steps to establishing this diagnosis; an isolated point on the growth curve at the time of the visit is insufficient. The differential diagnosis of CDGP includes Kallmann’s syndrome and isolated gonadotropin deficiency; lack of anosmia can exclude the former, but only time or genetic analyses can help distinguish between CDGP and the latter. Bone age is significantly delayed, which provides reassurance that sufficient time for growth remains for the child to reach the predicted adult height. Any physical or biochemical abnormalities should suggest another diagnosis. When CDGP occurs superimposed on FSS, the child’s short stature can appear severe; however, the child is still healthy, and his or her growth is still a normal variant.

Idiopathic Short Stature

Idiopathic short stature (ISS) refers to extreme short stature that does not have a diagnostic explanation after an ordinary growth evaluation. The U.S. Food and Drug Administration (FDA) set the threshold for ISS at a height more than 2.25 SD below the mean, roughly equal to the shortest 1.2% of the population. Although ISS may represent a statistical extreme, in some cases, specific genetic mutations may account for poor growth. For example, some 3% to 5% of children with ISS have deletions or mutations in the SHOX gene present on the short arms of the X and Y chromosomes (see below).

Intrauterine Growth Retardation and Small for Gestational Age

Intrauterine growth retardation (IUGR) results in a newborn who is small for gestational age (SGA); the most widely used definition for SGA is a birth weight less than 2.5 kg at a gestational age beyond 37 weeks or length or weight below the tenth percentile for gestational age. The SGA infant may have experienced IUGR caused by placental defects, infection (e.g., TORCH [toxoplasmosis or Toxoplasma gondii infection, other infections, rubella, cytomegalovirus, and herpes simplex virus]), or teratogens, but dysmorphic syndromes, chromosomal defects, and genetic mutations also account for prenatal growth impairment. Although most infants with SGA experience catch-up growth in the first 2 years of life, approximately 10% to 15% remain below the third height percentile. If history or physical examination in an SGA child suggests an intrinsic abnormality, an appropriate evaluation should be obtained (e.g., chromosomal analysis and genetics referral to evaluate possible syndromes or skeletal radiographs if the limbs are disproportionate).

Osteochondrodysplasias

The osteochondrodysplasias are a diverse group of genetic disorders whose common denominator is abnormality of cartilage, bone, or both. More than 100 different conditions falling under this heading have been identified. Most children with skeletal dysplasias grow slowly, and their growth is usually disproportionate because these disorders affect the limbs more than the torso. The ratio of upper-to-lower body segments is abnormal, but the sitting height may be only mildly reduced or normal. Moreover, based on the disorder, there may be disproportionate rates of growth between limb segments (rhizomelic affecting proximal limbs, mesomelic affecting distal limbs, or acromelic affecting the terminal parts of a limb). Osteochondrodysplasias are hereditary, so a careful family history should be obtained. However, many cases represent de novo mutations, so absence of a family history does not exclude the possibility. Careful measurement of body proportions should be taken; combined with radiographic evaluation, they can determine which bones are primarily involved (long bones, vertebrae, skull; epiphyses, metaphyses, or diaphyses).

Turner Syndrome (See Chapter 118, Figure 118-1)

Turner syndrome, a disorder in females associated with the partial or complete absence of one X chromosome, is relatively common (prevalence, one in 2500 live-born girls). As this variability suggests, girls with Turner syndrome may have a subtle or even normal phenotype. Short stature is the most common phenotypic manifestation in children and adults and is caused by loss of the SHOX gene. The SHOX gene is located on the short arm of each of the sex chromosomes in an area called the pseudoautosomal region. Genes in the pseudoautosomal regions do not undergo X inactivation, and healthy 46,XX and 46,XY individuals express two copies of these genes; thus, both copies of the SHOX gene are active and required for normal growth. SHOX encodes a transcription factor expressed in the growth plate that helps regulate chondrocyte differentiation and proliferation. Patients with Turner syndrome who lack the short arm of X (or one entire X chromosome) have only one functional copy of the SHOX gene. This condition, termed “SHOX haploinsufficiency,” is responsible for the 20-cm difference in height between women with Turner syndrome and women of the referent population, as well as for several skeletal defects.

Turner syndrome may be recognized in infancy because of some characteristic features, particularly a webbed neck, lymphedema, or cardiac malformations. Beyond infancy, the two most common features are short stature and lack of puberty caused by primary ovarian failure. Skeletal abnormalities include relatively large hands and feet, a wide body, short neck, cubitus valgus (increased carrying angle with the elbows turned in and the forearms deviating away from body), genu valgum (“knock knees”), and shortened fourth metacarpals. Additional features may include ptosis, strabismus, low-set or deformed ears, micrognathia, a high-arched palate, dental abnormalities, a low posterior hairline, a shield chest, and hypoplastic areolae. Because of the phenotypic variability, Turner syndrome should be considered in any female with unexplained short stature, and a karyotype should be determined either by standard G-banding techniques or by comparative genomic hybridization.

Multiple-organ system abnormalities are associated with Turner syndrome, so a comprehensive evaluation is needed to screen for abnormalities of the aortic arch, descending aorta, kidneys, and pelvocaliceal collecting system; hearing loss; hip dysplasia (between infancy and age 4 years); scoliosis; and subtle neurocognitive deficits (especially involving visuospatial functions, although overall IQ is frequently normal). Women with Turner syndrome have an increased risk of potentially fatal aortic aneurysms and dissection and thus require lifelong monitoring.

Abnormalities of the Growth Hormone–Insulinlike Growth Factor Axis

Dysfunction may appear at any level of the GH–IGF axis, including the hypothalamus and higher brain centers (e.g., congenital malformations, trauma, inflammation, central nervous system [CNS] tumors), pituitary (e.g., structural defects, pituitary tumors, hypophysitis, idiopathic GH deficiency,) GH receptor (e.g., Laron syndrome or GH insensitivity), or postreceptor signaling defects (e.g., primary IGF-I deficiency and IGF insensitivity). Idiopathic GH deficiency (GHD) occurs in as many as one in 3500 U.S. children. Factors that raise suspicion for GHD include a history of prolonged neonatal jaundice; hypoglycemia; microphallus; traumatic delivery; craniofacial midline abnormalities (e.g., septo-optic dysplasia, holoprosencephaly, or a central maxillary incisor); family history of similar presentations; or a medical history of suprasellar tumor, CNS infection or infarction, cranial irradiation, or certain chemotherapies. Infants with congenital isolated GHD tend to have normal birth size; however, postnatal growth is overtly abnormal. Severe GHD in early childhood results in early growth failure and in slower muscular development, resulting in potentially delayed gross motor milestones, such as standing, walking, and jumping. Body composition (i.e., the relative amounts of bone, muscle, and fat) is affected in many children with severe deficiency, so that mild to moderate chubbiness is common (although GHD alone rarely causes severe obesity). Some severely GH-deficient children have recognizable, cherubic facial features characterized by maxillary hypoplasia and forehead prominence.

Other features of both congenital and acquired GHD include normal skeletal proportions, increased adiposity (especially truncal), poor lean body mass gain, delayed dentition, and delayed average age of pubertal onset. A child suspected of having GHD should be referred to a pediatric endocrinologist for diagnostic evaluation.

Poor Nutrition

Optimal statural growth requires optimal nutrition; malnutrition is the most common cause of poor growth globally (see Chapter 13). Total calorie and/or protein-calorie malnutrition suppresses hepatic IGF-I production, decreasing negative feedback to the hypothalamus and pituitary. This results in increased GH production and secretion and thus elevated basal and stimulated serum GH levels. Inadequate food intake and malabsorption are both important causes of malnutrition. Decreased nutrient intake can result from oropharyngeal malformations (e.g., Pierre Robin sequence, cleft lip or palate), abnormal oral-motor function (e.g., pervasive developmental delay), as well as loss of appetite caused by use of certain medications (e.g., stimulants for treatment of attention deficit hyperactivity disorder or chemotherapeutic agents). Malabsorption can also cause malnutrition, and disorders such as celiac disease, inflammatory bowel disease, and cystic fibrosis can present as growth failure (see Chapter 111). Poor weight gain generally precedes the decrease, and eventual failure, of linear growth. Bone age and puberty are often delayed. Taking a detailed dietary history is essential to establishing this diagnosis. A 3-day diet log is a useful tool; this record can be analyzed for intake of total calories, macronutrients, and micronutrients. Laboratory evaluations should include all those involved in the evaluation for chronic illness.

Psychosocial Deprivation

Psychosocial growth failure, also known as psychosocial or deprivation dwarfism, is a disorder of growth associated with emotional deprivation, a pathologic environment, or both. It can affect children of all ages; failure to thrive is usually seen in infancy, but toddlers and older children often manifest bizarre behaviors surrounding food and eating and are frequently depressed. Delayed statural growth and puberty, growth arrest lines in long bones, and temporary widening of cranial sutures have been reported.

Chronic Systemic Illnesses

Many chronic illnesses are associated with short stature (see Box 73-1). General mechanisms include anorexia, nutrient malabsorption, chronic acidosis or hypoxemia, anemia, increased energy requirements, and medical therapy (e.g., glucocorticoids). In most children with short stature caused by chronic illness, weight tends to be depressed to a greater extent than height or there is a lag between the onset of weight deceleration and subsequent height deceleration. Bone age is usually delayed and approximates the height age. The growth curve typically shows a period of normal growth followed by growth deceleration or cessation consistent with the onset of illness.

Hypothyroidism

Growth failure is one of the most significant manifestations of hypothyroidism in children (see Chapter 68). Because most congenital hypothyroidism is detected with neonatal screening programs, most cases of hypothyroidism-associated growth failure are attributable to acquired hypothyroidism, most commonly from autoimmune Hashimoto (chronic lymphocytic) thyroiditis or from iodine deficiency. Growth retardation caused by acquired hypothyroidism can take several years to clearly manifest, but when it is clinically significant, it tends to be severe and progressive. Puberty is often delayed, but precocious puberty (still with a paradoxically delayed bone age) can be seen as well.

Measurement Techniques and Growth Charts

Measurement of length or stature must be accurate and reproducible to correctly assess the degree of interval growth. Children younger than 2 years should be measured in a supine position, children older than 3 years of age should be measured standing, and children in between can be measured either way depending on their ability to stand erect for the duration of measurement. Whether supine or standing, proper measuring technique is crucial; both processes involve fixed measurement equipment and proper positioning (Figure 73-3). Recumbent lengths should be plotted on the length (ages birth-36 months) growth charts and standing heights on the height (age 2-20 years) charts because a person’s length usually exceeds his or her height. A child’s current height and overall growth pattern should be interpreted within the context of standards typical for the local population. In the United States, most practitioners use the Centers for Disease Control and Prevention’s growth charts, which are percentile curves that illustrate the distribution by age, in U.S. children, of length or height, weight, head circumference (for ages birth-3 years), and BMI (BMI = Weight (kg)/Height (m)²). The data used to construct the updated 2000 growth charts were derived from cross-sectional population surveys rather than longitudinal studies following the same children over time. Thus, an individual’s growth pattern may differ somewhat from the standardized pattern, especially during periods of rapid growth when timing is important (infancy and the pubertal growth spurt).

Figure 73-3 Proper measurement techniques.

Specific Elements of the Physical Examination

When performing the physical examination, the practitioner should look for signs of underlying genetic abnormalities (e.g., dysmorphic features), midline defects suggesting possible hypothalamic or pituitary malformations (e.g., a central maxillary incisor), or systemic illness (e.g., papilledema, aphthous ulcers, rachitic rosary). The degree of dental maturation, which correlates with skeletal maturation (delayed dentition can imply delayed bone age), should also be assessed. Determining the child’s pubertal status using the Tanner staging criteria is a critical part of the examination (see Chapter 67). Disproportionate growth can be ascertained via measurement of the upper-to-lower body segment ratio (upper segment length is the distance from top of the head to the top of the symphysis pubis, and lower segment length is the distance from the top of the pubic symphysis to the floor; normal ratios are 1.7 : 1 at birth, 1.3 : 1 at 3 years of age, and 1 : 1 by age 7 years) and arm span (distance between the tips of the middle digits with both arms fully extended; normally arm span is less than standing height before age 8 years, equal to height at ages 8-12 years, and greater than height after age 12 years).

Bone Age

A radiograph of the left hand and wrist is used to determine the child’s bone age, which represents the maturation of the skeleton. The bone age is the only quantitative determination of somatic maturation, mirroring the tempo of growth and puberty and indicating the remaining growth potential. After the child is beyond infancy, an anteroposterior radiograph of the left hand and wrist is taken and compared with published standards (Greulich and Pyle or Tanner-Whitehouse); knee radiographs can be used at ages when hand and wrist films are not yet informative.

Diagnosis of Growth Hormone Deficiency

Because of the circadian rhythm of GH secretion, it is not useful to measure a random serum GH level. The evaluation of potential GHD involves measuring IGF-1 and its carrier protein, IGFBP-3. Further evaluation may include provocative GH testing and is best deferred to a pediatric endocrinologist. All children with diagnosed GHD warrant magnetic resonance imaging of the brain with designated pituitary cuts to exclude an intracranial tumor or structural abnormality as the underlying cause.

Management

Management of abnormal growth depends on the underlying cause: