Medical ProgressThe Biology of Stature
Section snippets
Clinical Vignette
A 6-year-old boy presents for evaluation of short stature. He was born at term with a length and weight appropriate for gestational age. By 2 years of age, his length percentile had dropped below the third percentile. Weight was less affected. He has been otherwise healthy. His mother and father are both 160 cm (63 in) tall. On physical examination, the boy's height is below the first percentile at −2.2 SDS. His sitting to standing height ratio is at the 95th percentile for age. His father's
Linear Growth in Children Is Driven by Growth Plate Chondrogenesis
Children grow taller because their bones grow longer. This bone elongation occurs at the growth plate, a cartilaginous structure that is located near the ends of many bones in children, including long bones, the short tubular bones of the hands and feet, and the vertebrae. The growth plate comprises 3 distinct layers: the resting, proliferative, and hypertrophic zones (Figure 1). Each zone has unique roles. The resting zone serves as a reservoir of progenitor chondrocytes.1 The proliferative
Linear Growth Is Rapid in Infancy but Subsequently Slows as the Result of Programmed Senescence of the Growth Plate
The human fetus grows rapidly. From 12 weeks of gestation until term, the length of the fetus increases from approximately 6 to 50 cm, an average growth velocity of 82 cm/year.3 If newborns were to maintain this growth rate after birth, the child would reach adult size before 2 years of age. The growth rate, however, declines rapidly after birth. The decline is temporarily interrupted by the pubertal growth spurt but then resumes until the growth rate reaches zero (Figure 2).4
The decline in the
Variations in Tempo of Growth, Including Catch-Up Growth
Importantly, growth plate senescence is not driven by time but rather by the process of growth itself.7, 16 Consequently, childhood malnutrition or systemic illness slows not just the rate of linear growth but also the rate of growth plate senescence.7, 17 If the illness resolves, the growth plates do not just resume a normal growth rate. Instead, the growth plates, which are less senescent than normal for age, function at the more rapid rate that would be appropriate for a younger child,
The Pubertal Growth Spurt
As reviewed previously, a local developmental program termed growth plate senescence causes the linear growth velocity in children to decline through infancy and childhood, reaching 5 cm/per year just before the onset of puberty (Figure 2)4; however, with puberty, the gonads increase production of sex steroids, which exert strong positive effects on linear growth (Figure 2). Estrogen contributes to the linear growth acceleration, in part by stimulating secretion of growth hormone by the
Short and Tall Stature Are Caused by Altered Rates of Growth Plate Chondrogenesis
Because linear growth in children is driven primarily by growth plate chondrogenesis, short stature is essentially always caused by decreased chondrogenesis in the growth plate and tall stature by increased chondrogenesis. The primary causes of short or tall stature can lie either in the growth plate itself (primary linear growth condition) or can lie outside the growth plate but affect chondrocytes through abnormal concentrations of hormones, cytokines, nutrients, and other molecules necessary
Regulation of Linear Growth
The rate of growth plate chondrogenesis, and therefore the rate of linear growth in children, is subject to extensive regulation by nutritional intake, hormones, inflammatory cytokines, paracrine growth factors, extracellular matrix factors, and intracellular proteins.
Short Stature Can Result from Numerous Genetic Defects Affecting Growth Plate Chondrogenesis
As discussed previously, growth plate chondrogenesis is under complex regulation at multiple levels, including nutritional, endocrine, cytokine, paracrine, extracellular matrix, and intracellular protein factors. Consequently, mutations in genes that participate in any of these levels of regulation can result in short stature. Even a mutation that diminishes growth plate chonodrogenesis by only 10% will produce clinically-significant short stature. The Table provides examples of the genetic
Normal Variation in Height and Polygenic Short Stature
Recent GWA studies have provided important new insights into the genetic determinants of stature. Large meta-analyses of GWA studies have identified more than 400 loci scattered throughout the genome that are associated with adult height in the general population.68 Although the precise gene that affects height at each locus cannot always be pinpointed, bioinformatics analyses indicate that a large subset of these genes affect height because of a role in growth plate cartilage.68, 69 Although
Conclusion
Growth plate chondrogenesis is the fundamental biological process that drives linear growth in children and therefore determines stature. Recently, a complex cartilage developmental program, termed growth plate senescence, has been elucidated that is responsible for the normal deceleration and eventual cessation of linear growth. Recent laboratory and clinical studies have revealed that estrogen accelerates growth plate senescence, thus explaining the clinical growth patterns seen in patients
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Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors declare no conflicts of interest.