Somatic Growth and Maturation
Determinants of Normal Growth
The body grows primarily through proliferation of cells by mitosis.1,2 In contrast, increased cell size generally plays a greater role in organ growth as development approaches completion. Growth factors and other environmental signals are necessary for the entry of a quiescent cell into the cell cycle, and they affect cell division by modulating passage through the first phase of the mitotic cell cycle (G1).3,4 The first subphase of G1 requires “competence factors,” such as fibroblast growth factor, which induces cells to become competent to synthesize DNA. Cells then require essential amino acids to progress to a critical point in the cycle at which “progression factors” can induce completion of G1. Progression factors are exemplified by insulin-like growth factors (IGFs), insulin, thyroxine, and hydrocortisone. Growth factors modulate the internal regulatory pathways governed by cyclins and cyclin-dependent kinases (CDKs), which are proto-oncogenes, and CDK inhibitors (CDKI), which are tumor suppressors. Specifically, growth factors lead to accumulation of the D-type cyclins, which sense and mediate growth factor stimulation in G1. The binding of cyclin D with CDK 4/6 results in phosphorylation of “pocket” proteins (pRb, p107, and p130) and release of inhibitory control of these proteins on the E2F family transcription factors, which then drive expression of various effectors of DNA synthesis.5 It is important to note that free E2F initiates a positive feedback loop by increasing cyclin E transcription and protein stabilization, because binding of cyclin E with CDK2 also phosphorylates pocket proteins and causes further release of E2F. The balance between cyclin, CDK, and CDKI activity therefore determines the start of DNA synthesis (S phase of the cell cycle). From this point onward, cell-cycle processes depend entirely on intracellularly triggered controls involving cyclins. After completing DNA synthesis, the cell finishes doubling its entire contents (G2 phase) and then undergoes the M phase of the cycle, during which cell division is completed.
The cell cycle to a great extent is also regulated by nuclear factor-κB (NF-κB).6 This transcription factor is held inactive in the cytoplasm when bound to its inhibitory partner Iκβ. When Iκβ undergoes regulated serine phosphorylation, it is polyubiquinated, which targets it for degradation within the proteosome. This releases NF-κB to move to the nucleus, where it promotes cell-cycle progression and inhibits programmed cell death (apoptosis).
Cell senescence is the response of the cell to conditions such as telomere attrition, DNA damage, and oncogene activation—processes that appear to be interrelated. During each mitotic cycle, a portion of the terminal end (the telomere) of each chromosome is lost; this eventually shortens the chromosome to the point where cell proliferation becomes impossible and the cell dies.7 The enzyme telomerase supports the synthesis of telomeric DNA, which maintains telomere length and proliferative potential. Telomerase is present in somatic cells of the fetus, permitting continued growth. With maturation of the fetus, however, telomerase levels begin to fall and decline progressively with aging, thus limiting mortality.
Somatic Growth
Prenatal and postnatal requirements for growth differ in several respects. Embryonic growth is determined primarily by genetic programming of local sequential inductions.8 Coordination of cell differentiation and morphogenesis requires a class of developmental genes that belong to the homeobox family.9–11 Homeobox genes encode transcription factors that bind DNA, thereby controlling gene expression, cell differentiation, and organ development. Abnormalities of several homeobox genes are known to cause organ malformation and to affect linear growth. Fetal growth depends heavily on the delivery of nutrients, metabolic substrates, and oxygen, as well as IGFs, from the mother. The placenta regulates many of these and contributes to the fetal nutritional and hormonal milieu.12–14 Placental size is a determinant of fetal growth, and placental growth itself is influenced by genomic factors,14,15 growth factors, maternal weight and nutrition (perhaps via leptin),16 parity, parental size,17 and uterine blood flow. Placental regulation of fetal blood flow is, in turn, a determinant of growth; discordance in the size of monozygous twins has been attributed to the unequal distribution of blood flow that results from placental arteriovenous anastomoses.18
Both placental growth and function involve hormones. Specific deletion of placental IGF-2, which is an imprinted gene expressed from the paternal allele, sequentially reduces placental growth, decreases nutrient delivery, and restricts fetal growth.14 The placenta also influences fetal growth through its elaboration of hormones. For example, human placental lactogen seems to influence regulation of fetal IGF-1,19 although the role of the placental variant of GH in regulating fetal IGF-1 and growth remains unclear.20,21 Umbilical cord leptin appears to be an index of fetal nutrition in humans and correlates with birth size independent of IGF-1.22,23
Familial and environmental variables that predict birth size independent of gestational age include parental heights, sibling birth weight, maternal weight, parity, glycemic status and history of smoking, altitude, gender, and uterine constraints, such as the number of fetuses carried.17,24–30
Some of the hormonal requirements for fetal growth differ from those that regulate postnatal growth. For example, prenatal growth is less dependent on GH and thyroxine. Individuals with congenital GH deficiency or resistance often have normal birth length despite low IGF-1 levels, although in large population studies, average birth length is reduced by 1 standard deviation (SD).12,31,32 Similarly, newborns with congenital hypothyroidism typically have normal birth size, although their bone maturation lags during the last trimester.33
In contrast, the IGF system affects prenatal and postnatal growth, although specific influences and regulatory components differ according to stage of development. Immunoreactive IGF is present in most fetal tissues. Rodent models that lack IGF-1, IGF-2, or the IGF-1 receptor have reduced birth weights, suggesting a role for both IGF-1 and IGF-2 in prenatal growth.34–37 IGF-1 and IGF-2 act through the IGF-1, insulin, and IGF-2 receptors, and IGF-2 is approximately equal in importance to IGF-1 for fetal growth, each contributing about 40%.37,38 IGF-2 abundance in early pregnancy promotes fetal growth and viability near term, primarily through effects of IGF-2 on placental growth and differentiation.39 IGF-1, in contrast, is important for fetal but not placental growth, and its effects are mediated by decreased release of vasoconstrictors, thus optimizing placental blood flow and nutrient delivery to the fetus. Six IGF binding proteins (IGFBPs) regulate the amount of free IGF available and are regulated in turn by IGFBP proteases. High levels of IGFBPs have been associated with fetal growth inhibition, likely from sequestration of fetally derived IGF-1.40–43 IGFBP-3 also prolongs the half-life of IGFs in circulation, and levels are reduced in the cord serum of small for gestational age (SGA) fetuses.44
Pregnancy-associated plasma protein A (PAPP-A), which cleaves IGFBP-4, increases free IGF availability,45 and low first-trimester PAPP-A levels in pregnant women are associated with lower birth weight.46
In contrast to fetal growth, postnatal growth is less dependent on IGF-2 than on IGF-1 levels. Whereas animals lacking IGF-2 that survive may have relatively normal postnatal growth, those with IGF-1 deficiency remain stunted. During fetal life, IGF-1 is relatively independent of GH and is regulated greatly by nutritional status (particularly glucose availability and consequent fetal insulin secretion) and placental lactogen, whereas postnatal levels are dependent on both GH and nutritional status.8,12,19,31 Although the serum IGF level is even lower prenatally than in infancy, it rises during gestation and correlates with size at birth.12 IGF-2 blood levels are higher than those of IGF-1 in utero, in contrast to postnatal life. Human correlates, substantiating the role of IGFs in prenatal growth, are the identification of a patient with homozygous partial deletion of the gene encoding IGF-1 and identification of patients with IGF-1 receptor mutations with severe intrauterine growth retardation, as well as postnatal growth failure.47
In addition to IGFs, insulin influences fetal growth. Infants of diabetic mothers and children with Beckwith-Wiedemann syndrome (with hyperinsulinism) have excessive fetal growth, and those with pancreatic agenesis have poor fetal growth. Mutations in the insulin receptor and in IRS-1, a downstream molecule in the signaling pathways of both IGF-1 and insulin receptors, are also associated with suboptimal fetal growth and insulin resistance.48
Sex hormones may play a subtle role in normal fetal growth: Plasma levels of testosterone, estradiol, and dehydroepiandrosterone are at or above pubertal levels by mid-gestation; estrogen promotes fetal bone development49; and androgen action seems to account for the greater birth weight of boys compared with girls.8,31
An understanding of the regulation of fetal growth has assumed particular importance because of potential links between prenatal growth and later disease. Strong experimental evidence in animal models indicates that an adverse fetal environment, as reflected in birth size, can lead to a poor health outcome in adults.50 Diverse causes of poor fetal growth (including maternal undernutrition or glucocorticoid exposure) can have similar deleterious effects on postnatal health (including hypertension, cardiovascular disease, and glucose intolerance). Considerable human data support such a “fetal origins of adult disease” model.36 The risks for insulin resistance, diabetes, and visceral adiposity are particularly high in SGA infants with rapid postnatal “catch-up growth.”51–53 Although the underlying mechanisms are not fully understood, evidence points to the development of a “thrifty” phenotype, with fetal metabolism adapting to undernutrition through epigenetic modifications in key genes (including the glucocorticoid receptors, peroxisome-proliferator–activated receptor [PPAR-α], Pdx1, and Glut4), which persists into adulthood.54–56 Another proposed mechanism invokes a defect in placental inactivation of maternal cortisol due to decreased 11β-hydroxysteroid dehydrogenase activity, leading to elevated fetal cortisol and reprogramming of the hypothalamic-pituitary-adrenal axis for hyperresponsiveness to stress.57 Dehydroepiandrosterone (DHEAS) and androstenedione levels have been reported to be higher in SGA children,58 and early pubarche and polycystic ovary syndrome (PCOS) may be important sequelae of SGA.59 In addition, a reduction in the total number of nephrons as a consequence of intrauterine growth retardation with compensatory effects influencing the renin-angiotensin system may predispose these individuals to subsequent hypertension.60
Postnatal Growth
Familial and environmental determinants of early postnatal growth include gestational age at delivery, birth size, parental heights, socioeconomic status, and breastfeeding.17
Genetic determinants exist for both postnatal and prenatal growth.61 Genes on the Y chromosome seem to enhance stature commencing in antenatal life,61,62 and the X chromosome carries genetic determinants, including the SHOX gene (see Skeletal Dysplasias below), which promotes linear growth and regulates body proportions.61,63 The epigenetic process of genomic imprinting, like X-inactivation, is due to methylation of genes to silence them,15 and clusters of autosomal “imprinted” genes also regulate growth. Although the exact nature of most imprinted genes is unknown, the genes for IGF-2 and its receptor on chromosome 15 are imprinted. The IGF-2 gene is silenced in eggs and thus is maternally imprinted, whereas the IGF-2 receptor is paternally imprinted. Other genes that regulate height include those implicated in Noonan syndrome64 and other genetic causes of short stature (described later). In addition, genome-wide analysis has allowed the identification of single nucleotide polymorphisms in regions that include candidate and novel genes and implicate pathways (let-7 targets, chromatin remodeling proteins, Hedgehog signaling) that may regulate height.65,66
The axial and appendicular skeletons account for the vast majority of postnatal linear growth. These bones are formed by endochondral ossification, which commences with chondrocytes of the epiphyses laying down an orderly cartilage template, which osteoblasts then convert to bone.67–69 The cranium and some of the clavicle are formed by direct intramembranous ossification. The cycle of bone cell remodeling for structural purposes is linked closely to the overall metabolic needs for calcium and phosphorus homeostasis, primarily through the actions of parathormone and calciferol. Chondrocyte proliferation is inhibited by parathyroid hormone–related protein (PTHrP) and fibroblast growth factor (FGF) paracrine signaling mediated through the PTH receptor and FGF receptor 3 (FGFR3). This effect is opposed by Indian hedgehog signaling, which operates in a negative feedback loop with PTHrP. The natriuretic factor system, particularly involving the C type, similarly appears to play a local role in endochondral ossification, in this case as positive regulators.70,71
Nutrition and metabolism must be adequate for normal growth. Adult height has been used as a marker for the nutritional status of populations during childhood and has been shown to be related to cognitive function.72,73 Calories seem particularly critical for cell multiplication. Two percent to 13% of normal energy consumption goes into promoting growth.1,74 Protein intake is particularly important for normal growth in cellular size. It must be adequate with respect to both amount and provision of essential amino acids or their ketoanalogues.75–77 Essential fatty acids are necessary for normal growth in lower animals, but this may not hold true for primates.78 Vitamins A and D are important for normal growth.1,79 Trace metals, such as zinc and copper, are probably essential for normal growth and sexual maturation80–83 because of their role as cofactors for enzyme function. The pH must be maintained at optimal levels to conserve mineral homeostasis.84
The general level of activity seems to promote overall body growth, just as normal muscular activity is necessary for limb growth. The mechanism is unclear; it may be related to neural trophic factors or to blood flow. The efficiency of nitrogen accretion and growth is decreased in inactive rats.85
