Growth is an important characteristic of human development that occurs from the time of conception through the final stages of puberty. A variety of complex factors take place during growth, but as complex as it may appear, growth during infancy, childhood, and adolescence can be remarkably predictable. Different patterns of growth should alert the clinician to promptly identify any deviation from normality. The assessment of growth should be made at every patient visit by obtaining anthropometric measurements that are subsequently plotted in the appropriate growth chart. It is imperative for clinicians to understand the power of this graphic tool, because it displays the size and growth velocities of a child for categories including height, weight, head circumference, and body mass index. These are expressed as percentiles or standard deviations, indicating the size of the child compared to standards for the specific age and gender.1 The plotting of measurements makes it possible to track patterns of growth, and as long as no centiles of growth are crossed, the height velocity is within normal range for age. If percentiles of growth are crossed, either above or below, then the child is growing at a faster or slower pace, respectively, than average velocity.2Table 1 depicts normal growth velocities by age groups.
Normal Growth Velocity in Various Age Groups
The technique to obtain measurements is an operator-dependent process that should be performed using proper tools and techniques to get accurate and reproducible results. This includes using a recumbent measuring tool for children up to age 2 years for the measurement of length, and a wall stadiometer for older children where the measurement is reported as height. The clinician should be aware that the use of “floppy arm” devices, which are usually seen in conventional scales, may yield errors in measurement. Any deviation from what is considered normal can be classified as short stature if the height is more than 2 standard deviations (SD) below the mean for age (<3rd percentile).3 Slowing of the growth pattern compared to the child's prior growth trajectory or genetic potential should also be investigated, even if the height SD for the child is not below 2 SD. Such measurements can help determine if short stature or slow growth is physiologic or pathologic.
Physiologic Short Stature
Familial Short Stature
Familial short stature is considered a physiological variant. It is characterized by a height <3rd percentile, normal growth velocity (Figure 1), a bone age concordant with chronological age, family history of short stature, a height percentile consistent with mid-parental height, normal onset of puberty, and normal physical examination. Laboratory tests, if performed, are negative for pathologic causes of short stature.4
Familial short stature is a diagnosis of exclusion that is defined by the presence of short parents and an otherwise normal short child. Arrow indicates mid-parental height.
Constitutional Delay of Growth and Puberty
This is also a normal variant of growth characterized by growth deceleration at age 10 to 14 years followed by a delayed growth spurt between ages 14 and 17 years, delayed pubertal maturation, and a final adult height close to initial target height5 (Figure 2). In these cases, the usual treatment is careful observation and evaluation to rule out causes of abnormal growth. Bone age is often delayed when compared to chronological age and can be helpful to reassure a patient's caregivers. A history of constitutional delay (ie, “late bloomers”) is often found within the family.6 However, it remains a diagnosis of exclusion after pathological causes of short stature have been ruled out.5
Growth chart representing growth pattern of boys with constitutional delay of growth and puberty. Arrow indicates mid-parental height.
Pathological Short Stature
Small for Gestational Age
Small for gestational age (SGA) is defined as infants with birth length or weight 2 SD or more below the mean for gestational age.7 The fetus does not achieve the expected in-utero growth potential due to genetic or environmental factors. Intrauterine development is multifactorial and shows its greatest length velocity by mid-fetal life. A variety of growth restriction problems might occur during this period, including genetic, infectious, placental, and umbilical cord anomalies, and/or maternal problems (Table 2). Most SGA children will demonstrate catch-up growth to get closer to their genetic potential by age 2 years. For children who do not have adequate catch-up growth by age 2 years (approximately 10%), investigation is warranted.8–10
Intrauterine Factors Contributing to Short Stature
Dysmorphism and Chromosomal Abnormalities
Various chromosomal disorders may present with short stature as a main characteristic. Common examples include Down syndrome (DS) and Turner's syndrome (TS). Most of these patients achieve less than the average adult height predicted by the mid-parental height. Characteristic clinical features of these syndromes may not always be present. For example, some girls with TS with genetic mosaicism present with short stature even when they do not have the classic historical or physical stigmata of TS, and for this reason a karyotype should always be strongly considered in girls with short stature. Another condition associated with short stature is Noonan's syndrome, which is an autosomal dominant genetic disorder in which patients exhibit features of growth hormone (GH) resistance along with other dysmorphic features and cardiac anomalies. Short stature is also a prominent feature in patients with Russell-Silver syndrome (RSS) and in patients with mutations in the short homeobox gene located on the X chromosome (SHOX). In these patients, hormonal or other causes for short stature are usually not detected. Whether the short stature is treatable or not depends on the underlying etiology. Patients with TS, RSS, or SHOX mutation may benefit from GH therapy, whereas other conditions such as achondroplasia or skeletal dysplasia do not. Syndrome-specific growth charts are available and should be used for plotting heights for these children before determining if the child's growth pattern is appropriate for their underlying diagnosis.11
Abnormalities in stature may manifest in patients suffering from acute or chronic illnesses due to an increased demand for energy or nutritional deficiencies.12–14 Examples of systemic disorders and the effect they have on growth and development includes gastrointestinal malabsorption syndromes,12 in which an inflammatory process increases caloric requirements and decreases the amount of nutrients absorbed in the gastrointestinal tract. A cornerstone in the treatment of rheumatologic disorders is the use glucocorticoids,13,14 which contributes to growth failure by altering the normal physiology of bone metabolism and growth as well as GH secretion.15 In patients with any form of cancer, the neoplasm uses up a large proportion of the calories consumed, depriving the body of the energy necessary for normal growth of the child, thus causing poor growth. In addition, treatments with chemotherapy or radiotherapy inevitably lead to growth failure.16,17 Besides the abnormalities mentioned above, structural congenital cardiac disease causes an increased basal energy requirement, leading to abnormal weight and growth.18 Lastly, states of high-caloric demand (such as competitive athletics) in which nutritional requirements are not met may also cause growth attenuation. Most systemic illnesses present with height deceleration but the effect they have on weight is more pronounced (Figure 3). On the other hand, when there is growth deceleration with weight sparing, an endocrine etiology is more likely.
Growth chart representing growth pattern of children with a systemic illness. Endocrine causes of growth attenuation (hypothyroidism, growth hormone deficiency, Cushing syndrome) are not associated with decreased weight for height. Arrow indicates mid-parental height.
Endocrine causes of growth attenuation are associated with a decline in height percentiles while weight gain remains unaffected (Figure 4). In patients with endocrine disorders, the body mass index is usually normal or sometimes high. Hypothyroidism, GH deficiency, adrenal insufficiency, and Cushing syndrome can present with growth deceleration that leads to short stature if not identified and treated in timely manner. Untreated hypothyroidism, congenital or acquired, especially if longstanding, can present with slow growth and excess weight, bradycardia, delayed dentition, and cool and dry skin. Congenital GH deficiency should be suspected in a child with midline defects, such as cleft lip and palate, a single central incisor, microphallus, septo-optic-dysplasia, empty sella syndrome, or Rathke cleft cyst.19 Congenital GH deficiency may be present as an isolated hormonal defect or as a component of multiple pituitary hormone deficiencies. Unless proven otherwise, hypoglycemia and microphallus in a male infant are due to hypopituitarism (isolated GH deficiency or multiple pituitary hormone deficiencies). Acquired GH deficiency may develop due to disruption of normal pituitary structure or function, and causes for this include head trauma, tumors involving the suprasellar region (such as craniopharyngioma or pituitary adenomas), surgery to the central nervous system, and radiation to the brain; however, some cases remain idiopathic. GH is secreted in pulses, usually overnight, and therefore a random level may not have full diagnostic value. Surrogate markers of GH secretion, such as insulin-like growth factor-1 (IGF-1) and its binding protein (IGFBP-3), which have more stable levels, can be used as a screening test to assess GH secretion. Levels of IGF-1 and IGFBP-3 are typically low for age, gender, and pubertal stage-specific standards in patients with GH deficiency. Although IGF-1 values also depend on other factors, such as nutrition, IGFBP-3 values are less affected in these conditions.20 Among the etiologies of Cushing syndrome, endogenous cortisol excess is rare in the pediatric population. As with the adult population, iatrogenic Cushing syndrome (ie, secondary to administration of excessive doses of exogenous glucocorticoids) is most common. Endogenous causes can be either adrenocorticotropic hormone (ACTH) dependent or ACTH independent, and may be part of associated syndromes. In addition to slow growth, the classic symptoms and clinical presentation include truncal obesity with relative sparing/thinning of extremities, round facies, hypertension, and presence of acne and striae. Depending on the nature of Cushing syndrome, the clinical features may develop between 2 and 6 months (or longer in rare cases), leading to a delay in diagnosis.21 Striae in Cushing syndrome are purple colored and “violaceous,” are >1 cm in diameter, and should be differentiated from the thin, pink or pale striae seen with obesity due to other causes.
Growth chart representing growth pattern of children with an endocrine “nonsystemic illness.” Endocrine causes of growth attenuation (hypothyroidism, growth hormone deficiency, Cushing syndrome) are associated with decreased height for weight. Arrow indicates mid-parental height.
Investigating Short Stature
The initial diagnostic approach should include obtaining an adequate pregnancy history, pertinent birth and developmental history, and a complete family history including maternal and paternal heights to be able to calculate mid-parental height (Table 3). Determining the mid-parental height is an important part of the investigation because often short children with growth problems have short parents, and thus have familial short stature.3 It is a good practice to measure the parents' heights to calculate mid-parental heights rather than using reported heights, as parents frequently report their own heights inaccurately.
Formulae for Calculating Mid-Parental Height
A thorough physical examination looking for characteristics that deviate from a normal phenotype is of crucial importance, as it can guide the clinician on further laboratory evaluations. In addition, the growth pattern plotted in a growth chart will help the clinician pursue further evaluation. With this information, the clinician can then use a bone age X-ray (a plain X-ray of the left wrist and hand) to compare to an atlas of norms for age and gender.22 A delayed bone age (bone age younger than chronological age) in a child with short stature may indicate conditions such as hypothyroidism, GH deficiency, constitutional delay of growth, and some forms of skeletal dysplasia. On the other hand, an advanced bone age (bone age older than skeletal age) in a child with short stature is far less common but can be seen in patients with Cushing syndrome,23 precocious puberty (initially growth is accelerated and child tall for age, but is then associated with advanced skeleton maturation, earlier cessation of growth, and final height shorter than expected), and some skeletal dysplasias. Bone age can also be used to project adult height and determine if the child will achieve a stature that corresponds to his or her genetic potential.
Laboratory tests that can be performed when evaluating short stature include a complete blood count (to look for evidence of anemia, acute or chronic infections, inflammation), complete metabolic panel (to look for acidosis, electrolyte imbalance suggestive of disorders such as diabetes insipidus, adrenal insufficiency, evidence of liver or kidney disease), thyroid-stimulating hormone and total/free T4 (determination of thyroid function), determination of IGF-1 and IGFBP-3 (as surrogate markers of growth hormone secretion), erythrocyte sedimentation rate (to rule out intestinal inflammatory conditions such as ulcerative colitis and Crohn's disease), and tissue transglutaminase immunoglobulin A (IgA) and total IgA (to screen for celiac disease). A karyotype may also be performed as a part of screening evaluation in the appropriate situation (eg, when clinical features of TS or Down syndrome are present or in a significantly short girl even without clinical features of TS). Second tier evaluation includes genetic testing for specific conditions depending on clinical suspicion and endocrine studies. Although establishing a genetic diagnosis may provide prognostic information, treatment decisions may also be based on this information. Patients with TS, SHOX mutation, or RSS are conditions that are candidates for GH therapy to improve height outcome. Figure 5 shows a flowchart summarizing evaluation of short stature.
Flowchart summarizing the clinical approach for evaluating a child with short stature. SD, standard deviation.
Once a primary care physician (PCP) has identified a child with short stature and/or slow growth, the most important task is to differentiate physiological variants from pathological conditions. Observation and reassurance is the most common strategy taken when evaluating a child with familial short stature or constitutional delay, because these are normal variants of growth and development.24 If nutritional support is required in an underweight child, this can be addressed in the primary care setting. Screening laboratory tests, as discussed above, can be performed by the PCP. Results of these tests and the growth pattern will help the PCP to decide whether and what kind of subspecialist to which a child should be referred. For example, a child with poor weight gain and secondary poor growth and positive celiac screen should be referred to a gastroenterologist for further evaluation, but a child with growth failure with normal weight gain and evidence of hypothyroidism should be referred to an endocrinologist. An endocrine evaluation may also be sought if the screening laboratory tests are inconclusive so that further testing, including second tier tests as discussed above, can be performed.
Human growth is a process influenced by many factors that work in conjunction to determine final height. The hormonal and genetic complexities account for variance in normal growth patterns and also for disordered growth. The importance of following the growth pattern of children plotted in a growth chart and pubertal staging should not be downplayed, as it provides an opportunity for early identification of abnormal growth pattern. Any deviation from a child's previous growth pattern or what is considered normal for his or her age, pubertal stage, or family background should prompt the clinician to start an investigation. Slow growth and weight sparing is a hallmark feature of endocrine disorders. On the other hand, if both height and weight are affected, the clinician should consider a variety of nonendocrine causes, including genetic disorders. Understanding of the physiological mechanisms of growth and development has improved our ability to diagnose and treat growth disorders. Although many children with short stature or slowed growth may have variants from normal patterns, vigilance and timely investigation on the part of a PCP can lead to prompt identification of children with health disorders that require treatment and further evaluation by a subspecialist.
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- American Academy of Pediatrics. Recommendations for preventive pediatric health care - periodicity schedule. https://www.aap.org/en-us/Documents/periodicity_schedule.pdf. Accessed December 15, 2017.
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Normal Growth Velocity in Various Age Groups
||Growth Velocity Per Year
|Birth to 12 months
||23–27 cm (9.06–10.63 in)
|12 months to 2 years
||10–14 cm (3.94–5.51 in)
|2 years to 3 years
||8 cm (3.15 in)
|3 years to 5 years
||7 cm (2.76 in)
|5 years to puberty
||5–6 cm (1.97–2.36 in)
||Girls: 8–12 cm (3.15–4.72 in)
Boys: 10–14 cm (3.94–5.51 in)
Intrauterine Factors Contributing to Short Stature
|Fetal genetic abnormalities
||Aneuploidy, uniparental disomy, single gene mutations, partial deletions or duplications, ring chromosome, aberrant genomic imprinting
|Maternal genetic abnormalities
||Mothers that experienced growth restriction at birth
||Cytomegalovirus, toxoplasmosis, rubella, varicella-zoster, malaria, syphilis, herpes, zika virus
||Birth, prepregnancy, and gestational weight; multiple gestations, preeclampsia, short inter-pregnancy period; umbilical cord and placental pathology
|Teratogens and environmental exposure
||Tobacco, caffeine, alcohol, drugs
Formulae for Calculating Mid-Parental Height
||[Paternal height (cm) – 13 cm + Maternal height (cm)] ÷ 2
[Paternal height (in) – 5 in + Maternal height (in)] ÷ 2
||[Paternal height (cm) + 13 cm + Maternal height (cm)] ÷ 2
[Paternal height (in) + 5 in + Maternal height (in)] ÷ 2