Evaluation of Short and Tall Stature in Children

Short stature is defined as height > 2 standard deviations (SD) below the mean height for age.
Tall stature is defined as height > 2 SD above the mean height for age.
Initial evaluation includes:
- Comprehensive history
- Physical examination
- Serial height measurements on CDC or WHO growth charts.
- Calculate estimated adult height and compare with midparental height
- Determine bone age
- Laboratory testing in select patients
Common causes of short stature:
- Constitutional delay of growth and puberty
- Familial short stature
- Idiopathic short stature
Pathologic etiologies (less common):
- Nutritional deficiencies
- Systemic disease
- Growth hormone deficiencies
- Genetic abnormalities
Common causes of tall stature:
- Constitutional advancement of growth
- Familial tall stature
- Obesity
Uncommon causes of tall stature:
- Precocious puberty
- Marfan syndrome
- Klinefelter syndrome
Referral to pediatric endocrinology is indicated for:
- Idiopathic short stature
- Management of select genetic and metabolic conditions
- Interventions to correct growth

Normal Childhood Longitudinal Growth

Varies with age.
Dependent on endocrine, paracrine, cytokine, nutritional factors, and physical mechanisms acting on the growth plate.
Newborn size is based on the intrauterine environment and influenced by genetic, maternal, and fetal factors.
Starting at approximately 6 months, children undergo catch-up or catch-down growth until they reach their genetically determined growth velocity.
Continues until 18-24 months of age.
During this time, growth hormone (GH) and insulin-like growth factor 1 play an increasing role in development.
During adolescence, sex hormones that drive puberty are exerting increasing influence on longitudinal growth.

Evaluation of Growth

First step: plot accurate anthropometrics on a growth chart and review past values.
Growth measurements should be recorded and plotted on a growth curve based on age, sex, and gestational age at birth.
Table 1 outlines anthropometric recommendations for well-child visits and evaluation by age.
WHO growth charts should be used for children < 2 years.
CDC growth charts should be used for children $≥ 2$ years.
WHO growth charts were derived from a multinational cohort of infants who were exclusively breastfed.
CDC and WHO growth charts available at: https://www.cdc.gov/growthcharts/index.htm
To account for variation in growth for children with specific conditions (e.g., prematurity, trisomy 21, Turner syndrome, achondroplasia), alternate growth charts are available.
Evaluate change in length and height over time (i.e., growth velocity) using multiple measurements every 3-6 months in children > 6 months to identify growth abnormalities.
Table 2 shows normal growth velocity values by age group.
Shorter intervals between measurements may be appropriate for younger children and specific clinical situations.
Percentile lines on CDC and WHO growth charts correspond with normal growth velocities for age and sex.
Height deviating more than two major percentile lines represents abnormal growth compared with peers.
Growth patterns in children with short and tall stature are shown in Figure 1.

Genetic Potential

Predicted adult height should be compared with sex-adjusted calculated midparental height.
This accounts for the genetic contribution of the biologic parents to the child’s growth.
It's used to establish normal vs pathologic short stature
Predicted adult height is estimated by projecting the current growth curve percentile for height into adulthood.
If bone age is found to be delayed or advanced, bone age should be used instead of chronologic age.
A normal predicted adult height falls within 2 SD (approximately 10 cm [3.9 in]) of calculated midparental height.
Identifying tall or short parents (more than 2 SD above or below normal adult height) could indicate a causative genetic etiology for the child’s growth abnormality.

Bone Age

Bone age should be obtained and compared with chronologic age to assist in identifying the cause of tall or short stature.
Typically, imaging should be performed on the non-dominant hand and wrist.
Ossification patterns should be evaluated and scored to determine bone age.
Bone age that is less than chronologic age by more than 2 SD is delayed.
Bone age greater than chronologic age by more than 2 SD is advanced.
Bone age that is more than 2 SD from chronologic age is associated with an increased risk of underlying pathologic etiology.
The use of new software programs that evaluate radiography and other technologies such as ultrasonography, magnetic resonance imaging, and dual-energy x-ray absorptiometry is increasing in the evaluation of bone age.
Current methods for the assessment of skeletal maturation are based primarily on a White population and are not necessarily generalizable to children of other ethnicities.

Body Proportions

Measurement of body proportions (i.e., upper to lower body segment ratios, arm span, or sitting height) is not necessary during the initial evaluation of short and tall stature.
Patterns in these measurements are suggestive of specific genetic conditions and syndromes (e.g., individuals with Marfan syndrome will have an arm span to height ratio greater than 1.05).

Short Stature

Short stature is defined as height that is more than 2 SD below the mean height for age.
This corresponds to a height at or below the 2.3rd percentile.
The CDC growth charts include a 3rd percentile growth line, and plotted height percentiles that fall below this line may identify short stature in children and be used to guide the need for further evaluation.
Evaluation of short stature usually reveals a nonpathologic growth variant such as familial short stature, constitutional delay of growth and puberty, or idiopathic short stature.
Pathology is present in approximately 5% of children with short stature and includes endocrine disorders, gastrointestinal disorders, nutritional deficiencies, medication use, genetic abnormalities, systemic disease, and GH deficiencies.
Idiopathic short stature is diagnosed in children when the evaluation does not identify a known classification or etiology.

Evaluation

The initial evaluation of short stature should include:
- Obtaining a history
- Performing a physical examination and growth assessment with anthropometrics plotted on a growth chart
- Comparing predicted adult height with calculated midparental height
- Performing radiography to determine bone age
History should include identification of drug therapy (e.g., steroids, anticonvulsants, medications for attention deficit/hyperactivity disorder) or environmental exposures (e.g., lead) that may contribute to short stature.
Growth assessment may show:
- Elevated height for weight or low body mass index (BMI) percentile, which is suggestive of malnutrition or malabsorptive disease.
- Low height for weight or high BMI percentile is suggestive of hypothyroidism, GH deficiency, and glucocorticoid excess.
Midline abnormalities, such as cleft lip or palate, suggest a deficiency in GH. Dysmorphic characteristics suggest a syndromic or genetic disorder.
In children with an initial evaluation that is concerning for a genetic, endocrine, nutritional, or gastrointestinal disorder, further laboratory evaluation is appropriate.
Table 4 shows the differential diagnosis of short stature in children.
Genetic testing or karyotyping should be performed in children with syndromic features. This testing may be deferred until pediatric endocrinology consultation.
Delayed bone age is associated with constitutional delay of growth and puberty, GH deficiency, hypothyroidism, celiac disease, anemia, other systemic illness, and malnutrition.
A normal bone age is consistent with familial short stature and idiopathic short stature.
In more than 60% of cases, children with short stature will have one of three diagnoses: constitutional delay of growth and puberty, familial short stature, or idiopathic short stature.
Figure 2 outlines an approach for the evaluation and diagnosis of short stature in children.

Referral

Referral is indicated in children who require consultation with gastroenterology, genetics, or endocrinology.
If pharmacologic treatment options are being considered, they are usually prescribed with the assistance of a pediatric endocrinologist.
Consultation before puberty is optimal for achieving projected midparental height.
Table 5 describes indications for referral.

Select Causes

Constitutional Delay of Growth and Puberty:
- Children with constitutional delay of growth and puberty typically experience decreased growth velocity between 6 and 18 months of age, after which, they experience a period of normal growth that parallels growth curves on standardized charts.
- Bone age is delayed.
- Onset of puberty is also delayed, but when it occurs, the child will experience catch-up growth and achieve a normal adult height.
- Specialty referral is not typically warranted; however, hormone therapy to induce puberty may be considered in children with delayed puberty if their growth delay causes significant psychological distress.
GH Insufficiency or Deficiency:
- Changes in the GH axis affects an estimated 1 in 1,100 to 1 in 8,000 children with short stature.
- The GH axis may be affected by congenital or acquired factors.
- There are multiple genes with loss-of-function or gain-of-function variations that can impact the GH axis.
- Children with acquired cases of GH insufficiency may have a history of head trauma, birth trauma, central nervous system infection, or cranial irradiation.
- Those with congenital cases of GH deficiency or insufficiency may grow normally initially, but neonatal history may reveal significant and prolonged hypoglycemia or jaundice in the newborn period.
Small for Gestational Age:
- Children born small for gestational age (SGA) will usually undergo catch-up growth by 4 years of age.
- Despite this, 10% to 15% of children born SGA meet the criteria for short stature.
- Those who do not undergo catch-up growth in the first 6 months or those who meet criteria for short stature at 2 years of age should prompt further evaluation. It may take more than 4 years for a preterm infant who is born SGA to attain a normal height.
Idiopathic Short Stature:
- Idiopathic short stature is defined as short stature in the absence of an identified etiology after a comprehensive evaluation; it is a diagnosis of exclusion.
- Pediatric endocrinology referral is appropriate for those who wish to discuss diagnosis, corrective therapy, and further evaluation.

Treatment

The mainstay of treatment for short stature is recombinant GH therapy.
The US Food and Drug Administration has approved recombinant GH therapy for GH deficiency or insufficiency, Turner syndrome, Prader-Willi syndrome, Noonan syndrome, chronic kidney failure, children born SGA without catch-up growth, those with short stature homeobox-containing (SHOX) gene deficiencies (e.g., SHOX gene deficiency or haploinsufficiency), and idiopathic short stature.
Individualized therapy should be started as soon as possible after diagnosis to achieve optimal height potential.
Treatment is typically continued for at least 1 year, with the goal of normalizing height, and should be discontinued when good height velocity is achieved or if there is an inadequate response to therapy.
Daily GH injections cost at least $25,000 annually, with reimbursement from insurance companies varying widely.
Expected mean height gain with therapy is 4 to 9 cm (1.6 to 3.5 in).
Recombinant GH therapy is generally well-tolerated, but adverse effects may occur including peripheral edema, headache, myalgia, arthralgia, glucose intolerance, slipped capital femoral epiphysis, and an increased incidence of scoliosis.
Additional research is being conducted regarding the use of targeted recombinant human insulin-like growth factor 1 and recombinant GH therapy for the treatment of genetic variations.
For males, injectable testosterone may be used to increase height velocity by speeding the onset of puberty; however, therapy does not increase adult height.

Tall Stature

Tall stature is defined as height that is more than 2 SD above the mean height for age and sex.
This corresponds to the 97.7th percentile on growth charts.
Tall stature should also be considered when the estimated adult height is more than 2 SD above the calculated midparental height.
Most children with tall stature have one of the following diagnoses: familial tall stature, constitutional advancement of growth, or obesity.
Familial tall stature should be suspected when one or both parents are tall and the child’s predicted adult height is within 2 SD of midparental height (approximately 10 cm [3.9 in]).
A typical growth pattern for constitutional advancement of growth includes early growth between 2 and 4 years of age, a period of normal growth velocity, advanced bone age, and early onset of puberty. Pubertal growth ends early and final adult height is normal.
Obesity is associated with early height growth and early puberty, which mimic the growth pattern of constitutional advancement of growth, and includes the finding of advanced bone age. Obesity-related tall stature results in a normal, final adult height.

Evaluation

The evaluation of tall stature in children should include:
- Obtaining a birth, developmental, and family history
- Performing a physical examination
- Measuring anthropometrics and plotting the measurements on WHO or CDC growth charts
- Comparing predicted adult height with calculated midparental height
- Performing radiography to determine bone age
The evaluation of suspected familial etiologies should include a review of ophthalmologic, cardiac, and musculoskeletal conditions and developmental abnormalities in tall family members.
The initial physical examination should include age-appropriate measurements of height and weight, head circumference, BMI, and an examination focusing on dysmorphic features and signs of early puberty.
Suspicion for syndromic causes of tall stature should be referred to a clinical geneticist or other specialist as indicated.
Figure 3 describes an approach to the evaluation of tall stature.
Laboratory tests are appropriate for the evaluation of other suspected etiologies (Table 6).
More extensive studies may be indicated in consultation with a pediatric endocrinologist to further clarify the diagnosis.

Treatment

Treatment is typically not needed for children with tall stature who are otherwise healthy.
For children with genomic syndromes, treatment should occur in consultation with a pediatric endocrinologist and target the syndromic cause.
Medical and surgical options are available for the treatment of tall stature.
The use of dose-dependent estradiol or testosterone to induce early epiphyseal closure or early puberty has been studied and is associated with slightly decreased adult height in females. This therapy may be associated with an increased risk of melanoma and decreased fertility.
A reduction in height of up to 5 cm (2 in) may be achieved with a bilateral epiphysiodesis of the distal femur and proximal tibia and fibula. This procedure is uncommon and controversial.