A diagnostic approach to pathologic short stature is presented in . This approach first requires that one differentiates between isolated short stature and short stature that is associated with other physical and/or developmental abnormalities. If the child falls within the latter group, the physician must then differentiate between proportionate and disproportionate short stature. A careful physical examination with measurements is necessary to determine whether there is a disproportionate body habitus.
Diagnostic algorithm for genetic evaluation of short stature.
The differential diagnosis of isolated short stature includes nonpathologic and pathologic familial short stature, constitutional growth delay (as discussed earlier), a primary endocrinopathy (), short stature in girls with X chromosome abnormalities (i.e., Turner syndrome or its variants), or short stature secondary to mutations in the SHOX gene. Although most SHOX gene mutations result in characteristic skeletal changes (Madelung deformity and mesomelia), mutations have also been identified in familial and simplex cases of idiopathic short stature.6
The skeletal changes of dyschondrosteosis may not be apparent until late childhood or pubertal age and are less commonly noted in males.6
The reported frequency of SHOX gene mutations in children with idiopathic short stature has varied from 1.1% to 12.5% depending on selection criteria and testing methodology.7
For this reason, skeletal survey should be considered in some cases of familial short stature to look for subtle changes that might be diagnostic. If there are any clinical or radiographic findings suggestive of dyschondrosteosis, SHOX gene testing could be considered. Skeletal survey should also be considered in cases with significant short stature (>3 standard deviations) if no other diagnosis is apparent.
Short stature with endocrinopathy
Review of the clinical, developmental, and family histories and a detailed physical examination are required to document the presence of major and/or minor malformations, degree of developmental delay if present, and other features that would suggest an underlying chromosome abnormality or recognizable syndrome.
If physical examination reveals disproportionate short stature, a skeletal survey () is recommended to look for evidence of a skeletal dysplasia. Molecular genetic testing is available for confirmation of some of these conditions (). In some of the more mild skeletal dysplasias, a skeletal survey performed in the first years of life may not be diagnostic, and periodic clinical and radiographic reevaluation is necessary. In other disorders, e.g., chondrodysplasia punctata, the characteristic features may be missed by taking the radiographs too late.
Selected skeletal dysplasias/dysostoses
If physical examination reveals proportionate short stature, a detailed physical examination may reveal signs that are consistent with a recognizable genetic syndrome. Molecular genetic testing is available for confirmation of some of these conditions (). If physical examination does not suggest a recognizable syndrome, then chromosome analysis should be performed, which has the added advantage of addressing the potential of mosaicism. If this analysis is negative, genomic array studies may be considered to evaluate for changes in genome copy number.
Short stature and other anomalies
For the children with intrauterine onset of short stature, the approach is similar to that of the older child with short stature. Comparison should be made of the infant’s birth weight, birth length and birth head circumference, body proportions, and documentation of major and minor anomalies. Depending on the age at which the SGA infant is being evaluated, assessment of the postnatal growth pattern will also yield clues to the underlying etiology. Selected syndromes associated with IUGR for which the genetic basis is known are presented in . Testing useful in the evaluation of infant with prenatal onset growth deficiency is presented in .
If no diagnosis is apparent after initial clinical evaluation and appropriate laboratory or radiographic studies, periodic reassessment is indicated. The timing of reassessment will depend on the child’s age, whether or not there are other significant developmental or physical features present, the family’s interest or anxiety, and changes in the family history. A specific diagnosis may become apparent or the differential diagnoses altered with evolution of the phenotype and additional family history that may become available. Furthermore, new diagnostic tests and techniques may allow diagnosis or confirmation of a clinical diagnosis in the future.