Children With Idiopathic Short Stature: An Expanding Role for Genetic Investigation in Their Medical Evaluation

Short stature in children is a common reason for referral to a pediatric endocrinologist. A myriad of genetic, nutritional, psychological, illness-related, and hormonal causes must be excluded before labeling as idiopathic. However, idiopathic short stature (ISS) is not a diagnosis, but rather describes a large, heterogeneous group of children, who are short and often growing at the lower limit of the normal range. As new testing paradigms become available, the pool of patients labeled as idiopathic will shrink, although most will still have a polygenic cause. Given that many of the new diagnoses are involved in growth plate biology, physical examination should assess for subtle dysmorphology or disproportion of the skeleton that may indicate a heterozygous mutation that in its homozygous state would be apparent. When laboratory evaluations are negative, one may consider genetic testing, such as targeted gene or gene panel, comparative genomic hybridization (cGH), or whole exome or whole genome sequencing (WES or WGS, respectively). With a known genetic diagnosis, targeted therapy may be possible rather than the use of recombinant human growth hormone (rhGH), where response is generally poorer than that for children with growth hormone (GH) deficiency, because the variety of diagnoses may have varying GH sensitivity. A firm diagnosis has heuristic value to truncate further diagnostic evaluation, alert the clinician to other possible co-morbidities, inform the family for genetic counseling, and direct appropriate targeted therapy, if available. Short stature in children is a common reason for referral to a pediatric endocrinologist. To begin a discussion about the evaluation of short children with particular reference to idiopathic short stature (ISS), an instructive patient is presented.