How Has Genetic Testing Changed the Diagnosis of Short Stature in Children?

Children with short stature have a height that is more than 2 standard deviations below the mean for their age, sex, and population.¹ A range of etiologies may result in short stature, including primary and secondary growth disorders, although many cases are deemed idiopathic short stature (ISS). Early diagnosis is critical so that growth hormone therapy, when indicated, can be initiated in time to exert optimal effects.² Studies have found diagnostic delays of ≥2 years in children with pituitary stalk interruption syndrome and growth hormone deficiency, celiac disease and associated growth failure, and Turner syndrome.²

“Traditionally, children with short stature have undergone extensive medical evaluation, often focused on identifying hormonal etiologies of short stature or other chronic medical conditions that affect growth,” wrote Andrew Dauber, MD, MMSc, chief of endocrinology at Children’s National Health System in Washington, DC, in a commentary published online in February 2019 in The Journal of Clinical Endocrinology & Metabolism.³

However, research findings have demonstrated that “standard medical evaluation rarely leads to a diagnosis in an otherwise healthy child with isolated short stature.” It has been reported that a pathologic cause is identified in only 5% of children who are referred to a specialist for evaluation of short stature, and an estimated 80% of cases are classified as ISS.^4,5

In his paper, Dr Dauber explained that advances in our understanding of how genetic factors influence height have made it clear that many cases labeled ISS actually have an underlying genetic etiology.³ For example, in study results published in The Journal of Clinical Endocrinology & Metabolism by Freire, et al, 15% of patients with isolated short stature born small for gestational age (SGA) were found to have pathogenic or likely pathogenic variants in genes associated with growth disorders.⁶ Similar results were observed in a 2018 study and published in Genetics in Medicine, which identified a genetic cause in 14% of patients with isolated short stature.⁷

Thousands of genes that influence an individual’s height have been identified in genome-wide association studies in the past decade.³ While certain rare genetic mutations can result in severe growth disorders such as Laron syndrome and achondroplasia, most cases of short stature with a genetic etiology likely result from a combination of genetic variants that each exert small effects on height.

Based on findings from genetic studies of growth disorders, Dr Dauber pointed out the following key themes:

● Most of the observed pathologic mutations have been associated with growth plate dysfunction or skeletal dysplasias rather than classic endocrine hormonal pathways, suggesting that “pediatric endocrinologists need to focus more attention on the growth plate as the primary site of growth disturbances.”

● The majority of mutations were heterozygous and inherited from an affected parent (in 69% of patients in the Freire study, for instance⁶). Thus, it is important to obtain measurements of parents’ height in evaluating children with short stature to consider the possibility of an inherited disorder.

● Rather than a single gene variant causing short stature, there is likely a “host of causative genes” that each contribute 1% to 2% or even less to the etiology of patients classified as ISS or SGA.

● Genetic testing yields more useful results than traditional hormonal testing in children with isolated short stature, indicating that genetic testing may be appropriate as first-line evaluation in these patients. Further research is needed to compare the cost-effectiveness of these 2 approaches and to determine how the potential causality of the identified genetic variants should be interpreted.

Meanwhile, Dr Dauber proposed that genetic testing should be the first-line evaluation in “patients who are otherwise healthy and have ISS or idiopathic SGA, especially those with a clear family history of short stature and more significant short stature (perhaps a height below -3 [standard deviations]).” Despite the challenges in interpreting results, he noted that “[g]eneticists, genetic counselors, and molecular diagnostic labs have expertise in interpreting these tests and conveying the meaning of the results to patients.”

To learn more about diagnostic challenges and new developments in this area, Endocrinology Advisor interviewed Dr Dauber and Adda Grimberg, MD, a pediatric endocrinologist and scientific director of the Growth Center at Children’s Hospital of Philadelphia in Pennsylvania.