EP155: Genetic investigation of idiopathic short stature in the endocrinology practice: The Mayo Clinic experience

Abstract

Childhood short stature is a common indication for referral in endocrinology. The differential diagnosis is broad including endocrine disorders, systemic disorders, and genetic disorders. Many genetic disorders are associated with growth disturbance including non-syndromic growth hormone disorders, syndromic short stature, and skeletal dysplasias. A subset of children are classified as having idiopathic short stature (ISS), which could be further subdivided into familial or non-familial short stature. The lack of cardinal features in ISS often prevents genetic evaluation and diagnosis of non-syndromic genetic short stature. However, emerging data indicates the identification of a genetic disorder in 25-40% of individuals with ISS when utilizing copy number variant analysis, targeted gene panels and exome sequencing. Genetic testing is becoming an essential component of the diagnostic evaluation and treatment of patients in traditionally underutilized clinical departments. The Pediatric Endocrinology department and Center for Individualized Medicine (CIM) at Mayo Clinic collaborated to develop a genetic testing service for pediatric ISS to explore the yield of genetic diagnosis and impact to medical management utilizing a novel genetic counseling model called the Genetic Testing and Counseling (GTAC) unit consisting of genetic counselors, genetic counselor assistants, genetic nurses, and a medical geneticist. Through GTAC, patients receive appropriate counseling, and test facilitation through partnership between the genetic counseling team and referring specialty provider. Eligibility for a referral to the GTAC service included children with proportionate short stature greater than 2 SD below mean for age and sex, in the absence of an identifiable causative etiology. Children with skeletal dysplasias and syndromic short stature were not included in this service and underwent genetic evaluation through traditional referrals to the Department of Clinical Genomics. Through the GTAC service, pre-test genetic counseling appointments range from 15-30 minutes focusing on pre-selected genetic tests. For ISS, a custom exome-based multi-gene panel was curated and created to include 53 genes associated with non-syndromic short stature or disorders with mild or variable expressivity such as some RAS-opathies. Chromosomal microarray (CMA) was also ordered as a standard first tier test. Genetic test results were reviewed by the endocrinologist and the GTAC Genomics team. Results were returned to the patient via post-test genetic counseling, and medical management and follow-up was facilitated by the endocrinologist. From April 2021 to November 2021, there have been 13 referrals to the GTAC service, and all 13 (100%) patients elected to proceed with genetic testing. Multi-gene custom panel and CMA were completed for 11 patients. CMA, as a standalone test, was completed for one patient because a diagnosis was obtained with this initial test. Testing is pending for the remaining 2 patients. The multi-gene panel revealed a likely pathogenic or pathogenic causative variant in 5/10 patients tested (ACAN, IGF1, IGF1R, and SHOX) and CMA revealed a pathogenic causative copy number variant resulting in deletion of the SHOX gene in 1/5 patients. Together, the diagnostic yield through this testing approach is 54%. Therapeutic options were available for all 6 (100%) solved cases. Three of the 6 (50%) diagnosed cases had family histories consistent with the finding and included reports of one or more close relatives (first or second degree) with associated features (eg, short stature, mesomelia, forearm deformity). The molecular finding was able to be confirmed in affected parents of 2 of these 3 cases; parental testing of the third is pending. Parental samples were submitted to aid in the interpretation of results in 6/11 cases; parents were not included in 2/11 cases and the patient was adopted in 3/11 cases. Genetic counseling and testing are important components in the overall evaluation of idiopathic short stature; however, genetic counseling expertise embedded in the endocrinology practice is rare. The collaboration between GTAC and the specialty area partners has demonstrated immediate and ongoing value to patients and providers. This partnership highlights the significant diagnostic genetic yield and impact to patient management in unexplained short stature. Genetic testing is underutilized and should be considered in pediatric patients with not only ISS but also cases of familial short stature. A genetic diagnosis in children with short stature is instrumental for informing prognosis, the potential to inform treatment decisions surrounding use of growth hormone or insulin-like growth factor 1 therapy and clarifying inheritance and recurrence risks.