Genetic Heterogeneity Underlying Familial Short Stature.

Background and Clinical Significance: Familial short stature is a common reason for referral in clinical genetics. While often attributed to a single genetic cause, genetic heterogeneity can complicate diagnosis and management. This report describes a family in which three distinct pathogenic variants in SHOX, PDE4D and ACAN caused overlapping phenotypes of familial short stature. Case Presentation: Clinical, radiological and molecular data were collected retrospectively at the Reference Centre for Constitutional Bone Diseases at Montpellier University Hospital. Targeted gene panels, whole genome sequencing and Sanger sequencing were employed to identify pathogenic variants. Variant interpretation followed the guidelines of the American College of Medical Genetics. A pathogenic SHOX variant (c.452G>A; p.Ser151Asn) was identified in the proband and her mother, which is consistent with dyschondrosteosis. A de novo PDE4D variant (c.671C>T; p.Thr224Ile) was identified in a cousin presenting with syndromic acrodysostosis. An ACAN splice variant (c.6833-1G>A) was detected in several family members and is associated with short stature and skeletal anomalies. An individual carrying both the SHOX and ACAN variants exhibited a more severe phenotype, suggesting an additive effect.

Conclusions

This case study highlights the importance of systematic molecular investigations in families with overlapping yet heterogeneous phenotypes. Comprehensive genetic familial analysis enables personalized care and accurate genetic counselling, particularly when multiple diagnoses coexist. A family history should not preclude molecular testing, since similar phenotypes can result from different genetic causes.