Acromelic dysplasias: similarities and differences in clinical and molecular findings in 12 Turkish patients.

UNLABELLED: The purpose of this study is to compare the natural history of clinical and radiologic features in patients with acromelic dysplasias. Twelve patients from nine families with genetically confirmed dysplasia types with acromelia were included in the study, and eight of them were followed-up for a median of 8.1 years. Monoallelic disease-causing variants were identified in FBN1 (acromicric dysplasia, n = 3) and GNAS (Albright hereditary osteodystrophy (AHO), n = 1). Biallelic disease-causing variants in ADAMTSL2 (geleophysic dysplasia type 1, n = 4), ADAMTS10 (Weill-Marchesani syndrome type 1 (WMS1), n = 3), and ADAMTS17 (Weill-Marchesani syndrome type 4 (WMS4), n = 1) were identified. Five novel variants were detected. Short stature was present in all patients. In all patients with geleophysic dysplasia, height normalized during follow-up, and in two, initial acromelia and broad phalanges on hand radiographs resolved over time. Pseudomuscular build, joint limitations, tiptoe walking, and delayed bone age were common findings in geleophysic dysplasia, while patients with WMS1 also had pseudomuscular build, joint limitations, and delayed bone age. Acromicric dysplasia showed mild joint limitation. Intellectual disability was observed only in the WMS4 patient. Spherophakia was specific to patients with WMS. Heterotopic ossification was present in the AHO patient.

CONCLUSION: These findings underscore the clinical and genetic heterogeneity of acromelic dysplasias and emphasize that integrated clinical and molecular evaluation is essential for accurate classification and follow-up.

WHAT IS KNOWN: • Acromelic dysplasias are rare connective tissue disorders characterized by short stature, brachydactyly, and joint stiffness, caused by variants in genes involved in extracellular matrix organization and TGF-β- related signaling.

WHAT IS NEW: • Five novel variants in ADAMTSL2, ADAMTS10, and ADAMTS17 expand the molecular spectrum of acromelic phenotypes. • Tiptoe walking, in association with early findings including short stature, acromelia, and broad proximal phalanges on radiographs, may suggest ADAMTSL2-related geleophysic dysplasia.