P.1.7 Contiguous gene syndrome causing ColVI myopathy, dysmorphism, frontal atrophy and diaphragmatic hernia

Abstract

Collagen VI (Col6) deficiency results in a broad spectrum of clinical manifestations ranging from Ullrich Congenital Muscular Dystrophy (UCMD) to Bethlem Myopathy with intermediate phenotypes. The COL6A3 gene encodes the α3(VI) subunit and maps to chromosome 2 in one of the most commonly deleted subtelomeric region, del2q37. UCMD is not classically associated with central nervous system involvement. However, some cases with intellectual disability have been reported, without any molecular explanation. We report the case of a 4-year-old boy born to unrelated French parents presenting with hypotonia, torticollis and club foot at birth. He had a motor delay (walked unaided at 3 years). Diaphragmatic hernia was discovered fortuitously and surgically corrected at 2y10m. At 3 years, he presented facial (mostly oral) and proximal weakness, distal hyperlaxity, no retractions and pectus excavatum. Moreover, we noted a mild facial dysmorphism with prominent forehead, down-slanted eyes, thin upper lip and low-set big ears. Scars from the diaphragmatic and muscle biopsy surgeries were slightly hypertrophic. The evolution was marked by seizures and two episodes of spontaneous fractures. Plasma CK levels were normal and the muscle biopsy findings were not specific. Cerebral MRI showed atrophy of the frontal lobe. Given the muscular phenotype, collagen VI immunolabeling was studied in cultured fibroblasts and demonstrated reduced Col secretion associated with intracytoplasmic retention. Currently aged 4y3m, the patient presents a positive evolution regarding motor and intellectual development. Interestingly, CGH array revealed a de novo translocation (2;4) with 2qter deletion (2q37.2–q37.3) and genomic gain at 4qter (4q35.1–q35.2), resulting in deletion of one COL6A3 allele. This is to our knowledge the 1st case report of a patient with Col6 myopathy phenotype associated with central nervous system involvement ascribed to a contiguous gene syndrome involving the COL6A3 locus.