A Case of Restrictive Dermopathy With Atypical Cardiac Anomalies and a Novel ZMPSTE24 Variant

Restrictive Dermopathy (RD, OMIM #275210) is an ultra-rare, lethal genodermatosis caused by defects in lamins and related proteins. RD is caused by biallelic pathogenic variants in ZMPSTE24, which encodes zinc metallopeptidase ZMPSTE24, an enzyme essential for processing prelamin A, the precursor of lamin A. While null variants leading to a total loss of prelamin A processing have been related to neonatally lethal RD, variants preserving residual prelamin A processing function cause an allelic disorder called Mandibuloacral Dysplasia Type B (MAD-B). RD is characterized by taut translucent skin, visible superficial vessels, joint contractures, and dysmorphic features, with death usually occurring within the first month of life. Cardiac anomalies, including ASD and PDA, have been reported in a few patients, most of whom were not genetically confirmed, and transposition of the great arteries (TGA) has been described only once, also without molecular confirmation. We report a patient with restrictive dermatopathy (RD) presenting with double outlet right ventricle (DORV) and pulmonary valve atresia which have not been previously reported in association with RD. Exome Sequencing (ES) was performed, revealing a novel homozygous splice-site variant in ZMPSTE24 (c.1203 + 1G>T). Segregation analysis was performed in the mother and two siblings. To our knowledge, DORV has not previously been reported in an RD patient. This case expands the genotypic spectrum of RD and suggests a possible link with complex cardiac malformations.