Beyond distal arthrogryposis: refining the phenotypic landscape of PIEZO2-related disorders.

Pathogenic variants in PIEZO2, encoding a mechanosensitive channel expressed in dorsal root ganglia and Merkel cells; dominant forms (distal arthrogryposis types 3 and 5, Marden-Walker syndrome) and a recessive form (distal arthrogryposis with impaired proprioception and touch).

This multicentre retrospective study assembled 44 individuals with a clinical diagnosis of PIEZO2-related disorder, 42 of them molecularly confirmed. Sixteen patients with biallelic variants typically presented with neonatal hypotonia and respiratory distress with feeding difficulties, distal arthrogryposis being associated with variable multisystem involvement (scoliosis, hip dislocation, laryngomalacia). Twenty-five patients with monoallelic variants showed a broad phenotypic spectrum, from mild to severe forms, with one prenatal diagnosis reported at 23 weeks of gestation. Ten previously unpublished causative variants were identified, and systematic assessment of skeletal muscle revealed severe myofibrillar disarray in one case. The authors emphasise the frequency of respiratory involvement and the need for regular respiratory follow-up in both dominant and recessive forms.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A solid phenotypic series in a rare condition, with a clear clinical distinction between dominant and recessive forms that is useful for genetic counselling and variant interpretation. The most directly transferable message for the clinic is systematic respiratory follow-up, including in heterozygotes, who are often assumed to be mildly affected. Retrospective multicentre recruitment introduces the expected severity bias: reported frequencies probably overestimate involvement across all carriers.

Analysis by Dr Thibaut Benquey