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

Piezo2 channels are mechanosensors expressed in dorsal root ganglia and Merkel cells, and involved in proprioception and touch sensation. PIEZO2 pathogenic variants cause rare autosomal dominant and recessive disorders. Dominant forms include distal arthrogryposis type 3, 5, and Marden-Walker syndrome, whereas the recessive form corresponds to distal arthrogryposis with impaired proprioception and touch (DAIPT). Given the rarity of these conditions, additional reports are essential to refine their phenotypic characterization. We conducted a multicenter, retrospective study to identify patients with genetically confirmed PIEZO2-related disorders. We collected clinical data through a standardized assessment. Previously published cases were included when more detailed phenotypic information was available. We identified 44 individuals with a clinical diagnosis of PIEZO2-related disorders. Among them, we selected 42 patients with a confirmed molecular diagnosis. Sixteen of them (10 males and 6 females; median age at diagnosis: 8 years; range 0.9-14) carried biallelic pathogenic PIEZO2 variants. They typically presented with neonatal hypotonia and respiratory distress with feeding difficulties. Distal arthrogryposis was associated with a variable multisystemic involvement, including the musculoskeletal system with scoliosis, hip dislocation and laryngomalacia. Twenty-five patients (11 males and 14 females; median age at diagnosis: 7 years; range 0.3-39 years) carried monoallelic variants, exhibiting a broad phenotypic spectrum. An additional prenatal diagnosis (at 23 weeks of gestation) was reported among heterozygous cases. In our cohort, ten previously unpublished causative variants were identified. A systematic assessment of skeletal muscle involvement revealed a severe myofibrillar disarray in one case. This study provides a comprehensive and systematic phenotypic characterization of patients across the spectrum of PIEZO2-related disorders. Our findings support a clear clinical distinction between recessive and dominant forms. The clinical manifestations extend beyond the peripheral nervous system and the Merkel cells, suggesting a broader PIEZO2 tissue expression during early developmental stages. Dominant PIEZO2-related disorders are heterogeneous, ranging from mild to severe forms. Our study also suggests that many patients exhibit a respiratory involvement, emphasizing the need for regular respiratory follow-up in the long-term clinical management of both dominant and recessive forms.