Piezo2-related Arthrogryposis & physiopathOLOgy 3

Arthrogryposis multiplex congenita (AMC; Orpha code 1037) is a clinically and genetically heterogeneous group of disorders defined by congenital joint contractures affecting at least two distinct body regions (Dahan-Oliel et al. 2019).

Its estimated prevalence ranges from 1 in 3,000 to 1 in 12,000 live births, based on population-based epidemiological studies (Darin et al. 2002; Lowry et al. 2010; Hoff et al. 2012). The pathophysiology of AMC is closely linked to impaired fetal movement, with the severity of musculoskeletal manifestations depending on the timing and degree of fetal akinesia during development (Pollard, McGonnell, and Pitsillides 2014; Nowlan 2015; Felsenthal and Zelzer 2017).

Advances in molecular genetics have identified gain-of-function variants in the mechanosensitive ion channel PIEZO2 as a key etiology in a distinct subgroup of distal arthrogryposis (Coste et al. 2013). PIEZO2 plays a central role in mechanotransduction, converting mechanical stimuli into ionic currents in peripheral sensory neurons, thereby mediating proprioception and mechanical nociception (Wu, Lewis, and Grandl 2017; Szczot et al. 2021; Ma et al. 2023; Sánchez-Carranza et al. 2024).

Structural studies have shown that PIEZO2 forms a large trimeric propeller-shaped mechanosensitive channel whose architecture enables rapid transduction of membrane tension into cation influx, particularly Na⁺ and Ca²⁺ (Wang et al. 2019). Experimental data indicate that PIEZO2 gain-of-function mutations lead to delayed channel inactivation, neuronal hyperexcitability, and aberrant mechanotransduction, which likely underlie the distinctive pain phenotype observed in affected patients (Coste et al. 2013).

Clinically, individuals with PIEZO2-related AMC frequently report chronic diffuse pain with episodic exacerbations that are often poorly responsive to conventional analgesic strategies. Despite this recognizable pattern, genotype-phenotype correlations and the mechanisms driving pain severity and distribution remain insufficiently characterized.

This single-center, non-interventional observational study aims to describe the pain phenotype of individuals with AMC caused by gain-of-function variants in PIEZO2 identified through the national PARART registry (NCT05673265).

The study consists of prospective remote collection of self-reported outcomes using validated questionnaires. On Day 1, participants complete assessments of pain quality (QDSA) and quality of life (SF-12 and EQ-5D-5L), along with documentation of prior analgesic strategies. From Day 1 to Day 14, participants record daily pain intensity using a Numerical Rating Scale (0-100) and pain localization on a body chart, enabling evaluation of pain intensity, temporal variability, and anatomical distribution.

The study relies exclusively on descriptive statistical analyses, without hypothesis testing or comparison groups. Data are collected and managed using REDCap, in accordance with predefined procedures for pseudonymization, data integrity, and regulatory compliance (Harris et al. 2009; Harris et al. 2019). By systematically characterizing pain features and their impact on quality of life, this study seeks to improve understanding of the clinical pain profile associated with PIEZO2 gain-of-function mutations and to provide a foundation for future mechanism-based therapeutic strategies in this rare condition.

Inclusion criteria

• PIEZO2 mutation gain of function
• Age ≥ 10 years
• Registered member of the PARART database (Pediatric and Adult Registry for Patients With ARThrogryposis)

Exclusion criteria

• Age < 10 years