Genotype‒Structurotype‒Phenotype Correlations in Patients with Pachyonychia Congenita.

Pachyonychia congenita (PC) is a genetic disorder of keratin that presents with nail dystrophy, painful palmoplantar keratoderma, and other clinical manifestations. We investigated the genotype‒structurotype‒phenotype correlations seen with mutations in keratin genes (keratin [K]6A, K6B, K6C, K16, K17) and utilized protein structure modeling of high-frequency mutations to examine the functional importance of keratin structural domains in PC pathogenesis. Participants of the International PC Research Registry underwent genetic testing and completed a standardized survey on their symptoms. Our results support previous reports associating oral leukokeratosis with K6A mutations and cutaneous cysts, follicular hyperkeratosis, and natal teeth with K17 mutations. Painful keratoderma was prominent with K6A and K16 mutations. Nail involvement was most common in patients with K6A mutation and least common in those with K6C mutation. Across keratin subtypes, patients with coil 2B mutations had the greatest impairment in ambulation, and patients with coil 1A mutations reported more emotional issues. Molecular modeling demonstrated that hotspot missense mutations in PC largely disrupted hydrophobic interactions or surface charge. The former may destabilize keratin dimers/tetramers, whereas the latter likely interferes with higher-order keratin filament formation. Understanding the pathologic alterations in keratin structure improves our knowledge of how PC genotype correlates with clinical phenotype, advancing insight into disease pathogenesis and therapeutic development.

PCQoL: A Quality of Life Assessment Measure for Pachyonychia Congenita.

BACKGROUND: Pachyonychia congenita (PC) is a rare but often debilitating, dominantly inherited disorder. New treatments require more accurate instruments for evaluating changes in the quality of life in these patients. OBJECTIVES: This study was undertaken to develop and validate a quality of life questionnaire for PC patients (PCQoL). METHODS: Relevant factors influencing quality of life in PC patients were identified and incorporated into the well-recognized, general questionnaire, the Dermatology Life Quality Index (DLQI), to establish a disease-specific measure, the PCQoL. Classical test theory (CTT) and Rasch analysis (RA) were used to analyze and validate the PCQoL. RESULTS: CTT analysis established test-retest reliability and internal consistency for the PCQoL. Concurrent and construct validity for the DLQI and the PCQoL were also validated. Chi-square-based infit and outfit statistics indicated that the Rasch model fits the observed responses very well. RA reconfirmed reliability, internal consistency, reasonable homogeneity, construct validity, and the presence of three RA-based domains. CONCLUSION: The PCQoL questionnaire is a measure validated by both CTT and RA. It appears to be a valuable tool in measuring quality of life modifications in PC individuals with keratoderma.