Non‐pachyonychia congenita conditions in the International Pachyonychia Congenita Research Registry

Pachyonychia congenita (PC) is a rare disorder characterized by palmoplantar keratoderma, hypertrophic nail dystrophy, steatocystoma, pilosebaceous cysts, oral leukokeratosis, and pain.1 Prevalence is estimated at up to 10,000 cases globally. As a result of a lack of awareness and access to standardized genetic testing worldwide, these numbers likely underestimate the true prevalence of PC.2 There are five keratin genes known to cause PC: KRT6A, KRT6B, KRT6C, KRT16, and KRT17.1 PC Project established the International PC Research Registry (IPCRR) in 2004 (WIRB Study #20040468), a physician-verified registry that not only collects data about PC but also serves as a diagnostic pathway for patients worldwide who are often undiagnosed or misdiagnosed. There are now over 2700 individuals in the registry, and over 1100 are fully enrolled with a genetic diagnosis. While manifestations including hypertrophic nails, palmoplantar keratoderma, and plantar pain may support a clinical PC diagnosis, genetic testing is the key to an accurate diagnosis.1 The IPCRR collects patient-reported data and provides free genetic testing to patients with clinical features of PC. However, among this population, genotyping has revealed that a substantial number of these individuals do not have PC. Through the exploration of data from the IPCRR, a list of genes with pathogenic variants was compiled (Figure 1). These genes included variants not in the five keratin genes known to cause PC. Further review yielded clinical information on these skin disorders with similar PC phenotypes but not caused by a PC variant. An updated count of all non-PC gene variants in the IPCRR was performed. The IPCRR now houses data from other rare skin disorders with variants in approximately 10 genes (Figure 1). Most of the conditions identified in the registry had phenotypic features similar to PC's, which were difficult to distinguish from PC without genetic confirmation. Specifically, plantar keratoderma occurs in most of these conditions, closely resembling the plantar calluses seen in PC (Figure 2). The three most commonly encountered non-PC conditions in the IPCRR are Clouston syndrome (OMIM 129500), Olmsted syndrome (OMIM 614594), and striate palmoplantar keratoderma (OMIM 148700) (SPPK). Clouston syndrome is caused by a variant in the GJB6 gene that encodes the gap junction protein, connexin 30. Clouston syndrome characteristics similar to PC include nail dystrophy and palmoplantar keratoderma.3 Key features also include reduced or loss of hair to the scalp and/or eyebrows, which is a finding not found in PC. SPPK occurs because of desmoglein-1 (DSG1) gene variants, which play a role in cell–cell adhesion. These individuals typically present with palmoplantar keratoderma, which may have striate or diffuse patterns in areas subjected to high friction.4 Variants in GJB6 or DSG1 genes generally cause less painful keratoderma than that observed in PC. Olmsted syndrome occurs because of variants in the TRPV3 gene and is characterized by very painful bilateral palmoplantar keratoderma and periorificial plaques. Many individuals also suffer from nail involvement, eye lesions, and inflamed lacrimal glands.5 Early recognition of these syndromes is important, given that they can require different clinical management. Information from the PC Project's IPCRR emphasizes the importance of genetic testing to accurately diagnose these rare skin diseases, some of which cannot be accurately distinguished from others without genotyping. The impact of this registry cannot be understated. Patients can find answers regarding their disease through the registry and receive guidance regarding their medical care and the genetic impact on their families. As targeted treatments are being developed, having a genetic diagnosis will be critical, and the growing data in the IPCRR for each of these additional conditions will contribute to the collective knowledge of these non-PC conditions.