Revisiting pachyonychia congenita: a case‐cohort study of 815 patients

Abstract

Summary Background Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17). The establishment of an international registry containing clinical and molecular data led to the development of a disease classification based on the mutant gene and associated features. Objectives To harness the same resource to clarify the prevalence of PC‐associated clinical features, delineate phenotype–genotype correlations and identify prognostic features for disease severity. Methods In total, 815 individuals with confirmed keratin mutations registered in the International Pachyonychia Congenita Research Registry were surveyed for clinical findings associated with PC. Data were analysed using various statistical methods, including the Student's t‐test, χ2‐test and anova tests for differences in means/proportions. Spearman correlation and logistic regression were used for phenotype–genotype correlations. Results KRT6A mutations were associated with oral leucokeratosis, hoarseness, youngest age or highest number of fingernails/toenails involved, and use of walking aids. KRT17 mutations were most commonly associated with cysts and natal teeth. Using logistic regression, we found that oral leucokeratosis was correlated with earlier toenail involvement, walking aids, nursing difficulties and hoarseness. Cysts were correlated with oral leucokeratosis, natal teeth and ear wax. Natal teeth predicted earlier toenail involvement, walking difficulties and cyst formation. Hoarseness was correlated with an increased number of involved fingernails. Conclusions Here, we establish phenotype–genotype correlations in the largest cohort of patients with PC described to date and reveal novel and clinically useful predictors of disease course and manifestations. What's already known about this topic? Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17). The main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts. The establishment of an international registry containing the clinical and molecular data of patients with PC led to the development of a disease classification based on the mutant gene and associated features. What does this study add? Data were collected via an international registry to clarify the prevalence of PC‐associated clinical features, delineate phenotype–genotype correlations and identify prognostic features for disease severity. This is the largest cohort of patients with PC described to date. The earliest clinical manifestations of PC are nail dystrophy and palmoplantar keratoderma. Diagnosis can be suspected and confirmed in preschool years. Painful plantar keratoderma has the most profound and debilitating effect on quality of life and daily function. Linked Editorial: Steele and O’Toole. Br J Dermatol 2020; 182:521–522. Linked Comment: Mordaunt. Br J Dermatol 2020; 182:537.

Molecular epidemiology of pachyonychia congenita in the Israeli population

“…18 By contrast, nail dystrophy was evident in only 81% of our patients compared with 96% of patients reported in the IPCRR. 18 Pilosebaceous cysts were found in 29% of our patients, a similar rate to IPCRR, 18 whereas oral leucokeratosis was observed in only 31% of cases, compared with the rate of 54% reported in the IPCRR. The prevalence of prenatal/natal teeth in our cohort was similar to that in the IPCRR (13% and 14%, respectively) (Table 3).…”

High Glucose Causes Distinct Expression Patterns of Primary Human Skin Cells by RNA Sequencing

“…Abnormal expression of KRT17 has been found in various dermatoses, including psoriasis, alopecia, and pachyonychia congenita (PC) ( 38 ). The genetic mutation in KRT17 is related to PC, which mainly manifests itself as hyperkeratosis of the nails, palm, and pelma ( 39 ). Meanwhile, microarray analysis of non-healing chronic ulcers identified that the KRT17 gene was significantly downregulated relative to expression levels in healing chronic ulcers ( 40 ), suggesting that dysregulation of KRT17 is involved in defective healing.…”

Successful treatment of Pachyonychia congenita with Rosuvastatin

“…Patients with PC present with nail thickening and painful plantar keratoderma. Additional features include hyperhidrosis, oral leukokeratosis, follicular keratosis, palmar keratoderma, cutaneous cysts, hoarseness or laryngeal involvement, coarse or twisted hair and abnormalities of the teeth 1 . Current treatment focuses on symptom relief 2 .…”

“…Pachyonychia congenita is a keratinopathy caused by pathogenic variants in one of four genes, namely KRT6A, KRT6B, KRT16 or KRT17 1,6 . The dominant negative effect of amino acid substitutions leads to aggregation of keratin intermediate filaments and to mechanical fragility of keratinocytes.…”