Pachyonychia Congenita: A Research Agenda Leading to New Therapeutic Approaches.

Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles.

Phenotype and genotype features of Vietnamese children with pachyonychia congenita.

BACKGROUND: Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). PC is an extremely rare condition. To our knowledge, this is the largest genotype-phenotype study of PC in a Vietnamese population to date. MATERIALS AND METHODS: We investigated keratin gene mutations and clinical features of seven Vietnamese children with PC. RESULTS: The seven Vietnamese patients were from six different families (two patients in the same family) from across Northern, Central, and Southern Vietnam. All children displayed PC symptoms before 1 year of age, but diagnosis was delayed in 4/7 patients. Thick fingernails, thick toenails, oral leukokeratosis, and follicular hyperkeratosis were the most common features recorded by all seven patients. Plantar keratoderma and thick fingernails were the clinical features associated with the most significant effect on daily function. All patients had mutations in KRT6A (PC-K6a) focused on the 1A and 2B domains. We found three distinct types of mutations (K6a R466P, K6a N171K, and K6a N172del). One mutation (N172del) was common to 5/7 (71.4%) of the patients. CONCLUSIONS: Individuals displaying nail dystrophy, oral leukokeratosis, follicular hyperkeratosis, and plantar keratoderma should be referred for genetic testing given the high likelihood of a PC-K6a-related mutation in patients with this constellation of clinical signs.

EGFR Signaling Is Overactive in Pachyonychia Congenita: Effective Treatment with Oral Erlotinib.

Pachyonychia congenita (PC) is a rare keratinizing disorder characterized by painful palmoplantar keratoderma for which there is no standard current treatment. PC is caused by dominant mutations in keratin (K) K6A, K6B, K6C, K16, or K17 genes involved in stress, wound healing, and epidermal barrier formation. Mechanisms leading to pain and painful palmoplantar keratoderma in PC remain elusive. In this study, we show overexpression of EGFR ligands epiregulin and TGF-α as well as HER1‒EGFR and HER2 in the upper spinous layers of PC lesions. EGFR activation was confirmed by upregulated MAPK/ERK and mTOR signaling. Abnormal late terminal keratinization was associated with elevated TGM1 activity. In addition, the calcium ion permeable channel TRPV3 was significantly increased in PC-lesional skin, suggesting a predominant role of the TRPV3/EGFR signaling complex in PC. We hypothesized that this complex contributes to promoting TGM1 activity and induces the expression and shedding of EGFR ligands. To counteract this biological cascade, we treated three patients with PC with oral erlotinib for 6‒8 months. The treatment was well-tolerated and led to an early, drastic, and sustained reduction of neuropathic pain with a major improvement of QOL. Our study provides evidence that targeted pharmacological inhibition of EGFR is an effective strategy in PC.

KERATIN 17-related recessive atypical pachyonychia congenita with variable hair and tooth anomalies.

We present the first pachyonychia congenita (PC) to involve all ectodermal derivatives and the first recessive KRT17-related PC in total seven members of two consanguineous Pakistani families. This atypical PC is characterized by an unusual combination of pachyonychia, plantar keratoderma, folliculitis, alopecia, sparse eyebrows, dental anomalies and variable acanthosis nigricans of neck, dry skin, palmoplantar hyperhidrosis, recurrent blisters on soles and/or arms, rough sparse hair on scalp and keratosis pilaris. By exome sequencing we detected homozygous KRT17 c.281G>A (p.(Arg94His)) in affected individuals, and linkage mapping indicated a single locus. Heterozygous variants in KRT17 cause PC2 (PC-K17) with main characteristics of pachyonychia, subungual keratosis, palmoplantar keratoderma, hyperhidrosis, oral leukokeratosis and epidermal cysts, or steatocystoma multiplex, both with dominant inheritance. The causative variant has been reported in heterozygous state in a family afflicted with severe steatocystoma multiplex and in a sporadic PC2 case, and thus we also define a third phenotype related to the variant. Both exome sequencing and linkage mapping demonstrated recessive inheritance whereas Sanger sequencing indicated heterozygosity for the causal variant, reiterating caution for simple targeted sequencing for genetic testing. Testing parents for variants found in sibs could uncover recessive inheritance also in other KRT genes.

Scrutinising the role of simvastatin in a patient of Pachyonychia Congenita with KRT6A gene mutation.

A 25-year-old male patient presented with palmoplantar keratoderma, dystrophic nails, severe plantar pain and oral leukokeratosis since birth. On genetic analysis, a heterozygous KRT6A gene missense mutation (c.1381G > A, p.Glu461Lys in exon 7) was identified by next-generation sequencing technology, consistent with pachyonychia congenita 6a. Oral simvastatin 40 mg was started once daily, and after 16 weeks of therapy, excellent improvement was noted in palmoplantar keratoderma and plantar pain. The maximum thickness of his foot callosity reduced by 4 mm on ultrasonography, and the Dermatology Life Quality Index score dropped significantly by eight points. These benefits may be attributed to inhibition of KRT6A gene expression, modulation of autophagy and mitophagy and Keap1-Nrf2 signalling activation; the latter two mechanisms of statins previously undiscussed in the context of pachyonychia congenita. Simvastatin and other statins are pathogenesis-targeted, disease-modifying therapy in pachyonychia congenita, therefore qualifying as a promising treatment avenue and warranting further clinical trials.

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.

Identification of clinically useful predictive genetic variants in pachyonychia congenita.

BACKGROUND: Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in five keratin genes (KRT16,KRT6A,KRT17,KRT6B or KRT6C). Current disease classification is based on the gene harbouring disease-causing variants. AIMS: We harnessed the International Pachyonychia Congenita Research Registry (IPCRR) containing both clinical and molecular data on patients with PC worldwide, to identify genetic variants predicting disease severity. METHODS: We ascertained 815 individuals harbouring keratin mutations registered in the IPCRR. We looked for statistically significant associations between genetic variants and clinical manifestations in a subgroup of patients carrying mutations found in at least 10% of the cohort. Data were analysed using χ2 and Kruskal-Wallis tests. RESULTS: We identified five mutations occurring in at least 10% of the patients registered in the IPCRR. The KRT16 p.L132P mutation was significantly associated with younger age of onset, presence of palmar keratoderma oral leucokeratosis and a higher number of involved nails. By contrast, the KRT16 p.N125S and p.R127C mutations resulted in a milder phenotype featuring a decreased number of involved nails and older age of onset. Patients carrying the p.N125S mutation were less likely to develop palmar keratoderma while p.R127C was associated with an older age of palmoplantar keratoderma onset. Moreover, the KRT17 p.L99P mutation resulted in an increased number of involved fingernails and patients demonstrating 20-nail dystrophy, while the opposite findings were observed with KRT17 p.N92S mutation. CONCLUSIONS: We have identified novel and clinically useful genetic predictive variants in the largest cohort of patients with PC described to date.

Molecular epidemiology of pachyonychia congenita in the Israeli population.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant disorder featuring palmoplantar keratoderma, nail dystrophy, oral leucokeratosis, pilosebaceous cysts and natal teeth. PC results from dominant mutations in one of five genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17) encoding keratin proteins. AIM: To delineate the clinical and genetic features of PC in a series of Israeli patients. METHODS: We used direct sequencing of genomic DNA, and also used cDNA sequencing where applicable. RESULTS: We collected clinical information and molecular data in a cohort of Israeli families diagnosed with PC (n = 16). Most of the patients were Ashkenazi Jews and had a family history of PC. The most common clinical findings were painful focal plantar keratoderma (94%) accompanied by nail dystrophy (81%), pilosebaceous cysts (31%) and prenatal/natal teeth (13%). In contrast to the high prevalence of KRT6A mutations in other populations, we found that KRT16 mutations were the most common type among Israeli patients with PC (56%). Most (77%) of the Israeli patients with PC with KRT16 mutation carried the same variant (c.380G>A; p.R127H) and shared the same haplotype around the KRT16 locus, suggestive of a founder effect. CONCLUSION: The data gleaned from this study emphasizes the importance of population-specific tailored diagnostic strategies.

Generalized bullae in a young girl with KRT6A-related pachyonychia congenita.

Pachyonychia congenita (PC) is a rare genodermatosis showing heterogeneity with five causative keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). Clinically, PC is characterized by hypertrophic onychodystrophy, painful palmoplantar keratoderma, oral leukokeratosis, and follicular hyperkeratosis. We describe an atypical case of PC in a young Chinese girl presenting with generalized bullae and identified a recurrent heterozygous missense mutation c.1406T > C (p.Leu469Pro) in KRT6A. This suggests that bullae may represent an important feature of KRT6A-related PC.

Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment.

BACKGROUND: Pachyonychia congenita (PC), a rare genodermatosis, primarily affects ectoderm-derived epithelial appendages and typically includes oral leukokeratosis, nail dystrophy and very painful palmoplantar keratoderma (PPK). PC dramatically impacts quality of life although it does not affect lifespan. PC can arise from mutations in any of the wound-repair-associated keratin genes KRT6A, KRT6B, KRT6C, KRT16 or KRT17. There is no cure for this condition, and current treatment options for PC symptoms are limited and palliative in nature. OBJECTIVES: This review focuses on recent progress made towards understanding the pathophysiology of PPK lesions, the most prevalent and debilitating of all PC symptoms. METHODS: We reviewed the relevant literature with a particular focus on the Krt16 null mouse, which spontaneously develops footpad lesions that mimic several aspects of PC-associated PPK. RESULTS: There are three main stages of progression of PPK-like lesions in Krt16 null mice. Ahead of lesion onset, keratinocytes in the palmoplantar (footpad) skin exhibit specific defects in terminal differentiation, including loss of Krt9 expression. At the time of PPK onset, there is elevated oxidative stress and hypoactive Keap1-Nrf2 signalling. During active PPK, there is a profound defect in the ability of the epidermis to maintain or return to normal homeostasis. CONCLUSIONS: The progress made suggests new avenues to explore for the treatment of PC-based PPK and deepens our understanding of the mechanisms controlling skin tissue homeostasis. What's already known about this topic? Pachyonychia congenita (PC) is a rare genodermatosis caused by mutations in KRT6A, KRT6B, KRT6C, KRT16 and KRT17, which are normally expressed in skin appendages and induced following injury. Individuals with PC present with multiple clinical symptoms that usually include thickened and dystrophic nails, palmoplantar keratoderma (PPK), glandular cysts and oral leukokeratosis. The study of PC pathophysiology is made challenging because of its low incidence and high complexity. There is no cure or effective treatment for PC. What does this study add? This text reviews recent progress made when studying the pathophysiology of PPK associated with PC. This recent progress points to new possibilities for devising effective therapeutics that may complement current palliative strategies.

Symptomatic mucosal involvement in pachyonychia congenita: challenges in infants and young children.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16 or KRT17). Characteristic features of PC are painful palmoplantar keratoderma, variable nail dystrophy, cysts, follicular hyperkeratosis and often oral leukokeratosis. Although oral leukokeratosis can go unnoticed, mucosal involvement of the oral cavity and upper airways can manifest with pain during feeding, hoarseness, stridor and, occasionally, life-threatening obstruction. OBJECTIVES: To characterize patients with PC with symptomatic mucosal involvement. METHODS: We present a case series of nine children with PC with symptomatic mucosal involvement, all with heterozygous mutations in KRT6A. Seven patients complained of painful feeding problems. Four patients were diagnosed with failure to thrive, three of whom required a feeding tube. Simple feeding solutions were beneficial in most cases. Seven patients had laryngeal involvement and one patient died at 4 years of age from acute laryngeal obstruction. CONCLUSIONS: It is important for dermatologists and otolaryngologists to be aware that symptomatic mucosal involvement, and very rarely laryngeal obstruction, can occur in patients with PC. Usually simple feeding solutions may prevent complications and failure to thrive. What's already known about this topic? Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes. Symptomatic mucosal involvement is an important clinical feature of PC and appears to be more pronounced in KRT6A mutation carriers. Only leukokeratosis is frequently seen in PC and can be one of the earliest signs of disease. Laryngeal involvement is a less common feature. It might be symptomatic but usually presents as hoarseness, stridor and, occasionally, as a life-threatening respiratory distress. What does this study add? In most cases of laryngeal involvement, there is no need for any intervention. Although pain and feeding difficulties are usually attributed to the oral leukokeratosis, they can be related to a phenomenon called 'first bite syndrome' (FBS). Symptomatic mucosal involvement with feeding difficulty is important but can be managed in most cases with simple feeding solutions (e.g. softer nipple with a larger hole, thicker formula and feeding with a syringe). Linked Comment: Youssefian and Vahidnezhad. Br J Dermatol 2020; 182:536-537.

Revisiting pachyonychia congenita: a case-cohort study of 815 patients.

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.

Follicular occlusion tetrad in a male patient with pachyonychia congenita: clinical and genetic analysis.

The case of a 24-year-old male patient affected by follicular occlusion tetrad (acne conglobata, hidradenitis suppurativa, pilonidal cyst and dissecting cellulitis of the scalp) associated with clinical signs of pachyonychia congenita (PC)-2 (focal palmoplantar keratoderma, plantar pain, onycodystrophy and multiple cysts) is reported. The diagnosis was supported by genetic analysis that showed heterozygous mutation within the exon 1 of KRT17 gene. This case may reflect different expressions of a phenotypic spectrum induced by a common genetic alteration.

Pachyonychia congenita responding favorably to a combination of surgical and medical therapies.

Pachyonychia congenital (PC) is a rare genetic disorder of cornification and is classified into five types on the basis of keratin gene involved. There are no established treatment options available for PC. Sirolimus in both topical and oral form has been studied in management of PC. We report a young female with a novel genetic mutation in KRT6A gene who presented with painful palmoplantar hyperkeratosis and onychogryphosis, which was cosmetically disfiguring. She was prescribed oral sirolimus after all investigations. There was significant improvement in pain within a week. Pain relief was sustained at 1 year follow-up with topical treatment only. Serial nail avulsion surgeries were also done with showed significant cosmetic improvement in the nails. Medical therapies can be combined with surgery for a better cosmetic outcome and improvement in patient quality of life.

A systematic review of reported cases of pachyonychia congenita tarda.

Pachyonychia congenita (PC) describes a group of genodermatoses manifesting as thickened nails, palmoplantar keratoderma (PPK) and increased risk of cutaneous infections. PC tarda (PCT) describes late-onset PC, and associated genetic polymorphisms have been identified. There has been discussion that PCT may not be a distinct entity but rather misdiagnosed ectodermal dysplasia (ED) or PPK. Clarification of this is important for appropriate diagnosis, management and patient and genetic counselling. We aimed to conduct a systematic review of all reported cases of PCT in the published literature and collate evidence of genetic polymorphisms and clinical features to compare with known features of PC, ED and PPK. PubMed (1946 to 1 July 2018), Scopus (1955 to 1 July 2018) and Web of Science (1990 to 1 July 2018) databases were searched for case reports of PCT with no search restrictions on date or language. The search strategy included the terms pachyonychia congenita tarda OR pachyonychia congenita AND (late onset OR delayed OR PCT). In total, 13 reports describing 19 individual cases of PCT were identified. Of the three identified genetic polymorphisms, the earliest identified has been shown to be highly probably pathogenic, with the second likely to result in a benign amino acid change, while the third has since been shown to be nonpathogenic,. No epigenetic studies have been performed on any reported cases. Previous authors have suggested that a number of cases of PCT may be misdiagnosed ED or PPK. The findings of our review cannot refute this suggestion, and highlight the need for thorough clinical documentation of suspected cases of PCT and thorough genetic screening of kindred to identify causative genetic polymorphisms. Further high-quality datasets and reporting are needed to give further insight into the nature of PCT as a unique entity.

Pachyonychia Congenita Associated with a Novel Variant of KRT17 Presenting Unusual Oral Manifestations.

Pachyonychia congenita (PC) is a rare autosomal dominant condition caused by heterozygous mutation in one of five keratin genes. The purpose of this paper is to report a five-day-old infant with PC whose initial presentation revealed multiple malformed natal teeth and gingival lesions on the alveolar crest. Further investiga- tions led to genetic molecular testing of the child and his parents, which revealed a de novo and novel missense variant of KRT17 (c. 307C>T, p. Arg103Cys), resulting in a non-conservative amino-acid substitution and a diagnosis of PC. This case high- lights the need for multidisciplinary care and the relevance of molecular investigations for patients with multiple natal teeth. (J Dent Child 2019;86(1):61-3)
Received September 26, 2018; Last Revision November 19, 2018; Accepted November 19, 2018.

Pachyonychia congenita: a case report of a successful treatment with rosuvastatin in a patient with a KRT6A mutation.

Pachyonychia congenita (PC) is a rare autosomal dominant disorder characterized by nail dystrophy and palmoplantar keratoderma with severe plantar pain affecting quality of life. There is no effective treatment. Heterozygous mutations in the keratin genes KRT6A, KRT6B, KRT6C, KRT16 and KRT17 have been reported as a cause of PC. Herein we present a female patient with an amino acid substitution mutation in KRT6A (c.1381G>A, p.Glu461Lys in exon 7) and classic features of PC associated with oral leucokeratosis and follicular hyperkeratosis. We also demonstrate successful treatment of the patient with rosuvastatin. A 3.6-mm reduction in plantar callosity thickness was demonstrated by sonography. Our patient also experienced significant pain relief that allowed her to increase physical activity (Children's Dermatology Life Quality Index score dropped nine points following treatment). Collectively, these improvements suggest that rosuvastatin may offer a promising treatment for PC. What's already known about this topic? Pachyonychia congenita (PC) is an autosomal dominant disease characterized by nail dystrophy and painful plantar keratoderma. Keratolytics, emollients, retinoids and steroids have been used for treatment but with limited benefits. What does this study add? A patient with PC who had a KRT6A mutation was treated with rosuvastatin with significant improvement in plantar hyperkeratosis and pain. Statins could be a promising treatment for PC with long-term safety, but further studies are needed.