International Pachyonychia Congenita Research Registry Research Articles

Pachyonychia Congenita: Clinical Features and Future Treatments.

Pachyonychia congenita (PC) is a rare, autosomal dominant inherited disorder of keratinization that is characterized by a triad of focal palmoplantar keratoderma, plantar pain, and hypertrophic nail dystrophy. It can be debilitating, causing significantly impaired mobility. PC is diagnosed clinically alongside identification of a heterozygous pathogenic mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17. Each keratin gene mutation is associated with a distinct clinical phenotype, with variable age of onset and additional features, which has allowed classification by genotype. Additional features include pilosebaceous cysts, follicular hyperkeratosis, natal teeth, oral leukokeratosis, hidradenitis suppurativa, itching, and neurovascular structures. Although classed as rare, the prevalence of PC is likely to be underestimated. There is no cure or specific treatment for PC at present. Current treatments are limited to conservative measures to reduce plantar friction and trauma, mechanical debridement, topical treatments, and treatments for associated features or complications, most commonly infection. However, through active research in collaboration with PC Project, a patient-advocacy group, and the International PC Research Registry, a global registry of PC patients, there are now many new potential therapeutic options on the horizon. This review summarizes the clinical features associated with PC and highlights the current and future treatment of its manifestations.

Coexistence of pachyonychia congenita and hidradenitis suppurativa: more than a coincidence.

The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. To determine the genetic defect underlying the coexistence of PC and HS in a large kindred, to delineate a pathophysiological signalling defect jointly leading to both phenotypes, and to estimate the prevalence of HS in PC. We used direct sequencing and a NOTCH luciferase reporter assay to characterize the pathophysiological basis of the familial coexistence of HS and PC. A questionnaire was distributed to patients with PC registered with the International Pachyonychia Congenita Research Registry (IPCRR) to assess the prevalence of HS among patients with PC. Direct sequencing of DNA samples obtained from family members displaying both PC and HS demonstrated a missense variant (c.275A>G) in KRT17, encoding keratin 17. Abnormal NOTCH signalling has been suggested to contribute to HS pathogenesis. Accordingly, the KRT17 c.275A>G variant resulted in a significant decrease in NOTCH activity. To ascertain the clinical importance of the association of HS with PC, we distributed a questionnaire to all patients with PC registered with the IPCRR. Seventy-two of 278 responders reported HS-associated clinical features (25·9%). Disease-causing mutations in KRT17 were most prevalent among patients with a dual phenotype of PC and HS (43%). The coexistence of HS and KRT17-associated PC is more common than previously thought. Impaired NOTCH signalling as a result of KRT17 mutations may predispose patients with PC to HS. What is already known about this topic? The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. What does this study add? A dual phenotype consisting of PC and HS was found to be associated with a pathogenic variant in KRT17. This variant was found to affect NOTCH signalling, which has been previously implicated in HS pathogenesis. HS was found to be associated with PC in a large cohort of patients with PC, especially in patients carrying KRT17 variants, suggesting that KRT17 variants causing PC may also predispose to HS. What is the translational message? These findings suggest that patients with PC have a higher prevalence of HS than previously thought, and hence physicians should have a higher level of suspicion of HS diagnosis in patients with PC.

25417 Novel distinctions in the profiles, impact, and management of nail disease in pachyonychia congenita

Background: Pachyonychia congenita (PC) is a rare dermatosis that confers lifelong physical and emotional morbidities in patients. The clinical manifestations, self-management, and patient life impact of this disease is still poorly characterized. The International PC Research Registry (IPCRR), a multinational initiative to collect data on PC patients has allowed an opportunity to distinguish the salient features of this disease.

Pachyonychia Congenita Type PC-K6a: The first report in the Vietnamese population

Background: Pachyonychia congenita (PC) comprises a group of rare autosomal dominant genetic disorders. It is characterized by hypertrophic nail dystrophy, focal palmoplantar keratoderma, follicular keratosis, and oral leukokeratosis. It is associated with mutations in five differentiationspecific keratin genes: KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The case is being reported for its rarity. To the best of our knowledge, this is the first report of PC, from Vietnam, confirmed by genetic analysis.
 Case presentation: A four-year-old Vietnamese girl presented with a thickened nail and oral leukokeratosis soon after birth. She was diagnosed with onychomycosis and chronic oral candidiasis and was treated with systemic anti-fungals in children's hospitals and dermatology departments multiple times; however, no treatments were effective. In collaboration with the International Pachyonychia Congenita Research Registry (IPCRR), the clinical features were consistent with a diagnosis of PC type PC-K6a. The genetic testing, performed through the IPCRR, shows a K6a N171K mutation.
 Conclusions: The IPCRR helps screen PC's clinical features and confirm a diagnosis at the molecular level, which is beneficial and crucial for validating the condition's clinical impression.

Identification of clinically useful predictive genetic variants in pachyonychia congenita.

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. 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. 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. 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. We have identified novel and clinically useful genetic predictive variants in the largest cohort of patients with PC described to date.

Distinctions in the Management, Patient Impact, and Clinical Profiles of Pachyonychia Congenita Subtypes

Introduction: Pachyonychia congenita (PC) is a rare dermatosis that confers lifelong physical and emotional morbidities in affected patients. However, the clinical findings, treatments, and psychosocial impact of this disease have not been adequately described. The International PC Research Registry (IPCRR), a multinational initiative to collect data on PC patients, has allowed an opportunity to distinguish the salient features of this disease. We aimed to characterize the breadth and extent of nail disease, treatments, and quality of life in PC patients, and to describe any significant differences in clinical presentation or treatment of PC subtypes. Methods: The most recent IPCRR patient survey data consisting of an 857-response questionnaire and a 102-response addendum were analyzed in a retrospective analysis. The survey data were collected as part of a multinational, multicenter initiative and comprise the largest representative population of PC to date. Participants (survey respondents) were included in the study based on questionnaire responses and a genetic confirmation of having a PC subtype. Results: A total of 857 survey responses were collected. Genetic variations among PC subtypes influence nail disease onset and severity of symptoms. Nail disease negatively impacts patients’ emotional health, especially during the adolescent and young adult years. Nail treatment tools vary little in terms of effectiveness and acquired infection rates. Conclusion and Discussion: Patients with different PC subtypes have distinct clinical nail presentations and psychosocial impact. Genetic testing should be used to confirm PC diagnoses. Further characterization of PC, especially the rarer subtypes, may allow for more individualized patient education.

Paquioniquia congénita tipo I o síndrome de Jadassohn-Lewandowsky: un caso de presentación familiar

La paquioniquia congénita es una rara genodermatosis de herencia autosómica dominante, que produce alteración de la queratinización a nivel de piel, uñas y mucosas. El primer caso fue descrito por Jadassohn y Lewandowsky en 1906, y actualmente afecta a miles de personas en el mundo. El Registro Internacional de Investigación de Paquioniquia Congénita (IPCRR, del inglés, International PC Research Registry) ha identificado a nivel mundial hasta enero de 2020, 977 individuos en 517 familias con paquioniquia congénita, confirmadas genéticamente. Esta condición es considerada en nuestro país como una enfermedad huérfana, y previamente solo hay un reporte en la literatura de un caso en 2009. Se presenta el caso clínico de un paciente masculino de 23 años de edad procedente del área rural del municipio de Timbío, Colombia, con historia clínica de distrofia ungueal hipertrófica en todas las uñas de manos y pies, queratodermia palmoplantar y dolor plantar moderado a severo. Además, presentaba leucoqueratosis oral, hiperqueratosis folicular en muslos e hiperhidrosis palmoplantar. No presentaba quistes foliculares ni antecedente de dientes natales. Sus manifestaciones clínicas se catalogaron como propias de la paquioniquia congénita tipo I. Sumado a lo anterior, se identificaron características clínicas similares en otros miembros de la familia en tres generaciones, incluidos un hermano, la madre y la abuela materna, lo cual evidenció un patrón de herencia propio de esta enfermedad.

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

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. 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. 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. 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. 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.

087 Revisiting pachyonychia congenita: a case cohort study in 815 patients

Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of 5 keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). The establishment of an international registry containing both clinical and molecular data led to the development of a disease classification based on the mutant gene and associated features. Here we harnessed the same resource to clarify the prevalence of PC-associated clinical features, delineate phenotype-genotype correlations and identify prognostic features for disease severity. 815 individuals with confirmed keratin mutations registered in the International Pachyonychia Congenita Research Registry (IPCRR) were surveyed for clinical findings associated with PC. Data were analyzed using Student T-test, Chi-Square, ANOVA tests (for differences in means/proportions), Spearman correlation and logistic regression (for phenotype-genotype correlation). KRT6A mutations were most common and evident in 40% of cases. Plantar keratoderma and toenail dystrophy were the most common clinical findings, with plantar keratoderma most significantly affecting patient’s quality of life. KRT6A mutations were associated with young age of onset, high number of fingernails/toenails involvement, oral leukokeratosis and hoarseness. Cysts and natal teeth were most common among patients carrying KRT17 mutations. Logistic regression models revealed that oral leukokeratosis correlated with earlier toenail involvement, walking aids use, nursing difficulties and hoarseness. Natal teeth and oral leukokeratosis were inversely correlated one relative to the other, while natal teeth and cysts positively correlated one with the other. Hoarseness predicted an increased number of involved fingernails. Our study reveals novel and clinically useful prognostic predictors in PC, and more generally demonstrates the importance of large registry-based careful studies in rare disorders.

Pachyonychia Congenita - Can a Specific Phenotype be a Clue to a Genetic Defect? - a Case Report and Literature Review

Abstract Pachyonychia congenita (PC) is a rare inherited disorder of keratinization characterized by hypertrophic nail dystrophy, painful palmoplantar blisters, cysts, follicular hyperkeratosis and oral leukokeratosis. These pathological clinical features are resulting from mutations in keratin proteins including KRT6A, KRT6B, KRT6C, KRT16, and KRT17. We present a 6-year-old girl with hypertrophic nail dystrophy, follicular hyperkeratosis, circumscribed plantar keratoderma and oral leukokeratosis. The features were consistent with the diagnosis of PC. The patient has been registered in the International Pachyonychia Congenita Research Registry (IPCRR) and is waiting for a detailed genetic analysis. The IPCRR has contributed to publication of numerous papers which emphasized the importance of the mutation type affecting various clinical presentations of PC. Based on recent data, a new classification system has been developed for PC, and it is gradually replacing the earlier classifications. It is based almost exclusively on the mutated genes. In this report we have raised the hypothesis that distinctive clinical features may be highly suggestive of a specific keratin mutation.

The molecular genetic analysis of the expanding pachyonychia congenita case collection

BackgroundPachyonychia congenita (PC) is a rare autosomal dominant keratinizing disorder characterized by severe, painful, palmoplantar keratoderma and nail dystrophy, often accompanied by oral leucokeratosis, cysts and follicular keratosis. It is caused by mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16 or KRT17.ObjectivesTo identify mutations in 84 new families with a clinical diagnosis of PC, recruited by the International Pachyonychia Congenita Research Registry during the last few years.MethodsGenomic DNA isolated from saliva or peripheral blood leucocytes was amplified using primers specific for the PC-associated keratin genes and polymerase chain reaction products were directly sequenced.ResultsMutations were identified in 84 families in the PC-associated keratin genes, comprising 46 distinct keratin mutations. Fourteen were previously unreported mutations, bringing the total number of different keratin mutations associated with PC to 105.ConclusionsBy identifying mutations in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, this study has confirmed, at the molecular level, the clinical diagnosis of PC in these families.

Pachyonychia Congenita in Pediatric Patients

IMPORTANCE Nail dystrophy in early childhood often suggests a diagnosis of pachyonychia congenita (PC). No previous investigation has focused on the early signs of PC and the natural course of the disease. OBJECTIVES To determine the course of pediatric PC, correlate the disease course with the clinical appearance and specific gene mutations, and assess the effect of pediatric PC on quality of life. DESIGN, SETTING, AND PARTICIPANTS One hundred one patients or families with genetically confirmed PC from the International Pachyonychia Congenita Research Registry who completed a survey on the general clinical features of PC and an auxiliary questionnaire on the clinical presentation and quality-of-life issues related to pediatric PC. EXPOSURE Individuals with pachyonychia congenita. MAIN OUTCOMES AND MEASURES Completion of both surveys. RESULTS At birth, toenail changes were present in 47.5% of patients; fingernail changes in 40.6%; and plantar keratoderma in 6.9%. By 5 years of age, these 3 key manifestations were found in 81.2%, 74.2%, and 75.3%, respectively, of individuals with genotype-confirmed PC. The correct diagnosis was made during the first year of life in 26.7% of patients despite the presence of toenail dystrophy in more than 65.3%. Clinical differences that distinguished PC subtypes included (1) later onset and less frequent occurrence of nail dystrophy and keratoderma in PC-K6b, PC-K6c, and PC-K16; (2) concurrent fingernail and toenail thickening in PC-K6a and PC-K17; (3) more palmar keratoderma in PC-K16; (4) cysts primarily in PC-K17 and follicular hyperkeratoses primarily in PC-K6a; (5) hoarseness and/or oral leukokeratoses in the first year of life most often in PC-K6a; and (6) natal teeth exclusively in PC-K17. Among pediatric patients, PC affected the social interactions and function of adolescents most profoundly. CONCLUSIONS AND RELEVANCE Among patients with a detectable mutation, PC manifests with nail thickening and plantar keratoderma before school age in more than three-quarters of affected children, allowing early diagnosis. The highly visible nail changes and painful plantar thickening exert a psychosocial effect on most affected adolescents. Phenotype-genotype correlations in children with PC validate the new classification based on the affected gene.

The molecular genetic analysis of the expanding pachyonychia congenita case collection

Pachyonychia congenita (PC), a rare autosomal dominant keratin disorder characterized by severe, painful, palmoplantar keratoderma (PPK), hypertrophic nail dystrophy, cysts and oral leukokeratosis is caused by mutations in keratin genes; KRT6A, KRT6B, KRT16 or KRT17. Mutations in KRT6C cause PPK with insignificant nail changes. The International Pachyonychia Congenita Research Registry has collected clinical and molecular data from 600 PC patients in 261 families worldwide. We report molecular analysis of families registered during the last 2 years of this expanding case collection.

Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16

Pachyonychia congenita (PC) is an autosomal dominant, very rare keratin disorder caused by mutations in any of at least four genes (KRT6A, KRT6B, KRT16 or KRT17), which can lead to hypertrophic nail dystrophy and palmoplantar keratoderma, among other manifestations. Classically, patients with mutations in KRT6A and KRT16 have been grouped to the PC-1 subtype (Jadassohn-Lewandowsky type) and KRT6B and KRT17 to PC-2 (Jackson-Lawler type). To describe clinical heterogeneity among patients with PC who have genetic mutations in KRT6A and KRT16. In 2004, the Pachyonychia Congenita Project established the International PC Research Registry (IPCRR) for patients with PC. All patients reporting here underwent genetic testing and responded to a standardized, validated survey about their PC symptoms. We report results from 89 patients with KRT6A mutations and 68 patients with KRT16 mutations. Patients with PC who have KRT6A and KRT16 mutations display distinct phenotypic differences. Patients with PC-K6a experience earlier onset, more extensive nail disease and more substantial disease outside palms and soles, as they reported a higher prevalence of oral leucokeratosis (P < 0·001), cysts (P < 0·001) and follicular hyperkeratosis (P < 0·001) compared with their PC-K16 counterparts. Phenotypic differences between patients with KRT6A and KRT16 mutations support adoption of a new classification system based on the mutant gene (PC-6a, PC-16) rather than the PC-1 nomenclature.

Transgrediens pachyonychia congenita (PC): case series of a nonclassical PC presentation

Pachyonychia congenita (PC) is a rare keratin disorder that typically presents with nail dystrophy and focal plantar keratoderma. We present seven cases of PC with transgrediens involvement of the dorsal feet. To document the extension of their disease to the dorsum of the feet in patients with mutation-confirmed PC, to report the natural history of PC with such transgrediens involvement, to generate hypotheses regarding aetiology, and to suggest prevention and treatment modalities. Genetically confirmed cases of PC with transgrediens foot involvement were verified through the International Pachyonychia Congenita Research Registry (IPCRR) and characterized via telephone survey and photography. Seven patients with PC in the IPCRR were confirmed to have transgrediens lesions on the dorsal feet (six KRT6A mutations; one KRT16 mutation). Six cases had pre-existing nontransgrediens keratoderma and all cases reported standing, wearing shoes, foot moisture, and/or infection as exacerbating or predisposing factors. Improvement, reported in six cases, was attributed to use of antibiotics or gentian violet, or improved footwear. Transgrediens involvement of the dorsal feet is a rare manifestation of mutation-confirmed PC and may be more common in patients who carry a KRT6A mutation. Trauma, friction, infection and wound healing may exacerbate or predispose toward transgrediens lesions. It remains to be proven whether transgrediens-associated infection is causal or represents a primary or secondary process. Patients with PC who develop transgrediens lesions may benefit from fungal and bacterial cultures, followed by appropriate antimicrobial treatments. Efforts to decrease skin friction and moisture may also improve and/or prevent transgrediens spread.

A Large Mutational Study in Pachyonychia Congenita

Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by nail dystrophy and painful palmoplantar keratoderma. Additional clinical features include oral leukokeratosis, follicular keratosis, and cysts (steatocysts and pilosebaceous cysts). PC is due to heterozygous mutations in one of four keratin genes, namely, KRT6A, KRT6B, KRT16, or KRT17. Here, we report genetic analysis of 90 new families with PC in which we identified mutations in KRT6A, KRT6B, KRT16, or KRT17, thereby confirming their clinical diagnosis. A total of 21 previously unreported and 22 known mutations were found. Approximately half of the kindreds had mutations in KRT6A (52%), 28% had mutations in KRT16, 17% in KRT17, and 3% of families had mutations in KRT6B. Most of the mutations were heterozygous missense or small in-frame insertion/deletion mutations occurring within one of the helix boundary motif regions of the keratin polypeptide. More unusual mutations included heterozygous splice site mutations, nonsense mutations, and a 1-bp insertion mutation, leading to a frameshift and premature termination codon. This study, together with previously reported mutations, identifies mutation hotspot codons that may be useful in the development of personalized medicine for PC.

Genotype–Phenotype Correlations among Pachyonychia Congenita Patients with K16 Mutations

Pachyonychia congenita (PC) is a rare, autosomal dominant keratin disorder caused by mutations in four genes (KRT6A, KRT6B, KRT16, or KRT17). The International PC Research Registry is a database with information on patients' symptoms as well as genotypes. We sought to describe the heterogeneity of clinical symptoms and to investigate possible genotype-phenotype correlations in patients with two types of K16 mutations, p.Asn125 and p.Arg127, causing the PC-16 subtype of PC. We found that clinical symptoms depended on the type of amino-acid substitution. Patients with p.Asn125Asp and p.Arg127Pro mutations exhibited more severe disease than patients carrying p.Asn125Ser and p.Arg127Cys mutations in terms of age of onset of symptoms, extent of nail involvement, and impact on daily quality of life. We speculate that amino-acid substitutions causing larger, more disruptive changes to the K16 protein structure, such as a change in amino-acid charge in the p.Asn125Asp mutation or a bulky proline substitution in the p.Arg127Pro mutation, may also lead to more severe disease phenotypes. The variation in phenotypes seen with different substitutions at the same mutation site suggests a genotype-phenotype correlation. Knowledge of the exact gene defect is likely to assist in predicting disease prognosis and clinical management.