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

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

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.

Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.

Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and sweat gland. RNA-seq analysis revealed that all PC-associated keratins (except for Krt6c that does exist in the mouse genome) are expressed in the mouse enamel organ. We further demonstrated that these keratins are produced by ameloblasts and are incorporated into mature human enamel. Using genetic and intraoral examination data from 573 adults and 449 children, we identified several missense polymorphisms in KRT6A, KRT6B and KRT6C that lead to a higher risk for dental caries. Structural analysis of teeth from a PC patient carrying a p.Asn171Lys substitution in keratin-6a (K6a) revealed disruption of enamel rod sheaths resulting in altered rod shape and distribution. Finally, this PC-associated substitution as well as more frequent caries-associated SNPs, found in two of the KRT6 genes, that result in p.Ser143Asn substitution (rs28538343 in KRT6B and rs151117600 in KRT6C), alter the assembly of K6 filaments in ameloblast-like cells. These results identify a new set of keratins involved in tooth enamel formation, distinguish novel susceptibility loci for tooth decay and reveal additional clinical features of pachyonychia congenita.

A treatment protocol for botulinum toxin injections in the treatment of pachyonychia congenita-associated keratoderma.

BACKGROUND: Severely debilitating plantar keratoderma pain is the most distressing clinical feature of pachyonychia congenita (PC). Several earlier publications have reported therapeutic success with plantar injections of botulinum toxin (Btx). OBJECTIVES: To describe our 4-year experience during which we administered a total of 30 plantar Btx injections to five patients with PC following an optimized protocol. METHODS: Five patients with PC (age 21-54 years) who were treated at our medical centre from April 2015 to June 2018 were included in the study. After an ultrasound-guided nerve block performed by an anaesthesiologist, the patients received plantar intradermal injections of Btx A. To ascertain the effect of the treatment, we used a dedicated quality-of-life questionnaire for patients with PC (PCQoL) and asked the patients to evaluate the intensity of eight parameters pertaining to their symptoms at baseline and before every treatment session. At study closure, patients were asked to evaluate the maximal improvement in the same eight parameters throughout the study period. RESULTS: All patients demonstrated a decrease in PCQoL scores during the follow-up period. All patients showed a significant improvement in PCQoL after the first treatment session and at the last evaluation (P = 0·043). The scores with the best improvement concerned morning feet burning and long-distance walking (> 500 m). The scores were significantly lower if the intervals between Btx injections were <100 days. CONCLUSIONS: Btx treatment of PC-associated keratoderma following an optimized protocol leads to a major change in patients' quality of life. What's already known about this topic? Plantar pain is considered by patients to be the most severe and debilitating manifestation of pachyonychia congenita (PC). Over the past few years, a number of reports have shown that plantar injections of botulinum toxin (Btx) reduce or even eliminate pain, blistering and callosities in patients with PC. However, the injection technique, doses of Btx and methods of anaesthesia varied between reports and patients. What does this study add? Here we report our 4-year experience in providing 30 treatments to five patients following an optimized protocol. Btx was found to provide a quantifiable improvement in all patients treated. What is the translational message? Btx treatment of PC-associated keratoderma using a structured approach, which includes the use of a sufficient dose of Btx (200-400 U of onabotulinumtoxinA or 500-1000 U of abobotulinumtoxinA), and regular intervals between treatment sessions (of < 100 days), leads to a major change in patients' quality of life.

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.

Chronic pain in pachyonychia congenita: evidence for neuropathic origin.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant skin disease, with chronic pain being the most prominent complaint. Histological studies showing alterations in sensory innervation, along with reports on alterations in mechanical sensitivity, suggest that PC may be a form of neuropathy. OBJECTIVES: Here, for the first time, we aim to evaluate systematically the sensory function of patients with PC vs. controls, in order to investigate the pathophysiology of PC. METHODS: Patients (n = 62) and controls (n = 45) completed the McGill and Douleur Neuropathique-4 (DN4) questionnaires. Sensory testing included detection and pain thresholds, pathological sensations, conditioned pain modulation (CPM) and temporal summation of pain. RESULTS: A moderate-to-severe chronic pain in the feet, throbbing and stabbing in quality, was highly prevalent among patients with PC (86%) and was especially debilitating during weight bearing. In addition, the majority of patients had a DN4 score ≥ 4 (62%), static allodynia (55%) and tingling (53%) in the feet. Compared with controls, patients with PC exhibited thermal and mechanical hypoaesthesia and mechanical hyperalgesia in the feet. CPM was reduced among the patients, and was associated with more enhanced mechanical hyperalgesia in the feet. The specific gene and nature of the causative mutation did not affect any of these features. CONCLUSIONS: Although thermal and mechanical hypoaesthesia may result from thicker skin, its presentation in painful regions, along with mechanical hyperalgesia and allodynia, point towards the possibility of neuropathic changes occurring in PC. The clinical features and DN4 scores support this possibility and therefore neuropathic pain medications may be beneficial for patients with PC.

Nociceptin/orphanin FQ opioid peptide-receptor expression in pachyonychia congenita.

Nociceptin/orphanin FQ opioid peptide (NOP)-receptor (NOP-R) is a member of the opioid receptor family. NOP-R activation has demonstrated analgesic effects in preclinical pain models without the addiction risks associated with other opiate targets. Pachyonychia congenita (PC) is a palmoplantar keratoderma characterized by neuropathic pain in affected skin. A cohort of KRT6A gene mutation PC patients with no other explanation for their neuropathic pain offered a unique opportunity to assess potential of NOP-R as a therapeutic target. Plantar biopsies from 10 PC patients and 10 age/gender matched controls were performed at the ball (PC-affected) and the arch (PC-unaffected) of the foot. NOP-R expression was assessed by immunohistochemistry. Localization of NOP-R in subsets of epidermal nerve fibers was investigated using the pan-neuronal marker PGP9.5, markers for unmyelinated peptidergic fibers (calcitonin gene-related peptide [CGRP] and substance P [SP]), as well as for myelinated Aδ and Aß fibers (neurofilament H [NFH]). Robust NOP-R expression was detected in epidermal keratinocytes and in a subset of PGP9.5+ fibers in both epidermis and dermis, confirmed by western blot and absorption experiments with NOP-R peptide. NOP-R expression in keratinocytes was significantly reduced in PC-affected plantar skin compared with PC-unaffected skin. In addition, NOP-R expression occurred in dermal NFH+ myelinated fibers in all groups, although few CGRP+ fibers co-expressed NOP-R. Furthermore, most SP+ fibers also co-expressed NOP-R. These findings indicate that NOP-R is expressed on epidermal keratinocytes, as well as on epidermal and dermal nerve fibers and has potential as a promising target to treat neuropathic pain in PC.

Can skin disease cause neuropathic pain? A study in pachyonychia congenita.

INTRODUCTION: Pachyonychia congenita (PC) is a rare skin disorder caused by an autosomal dominant mutation in one of five genes encoding keratin (K6a, K6b, K6c, K16 or K17; each defining one PC subtype). Pain is a prominent symptom, but its severity and type are poorly characterized. METHODS: In total, 35 genotyped US patients with PC consented to clinical assessment including the quality of life (QoL) questionnaire EQ-5D-3L, the Brief Pain Inventory (BPI) and painDETECT. Abbreviated quantitative sensory testing (QST) was also performed, and included mechanical detection threshold (MDT), mechanical pain threshold (MPT), wind-up pain ratio (WUR) and vibration detection threshold (VDT). RESULTS: Significant pain in patients with PC was confirmed, as indicated by mean BPI severity and interference of 4.2 ± 1.7 and 4.4 ± 2.2, respectively, as well as QoL impairment, as indicated by mean EQ-5D index of 0.69 ± 0.18. PD identified neuropathic pain in 62% of patients, the remainder being nociceptive. The painDETECT score was most significantly related to EQ-5D index (R(2)  = 0.26, P = 0.02). The K17 and K6a subtypes exhibited significantly worse QoL (0.584 and 0.613 respectively) than the K16 and K6b subtypes (P = 0.02). In QST analysis, abnormal pressure pain (assessed as MPT) was frequently observed, with more than half of patients with PC affected (54%), and 57% of patients with K17 also exhibiting abnormality in minimum touch threshold (assessed as MDT, P < 0.05). Very few patients were receiving analgesic therapy appropriate for neuropathic pain. CONCLUSION: Significant neuropathic pain was observed in PC, which warrants appropriate treatment. The health states observed in this sample are at a level that the average US citizen would forfeit one-third of their remaining lifespan to avoid.

Comparative study of high-resolution multifrequency ultrasound of the plantar skin in patients with various types of hereditary palmoplantar keratoderma.

BACKGROUND: High-variable-frequency ultrasound is used as an imaging tool for various cutaneous disorders. We utilized this tool in pachyonychia congenita (PC) patients, who typically present with plantar hyperkeratosis and often severely debilitating pain, compared to patients with epidermolytic palmoplantar keratoderma (EPPK) and mal de Meleda (MDM). OBJECTIVE: To ascertain the feasibility of ultrasound technology for the diagnosis of PC. METHODS: The study included a total of 16 patients, 7 with PC, 5 with EPPK and 4 with MDM, who underwent ultrasound examination of the plantar skin with high-resolution multifrequency ultrasound equipment. RESULTS: Ultrasound scans performed over the proximal and distal plantar foot calluses in PC patients demonstrated hyperechoic dots and lines within the epidermis compatible with hyperkeratosis, engorged varicose veins in the dermis and an anechoic layer interposed between the epidermis and the dermis, corresponding to blister fluid below the calluses. In contrast to PC patients, patients with MDM and EPPK demonstrated no blisters. CONCLUSION: PC patients, as opposed to a group of patients with MDM and EPPK, displayed subepidermal blistering beneath their calluses. This finding may help in the diagnosis of PC and in partially explaining plantar pain as part of PC symptomatology.

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.

Pachyonychia congenita with laryngeal obstruction.

Pachyonychia congenita is a rare genodermatosis that can affect the larynx. Laryngeal obstruction is very unusual with only a few cases reported. A 2-year-old girl presented with typical clinical features of pachyonychia congenita shortly after birth. At age 9 months, following an upper respiratory infection, she developed stridor and hoarseness and was found to have severe laryngeal obstruction, which was felt to be secondary to pachyonychia congenita based on direct laryngoscopy and laryngeal biopsy. Leukokeratosis of her larynx was treated with CO(2) laser on three occasions, with improvement in her respiratory distress after each treatment. This report is the first case of pachyonychia congenita with laryngeal obstruction in which the gene mutation has been established (a deletional mutation in K6a), confirming that laryngeal obstruction can occur in PC-1.

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 associated with median rhomboid glossitis.

A 3-year-old girl presented with subungual hyperkeratosis and nail plates with increased transverse curvature, distal elevation, yellow-brown discoloration, and mild thickening. The changes, which affected all 20 nails, had developed during the first year of life. Mucocutaneous examination showed the presence of median rhomboid glossitis. The patient's mother had similar nail changes, which had been present since infancy as well as a focal plantar keratoderma and hyperhidrosis. The patient's clinical presentation and history were compatible with a diagnosis of pachyonychia congenita, a rare heritable disease that affects the nails, skin, oral and laryngeal mucosae, teeth, and hair. Dominant-negative mutations in four keratin genes (K6a, K6b, K16, and K17) lead to keratinocyte fragility and the resultant pachyonychia congenita phenotype. Successful targeted therapies are currently lacking for this oftentimes disabling disorder. Although oral manifestations are a common feature of PC, to our knowledge, this represents the first report of median rhomboid glossitis in association with PC.

Laryngeal manifestations of pachyonychia congenita: a clinical case and discussion on management for the otolaryngologist.

BACKGROUND: Pachyonychia congenita is a rare keratinising disorder, which typically presents during the first three years of life and usually affects the nails and palmoplantar surfaces. It can involve the larynx and potentially result in life-threatening airway obstruction. METHODS: A case report is presented and the findings of a literature review are reported. The review involved a PubMed search using the keywords 'pachyonychia congenita' together with 'larynx', 'laryngeal involvement', 'laryngeal obstruction', 'airway obstruction', 'hoarseness' and/or 'stridor'. RESULTS: A five-year-old boy, with confirmed pachyonychia congenita, presented with complications of laryngeal involvement over a four-year period. He required three intubations and a tracheostomy for acute airway obstruction. Treatment with potassium titanyl phosphate laser laryngoscopy stabilised the progression of laryngeal disease. CONCLUSION: Patients with pachyonychia congenita and laryngeal involvement can have a varied presentation, ranging from hoarseness to acute airway obstruction. Management can be a challenge, requiring early evaluation, regular surveillance and aggressive treatment. This paper reports our experience in managing and treating the laryngeal complications of a child with pachyonychia congenita.

Chronic Foot Pain due to Pachyonychia Congenita in a Pediatric Patient: A Successful Management Strategy.

We report the case of an 11-year-old girl who presented to our multidisciplinary pain center with the chief complaint of chronic bilateral foot pain because of a rare congenital keratin disorder. This patient had been diagnosed with pachyonychia congenita, an extremely rare genetic disorder primarily affecting the skin and nails. The child had bilateral foot pain for years because of the characteristic blisters and calluses on the soles of her feet. Chronic pain was negatively impacting her quality of life; she was severely limited in her activities of daily living secondary to pain. Furthermore, she reported absenteeism from school, lack of social activities, and frequent nighttime awakenings. We discuss the successful management of her chronic foot pain using a multimodal, multidisciplinary approach.