The histopathological features of the nail plate in pachyonychia congenita.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant disorder of keratinization mediated by genetic mutations in KRT6A, KRT6B, KRT6C, KRT16, or KRT17. While nail dystrophy in PC has a significant impact on quality of life, the histopathological features of the nail plate in PC have not been previously reported. We report the histopathological features of nail plates provided by 19 patients with genetically confirmed PC. METHODS: Nineteen patients with genetically confirmed PC provided a total of 56 nail plates for histopathologic examination. The nail plates were examined for the presence of hyphae, yeast, bacteria, neutrophils, parakeratosis, plasma globules, and hemorrhage. Specimens with onychomycosis (three patients) were excluded from the analysis. RESULTS: No specific histopathological feature was identified in PC nails. Parakeratosis and plasma globules were the most prominent features in both clinically affected and unaffected PC nails. There was a significant association between clinical dystrophy of all 20 nails and KRT6A mutations, and a lack of dystrophy of all 20 nails in KRT6B mutations. CONCLUSIONS: Parakeratosis and plasma globules in the absence of other inflammatory disorders should raise PC in the histopathologic differential diagnosis. The presence of onychomycosis in a nail plate does not exclude a diagnosis of PC.

Walking a day in a pachyonychia congenita patient's shoes: Impact on plantar pain and activity levels measured with wristband activity trackers.

Background Plantar keratoderma is a common finding in pachyonychia congenita, significantly impairing ambulation and quality of life. Due to the variation of pain reporting in pachyonychia congenita clinical studies, it is difficult to evaluate the efficacy of treatment outcomes for painful plantar keratodermas. Objectives To objectively analyse associations between plantar pain and activity levels in pachyonychia congenita patients using a wristband tracker. Methods Pachyonychia congenita patients and matched normal controls wore wristband activity trackers and completed a daily digital survey to record their highest and total pain scores (0-10 scale) each day for 28 consecutive days during four different seasons. Results Twenty four participants (12 pachyonychia congenita patients and 12 matched normal controls) completed the study. Pachyonychia congenita patients walked 1801.30 fewer steps/day (95% CI, -3666.4, 64.1) than normal controls (P = 0.072) and had greater average total [5.26; SD, 2.10] and highest (6.92; SD, 2.35) daily pain than normal controls [0.11 (SD, 0.47), 0.30 (SD, 0.22), respectively] (P < 0.001, both). On average, for each one unit increase in daily highest pain level, pachyonychia congenita activity decreased 71.54 steps/day (SE, 38.90, P = 0.066). Limitation The study had a small number of participants, limiting statistical power. Only pachyonychia congenita patients, ages 18 years or older, with keratin 6a, keratin 16, and keratin 17 mutations were included, limiting generalizability. Conclusion Pachyonychia congenita patients were less active with significantly higher pain than normal controls. There was an inverse correlation between pain and activity. Our findings suggest that wristband tracker technology may be used to evaluate treatment efficacy in future trials on severe plantar pain; therapeutic interventions that decrease plantar pain should correlate with significant increases in activity using wristband trackers.

Pachyonychia Congenita Project: Advancing Research and Drug Development through Collaboration.

Pachyonychia Congenita Project (PC Project) is an international patient advocacy organization dedicated to patients who suffer from pachyonychia congenita (PC). This condition is a painful and debilitating skin disorder caused by a mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16,or KRT17. Through two primary programs, namely the International Pachyonychia Congenita Consortium (IPCC) and the International Pachyonychia Congenita Research Registry (IPCRR), PC Project provides comprehensive patient support and diagnostics while uniting patients, researchers, physicians, and industry partners on a global level to advance research and drug development for meaningful treatments and, ultimately, a cure for PC.

A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita.

BACKGROUND: Pachyonychia congenita (PC) is a group of autosomal dominant keratinizing disorders caused by a mutation in one of 4 keratin genes. Previous classification schemes have relied on data from case series and case reports. Most patients in these reports were not genetically tested for PC. OBJECTIVE: We sought to clarify the prevalence of clinical features associated with PC. METHODS: We surveyed 254 individuals with confirmed keratin mutations regarding their experience with clinical findings associated with PC. Statistical comparison of the groups by keratin mutation was performed using logistic regression analysis. RESULTS: Although the onset of clinical symptoms varied considerably among our patients, a diagnostic triad of toenail thickening, plantar keratoderma, and plantar pain was reported by 97% of patients with PC by age 10 years. Plantar pain had the most profound impact on quality of life. Other clinical findings reported by our patients included fingernail dystrophy, oral leukokeratosis, palmar keratoderma, follicular hyperkeratosis, hyperhidrosis, cysts, hoarseness, and natal teeth. We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations, and a strong association of natal teeth and cysts in carriers of a KRT17 mutation. Most keratin subgroups expressed a mixed constellation of findings historically reported as PC-1 and PC-2. LIMITATIONS: Data were obtained through questionnaires, not by direct examination. Patients were self- or physician-referred. CONCLUSIONS: We propose a new classification for PC based on the specific keratin gene affected to help clinicians improve their diagnostic and prognostic accuracy, correct spurious associations, and improve therapeutic development.

An appraisal of oral retinoids in the treatment of pachyonychia congenita.

BACKGROUND: Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused by mutations in keratin genes KRT6A/B, KRT16, or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Available studies assessing oral retinoid treatment for PC are limited to a few case reports. OBJECTIVE: We sought to assess overall effectiveness, adverse effects, and patient perspective in patients with PC receiving oral retinoids. METHODS: In a questionnaire-based retrospective cross-sectional survey of 30 patient with PC assessing oral retinoids (10-50 mg/d for 1-240 months), we determined the clinical score, satisfaction score, visual analog pain scale, and adverse effects. RESULTS: In 50% of patients there was thinning of hyperkeratoses (average improvement 1.6 on a scale from -3 to +3) (95% confidence interval 1.2-1.9, P < .001). In all, 14% observed amelioration of their pachyonychia; 79% did not experience any nail change. The self-reported overall satisfaction score with oral retinoid treatment was 2 or greater in 50% of the patients (mean 4.5 on a scale of 1-10). Although 33% reported decreased and 27% increased plantar pain with treatment, 40% did not notice any pain change. All patients experienced adverse effects, and 83% reported to have discontinued medication. Risk/benefit analysis favored lower retinoid doses (≤25 mg/d) over a longer time period (>5 months), compared with higher doses (>25 mg/d) for a shorter time (≤5 months). LIMITATIONS: The retrospective, cross-sectional study design is prone to a recall bias. CONCLUSION: Oral retinoids are effective in some patients with PC. However, many patients discontinued medication because adverse effects outweighed the benefits. Careful dose titration is warranted in patients informed about potential adverse effects.

First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder.

The rare skin disorder pachyonychia congenita (PC) is an autosomal dominant syndrome that includes a disabling plantar keratoderma for which no satisfactory treatment is currently available. We have completed a phase Ib clinical trial for treatment of PC utilizing the first short-interfering RNA (siRNA)-based therapeutic for skin. This siRNA, called TD101, specifically and potently targets the keratin 6a (K6a) N171K mutant mRNA without affecting wild-type K6a mRNA. The safety and efficacy of TD101 was tested in a single-patient 17-week, prospective, double-blind, split-body, vehicle-controlled, dose-escalation trial. Randomly assigned solutions of TD101 or vehicle control were injected in symmetric plantar calluses on opposite feet. No adverse events occurred during the trial or in the 3-month washout period. Subjective patient assessment and physician clinical efficacy measures revealed regression of callus on the siRNA-treated, but not on the vehicle-treated foot. This trial represents the first time that siRNA has been used in a clinical setting to target a mutant gene or a genetic disorder, and the first use of siRNA in human skin. The callus regression seen on the patient's siRNA-treated foot appears sufficiently promising to warrant additional studies of siRNA in this and other dominant-negative skin diseases.

Androgen receptor expression patterns in Becker's nevi: an immunohistochemical study.

BACKGROUND: Becker's nevus (BN) is a hyperpigmented patch that traditionally presents on the upper torso in adolescent males. Previous studies have reported an association with increased androgen receptors (ARs) in lesional skin in men and women who have associated physical abnormalities. OBJECTIVE: This study was conducted to assess the presence of ARs immunohistochemically in female patients with BN but no other physical abnormalities and compare this finding with BN in males and in normal skin. METHODS: Biopsy specimens from Becker's nevi in 3 women and 3 men as well as normal skin in the 3 female subjects were stained with AR antibody, and the level of expression in various cutaneous structures was measured. RESULTS: ARs were increased in dermal fibroblasts in Becker's nevi compared to that found in normal skin. LIMITATIONS: The major limitation of the study was the small sample size. CONCLUSION: In BN there is increased AR expression in dermal fibroblasts; immunohistochemical staining may aid in making the biopsy diagnosis.

Peripheral neuropathic changes in pachyonychia congenita.

We compared patterns of intraepidermal nerve fibers and mechanoreceptors from affected and unaffected plantar skin from patients with pachyonychia congenita (PC) and control subjects. Plantar biopsies from 10 genetically confirmed patients with PC (with a mutation in KRT6A) were performed at the ball of the foot (affected skin) and the arch (unaffected) and were compared to biopsies from corresponding locations in 10 control subjects. Tissue was processed to visualize intraepidermal nerve fibers (IENF) (PGP9.5), subsets of IENF (CGRP, substance P, tyrosine hydroxylase), myelinated nerve fiber (neurofilament H, NFH), blood vessels (CD31), Meissner corpuscles, and Merkel cells (MCs). Structures were quantified using stereology or validated quantification methods. We observed that PC-affected plantar skin had significantly lower sweat gland innervation (sweat gland nerve fiber density) and reduced numbers of Meissner corpuscles compared to PC-unaffected or anatomically matched control skin. In contrast, Merkel cell densities and blood vessel counts were higher in PC-affected skin compared to either control or PC-unaffected skin. There were no differences in myelinated nerve fiber densities, SP, or CGRP between the groups. Pressure pain thresholds in PC-affected skin were lower compared to PC-unaffected and anatomically matched control skin. Additionally, MC densities in callused plantar skin from healthy runners with callus and one subject with a nonpainful palmoplantar keratoderma (AQP5 mutation) were similar to PC-unaffected and control skin consistent with callus alone not being sufficient to increase MC number. These findings suggest that alterations in PC extend beyond keratinocytes and may provide strategies to study neuropathic pain in PC.

Lesions resembling malignant atrophic papulosis in a patient with progressive systemic sclerosis.

Malignant atrophic papulosis (MAP), or Degos syndrome, is a rare disorder of unknown etiology. It is characterized by a deep subcutaneous vasculopathy resulting in atrophic, porcelain-white papules. We report the case of a 42-year-old woman with a history of progressive systemic sclerosis who presented with painful subcutaneous nodules on her abdomen along with chronic atrophic papules on her upper and lower limbs. Biopsy results of both types of lesions revealed vascular thrombi without surrounding inflammation. We briefly review the literature on MAP and its association with various connective tissue diseases. To our knowledge, there have been no previous reports of a patient with the clinical and histologic presentations described here. Although the histologic appearance of the subcutaneous nodules was very similar to that of the atrophic papules, the clinical characteristics of the 2 types of lesions were strikingly different. It is fair to theorize that Degos lesions do not start as atrophic porcelain-white papules but rather evolve from a primary lesion. We hypothesize that these lesions start as painful red nodules and may represent part of the disease spectrum in the evolution of MAP.

Intractable localized pruritus as the sole manifestation of intramedullary tumor in a child: case report and review of the literature.

IMPORTANCE: Persistent localized pruritus is a rare manifestation of central nervous system tumors. Delayed diagnosis can lead to devastating complications. OBSERVATIONS: We report an otherwise healthy 19-month-old girl who presented with signs of localized intractable pruritus of 6 months' duration on the left side of the neck, shoulder, and arm, resistant to systemic antihistamines and topical corticosteroids. Findings from skin biopsy, viral culture for varicella-zoster virus, and skin prick test to common food and animal allergens were nondiagnostic. Neurologic examination results were unremarkable. After several months of localized intractable pruritus, magnetic resonance imaging of the cervical spine with and without contrast was performed, which revealed an intramedullary spinal cord tumor extending from just above the foramen magnum to C6. The tumor was surgically resected and found to be a ganglioglioma. Within a week after the surgery her pruritus completely resolved. CONCLUSIONS AND RELEVANCE: We recommend a detailed neurologic examination in any case of persistent localized pruritus, in the absence of primary dermatologic causes. Given the challenges of performing a reliable neurologic examination in children, neuroimaging might be considered in children with intractable localized pruritus of unknown etiology of the head and neck or upper extremity, even in the absence of focal neurologic deficits.

The phenotypic and molecular genetic features of pachyonychia congenita.

Pachyonychia congenita (PC) is an autosomal dominant genodermatosis caused by heterozygous mutations in any one of the genes encoding the differentiation-specific keratins K6a, K6b, K16, or K17. The main clinical features of the condition include painful and highly debilitating plantar keratoderma, hypertrophic nail dystrophy, oral leukokeratosis, and a variety of epidermal cysts. Although the condition has previously been subdivided into PC-1 and PC-2 subtypes, the phenotypic characterization of 1,000 mutation-verified PC patients enrolled in the International PC Research Registry, coordinated by the patient advocacy group PC Project, shows that there is considerable overlap between these subtypes. Thus, a new genotypic nomenclature is proposed, in which PC-6a represents a patient carrying a mutation in the K6a gene, etc. Although a rare disorder, PC represents a good model for therapy development, and international efforts are ongoing to develop and deliver siRNA, gene, correction, small molecule, and other strategies to treat this painful, disabling skin condition. The special relationship between PC Project and the PC research community has greatly accelerated the development pathway from gene identification to clinical trials in only a few years and represents a paradigm of hope for other orphan diseases.

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.