Palmoplantar Keratoderma Research Articles

278 Gene therapy of an EPPK-causing K9 variant using a CRISPR/Cas9 nickase mediated approach in primary keratinocytes

Epidermolytic palmoplantar keratoderma (EPPK) is a rare, autosomal dominantly inherited skin disorder. The disease is often caused by heterozygous point mutations in the keratin 9 gene coding for type I intermediate filament (IF) protein keratin 9 (K9). The integration of mutant K9 into the IF cytoskeleton has a dominant negative effect resulting in IF fragility and massive thickening of palmoplantar skin. The aim of this project was to correct the IF fragility in EPPK patient-derived primary keratinocyte (KC) cultures by gene editing.

MYCOSIS FUNGOIDES (MF): THE MASTER OF MIMICRY

<h3>Introduction</h3> Mycosis fungoides (MF) is the most common form of primary cutaneous T-cell lymphomas, characterized by a long clinical course and malignant T-cell proliferation. The early stages of MF can mimic atopic dermatitis (AD), and psoriasis and thus, diagnosis can be challenging and oftentimes delayed. <h3>Case Description</h3> A 39-year-old African American female with developmental delay was referred for a mildly pruritic, generalized eczematous dermatitis, hyperkeratosis of the palms and soles, and contractures with fingernail clubbing. Skin biopsy two years prior was reportedly unremarkable. Treatment for an initial diagnosis of fungal dermatitis with mupirocin, clotrimazole, and lotrisone was started with regular debridement of the feet. Rheumatological workup was negative, including x-rays of the hands and chest. Clobetasol wraps provided short-term relief. Dupixent for AD was discussed but not started. A second skin biopsy ultimately revealed erythrodermic MF. Flow cytometry was compatible with Sezary syndrome and T-cell receptor gene rearrangement study was positive for monoclonal gene rearrangement. <h3>Discussion</h3> MF diagnosis is not easy, primarily due to the atypical clinical presentation of the disease at an early stage, and non-specific changes on histopathology. As such, multiple biopsies may be needed to make a diagnosis. This case highlights important points for the allergist. 1) Erythema in skin of color is hard to appreciate 2) MF can often look like AD and 3) Palmoplantar Keratoderma may be associated with MF.

Investigation of Nagashima-type palmoplantar keratoderma in China: A cross-sectional study of 234 patients.

Nagashima-type palmoplantar keratoderma (NPPK) is the most prevalent hereditary palmoplantar keratoderma (PPK) in China, but there is a paucity of epidemiological data on the Chinese population. To explore the clinical and genetic characteristics, evaluate the demographic distribution, and estimate the burden of disease of NPPK. A total of 234 Chinese patients with NPPK were enrolled from two medical centers and an online PPK support group. Next-generation sequencing and Sanger sequencing were performed to screen out and confirm pathogenic mutations in SERPINB7. Clinical features and quality of life (QOL) were evaluated using self-completed questionnaires. In total, 14 pathogenic mutations were identified in SERPINB7 from the cohort. The top four recurrent mutations were c.796C>T (355, 75.9%), c.522dupT (66, 14.1%), c.650_653delCTGT (24, 5.1%), and c.455G>T (12, 2.6%), accounting for 97.6% of Chinese NPPK patients. Other mutations (11, 2.4%) include c.455-1G>T, c.336+2T>G, c.635delG and seven novel mutations c.2T>C, c.434delG, c.455-16A>G, c.656T>C, c.745-553T>G, c.832C>T, c.1036G>T. The estimated prevalence of NPPK in China was found to be 0.975/10 000 based on Chinese databases. Clinically, there were no apparent genotype-phenotype correlations in NPPK patients. Pediatric patients mainly presented with palmoplantar peeling, while adults presented with scale (p< 0.001). The most common comorbidities in NPPK patients were onychomycosis (40.0%), eczema (36.8%), and tinea pedis (30.3%). As for burden of disease, NPPK patients' QOL was decreased by a moderate degree. In this study, pathogenic mutations' allele frequencies in SERPINB7 were updated, and prevalence of NPPK in China was estimated. This large-scale cohort study provides evidence-based recommendations for patient management. Identification of new mutations are important for timely diagnosis of NPPK. Palmoplantar peeling in children can be used as a hallmark for early recognition of NPPK.

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.

Cardiocutaneous Syndrome: Naxos Disease

Naxos disease is a recessively inherited condition, caused by mutation in genes encoding desmosomal proteins Plakoglobin. It is characterized by peculiar woolly hair, palmoplantar keratoderma with arrhythmogenic Right Ventricular dysplasia /cardiomyopathy. A syndrome (a variant of Naxos) with same cutaneous phenotype and predominant Left Ventricular involvement is CARVAJAL syndrome. Patients are at risk of sudden cardiac death due to cardiomyopathy. We herein report a rare case of Naxos disease in a 16 years old male born of a 3º consanguineous marriage, presented with features suggestive of congestive cardiac failure with clubbing (grade 1), woolly hair, and focal keratoderma over palms and soles. ECG demonstrated – inverted T waves (V1-V3), QRS prolongation and complete RBBB. Echocardiography revealed-severe biventricular dysfunction with EF-15-20%, severe MR, severe TR and PAH. Patient was treated with diuretics, ß blockers and ACE inhibitors. These children may need implantation of automatic cardioverter defibrillator to prevent arrhythmogenic attacks and sudden cardiac death. CONCLUSION: For child with woolly hair and palmoplantar keratoderma, the pediatrician should provide a cardiac assessment, considering Naxos/Carvajal disease associated cardiomyopathy. When an early diagnosis is made, life expectancy can be increased by treatment of Heart failure and arrhythmias. Keywords: Naxos disease, Palmoplantar keratoderma, Cardiomyopathy, Wolly hair

Debilitating Contractures of Hands in an Atypical Presentation of Juvenile Pityriasis Rubra Pilaris: A Rare Case Report

Introduction: Palmoplantar keratodermas (PPK) constitute a clinically and genetically complex group of cornification disorders characterized by defective epidermal differentiation leading to marked palmoplantar hyperkeratosis. Classically, keratodermas have been categorised as hereditary and acquired forms. Case Presentation: A 12-year-old male patient presented to our dermatology outpatient department with diffuse thickening and yellowish discoloration of skin over palms and soles since early childhood. He gradually developed progressive thickening and contractures of the fingers of both hands with functional impairment. No such history could be elicited in the family members. Dermatological examination showed bilaterally symmetrical thick hyperkeratotic fissured scaly plaques involving surface of entire palm with sharp demarcation at volar aspect of wrist. Similar plaques with yellowish hue were present over the soles with superficial fissures. The histopathological examination of skin biopsy specimen from the palm showed focal parakeratosis alternating with orthokeratosis in both horizontal and vertical directions (checkerboard pattern) with broadened rete ridges. The findings were consistent with pityriasis rubra pilaris (PRP). The patient improved with systemic and topical retinoids. Conclusions: This report focuses on the recognition of unusual presentations of PRP and emphasizes the importance of early diagnosis and timely treatment, which can avert the dreaded morbid and disabling complication of contractures.

34993 Aggressive squamous cell carcinoma in setting of Huriez syndrome

A 63-year-old man presented for a painful mass on his right thumbnail that had been present for several months. On examination, he had nail dystrophy and several ventral pterygia. Most interestingly, scleroatrophy of the distal upper extremities were noted on all 10 digits and the palms had marked keratoderma. Further history revealed that he had had keratoderma since childhood. History also noted conical dentition that led to dentures at the age of 17, and nail abnormalities. His condition went undiagnosed in childhood, and he did not follow up with a dermatologist.

Olmsted syndrome causing point mutants of TRPV3 (G568C and G568D) show defects in intracellular Ca2+-mobilization and induce lysosomal defects

TRPV3, a non-selective cation channel known to be activated by physiological temperature, is expressed in skin and is involved in different skin functions. Point mutations in TRPV3 cause severe pathological condition, known as Olmsted Syndrome (OS). Now we demonstrate that two OS-inducing point mutations (G568C and G568D) located at the lipid-water-interface region joining TM4 with the loop4 of TRPV3 cause reduced cell size and major defects in lysosomal numbers, and distribution. We detected these two mutants in the lysosome. However, G568C and G568D mutants differ from themselves and also from Wild-type in terms of Ca2+-influx in response to activation by agonist (FPP). These two mutants fail to mobilise Ca2+ from intracellular stores, especially when cytosolic Ca2+ is chelated and/or in absence of extracellular Ca2+. We demonstrate that OS-mutants cause defective pH-maintenance at the lysosomes. We propose that G568C and G568D mutants most-likely act as Ca2+-leaky channels from lysosomes with different abilities.

Palmoplantar Keratoderma: A Molecular Genetic Analysis of Family Cases.

Palmoplantar keratoderma is a clinically polymorphic disorder with a heterogeneous etiology characterized by marked hyperkeratotic lesions on the surface of palms and soles. Hereditary forms of palmoplantar keratoderma usually have autosomal dominant inheritance and are caused by mutations in dozens of genes, most of which belong to the keratin family. We carried out clinical and molecular genetic analysis of the affected and healthy members of four families with autosomal dominant palmoplantar keratoderma. In three out of four family cases of autosomal dominant palmoplantar keratoderma, the following molecular genetic causes were established: in two families—previously non-described missense mutations in the AQP5 gene (NM_001651.4): c.369C>G (p.(Asn123Lys)) and c.103T>G (p.(Trp35Gly)); in one family—a described splice site mutation in the KRT9 gene (NM_000226.4): c.31T>G. In one family, the possible cause of palmoplantar keratoderma was detected—a variant in the KRT1 gene (NM_006121.4): c.931G>A (p.(Glu311Lys)).

Clinical images: Huriez syndrome, a rare scleroderma mimic.

Clinical images: Huriez syndrome, a rare scleroderma mimic.

Ichthyosis follicularis syndromes in patients with mutations in GJB2.

Ichthyosis follicularis (IF) manifests as generalized spiny follicular projections found in syndromic diseases secondary to SREBF1 and MBTPS2 mutations. We sought the genetic cause of IF in two distinct families from a cohort of 180 patients with ichthyosis. In Family 1, the proband (Patient 1) presented with IF, bilateral sensorineural hearing loss and punctate palmoplantar keratoderma. Using DNA from peripheral blood lymphocytes, two compound heterozygous mutations, c.526A>G and c.35delG, were discovered in GJB2. In Family 2, the proband (Patient 2) presented with a previously unreported IF phenotype in the context of keratitis-ichthyosis-deafness syndrome, and whole-exome sequencing found a de novo heterozygous mutation, c.148G>A in GJB2. Histopathology was consistent with porokeratotic eccrine ostial and dermal duct naevus (PEODDN) and IF in Patients 1 and 2, respectively. Our findings add to the clinical and histopathological spectrum of IF and emphasize the association of PEODDN-like entities with GJB2 variants.

Dermoscopy of palmoplantar keratoderma: development and analysis methods

Palmoplantar keratoderma (KPP) is a group of inherited or acquired conditions characterized by palmar and plantar hyperkeratosis. The analysis can be difficult, however, thanks to dermoscopy, which is a non-invasive means of exploration, certain signs are very orienting for the right diagnosis. The available data concerning the dermoscopic profile of palmoplanar pathologies are still limited in the literature. we have reviewed the dermoscopic signs of KPP which target the acquired inflammatory dermatoses frequently found in the routine consultation of the dermatologist. The aim is to realize a dermoscopic guide for the dermatologist in front of KPP and to facilitate the diagnostic orientation in front of this topography using the Dermoscope. We have illustrated with dermoscopic images taken from patients followed in consultation.The analyzed images were taken with minimal pressure to preserve vessel morphology, and immersion with a clear, thick, colorless gel to ensure better visualization.

Papillion lefèvre Syndrome: Rarest of the Rare; But it is Still There

A rare autosomal recessives disorder, Papillon–Lefèvre syndrome (PLS) also known as palmoplantar keratoderma, anhidrosis and periodontitis was first described in 1924 by French Physician Papillon and Lefèver. The disorder is characterized by diffuse palmoplantar keratoderma and aggressive periodontitis, leading topremature loss of deciduous and permanent dentition at a very young age. Mutations in the cathepsin C gene (CTSC), located at human chromosome 11q14.1-q14.3, are the cause of PLS. A 22-year-old male boy was presentedwith all the characteristic feature of papillon-lefèvre syndrome. He had complaint of swollen and friable gums and discomfort in chewing the food along with persistent hyperkeratotic, Flaking and scaling of the skin of palms and soles. He also had early shedding of his milk teeth with family history of consanguineous marriage of parents.

841 EGFR signalling contributes to pachyonychia congenita pathogenesis and its inhibition improves patients’ quality of life

Pachyonychia congenita (PC) is a rare keratinizing disorder characterized by thickened nails, painful and inflammatory palmoplantar keratoderma (PPK) and blistering for which no standard treatment is currently available. PC is caused by dominant mutations in keratin (KRT) 6A, 6B, 6C, 16 and 17 genes which are involved in wound healing and epidermal barrier formation. Previous reports pointed to mTOR activation and oxidative stress with dysfunctional NRF2 as contributors to PPK. However, the relationship between KRT mutations and pathogenesis of pain and PPK in PC, remains elusive.

846 A new case series of olmsted syndrome subjects confirms EGFR activation and long term efficacity of oral erlotinib with acceptable tolerance

Olmsted syndrome (OS) is a rare, painful and severe form of palmoplantar keratoderma (PPK). It is most often caused by dominant mutations in the transient receptor potential vanilloid-3 (TRPV3) gene, a heat-sensitive ion channel that forms a signaling complex with the epidermal growth factor receptor (EGFR). TRPV3 mutations are thought to activate EGFR causing abnormal keratinocyte proliferation and differentiation. We previously reported that blocking EGFR with oral Erlotinib resulted in remarkable improvement in 4 young patients.

478 CRISPER/Cas 9 mediated introduction of the keratin 1 mutation in mice that are identified in patients with epidermolytic ichthyosis

Mutations in the KRT1 cause epidermolytic ichthyosis (EI). There is a strong demand for the development of novel treatment measures. A mutation of c. 1436 T >C; p. Ile 479 Thr of K1 was identified in our case with severe palmoplantar keratoderma, and exaggerated skin lesion on joint skin. Our in silico survey revealed that this amino acid change caused a severe conformational alteration in the K1 protein, strongly suggesting that it interfered with the formation of the K1 / K10 coiled- coil complex.

RSPO1-mutated keratinocytes from palmoplantar keratoderma display impaired differentiation, alteration of cell–cell adhesion, EMT-like phenotype and invasiveness properties: implications for squamous cell carcinoma susceptibility in patients with 46XX disorder of sexual development

BackgroundSecreted R-spondin (RSPO) proteins play a key role in reproductive organ development, epithelial stem cell renewal and cancer induction by reinforcing canonical Wnt signaling. We have previously reported that palmoplantar keratoderma (PPK), predisposition to cutaneous squamous cell carcinoma (SCC) development and sex reversal segregate as autosomal recessive trait in patients carrying RSPO1-mutations.Although our previous findings suggested that RSPO1 secreted from fibroblasts regulates keratinocyte growth or differentiation, the role of this protein in the epidermis remains largely unexplored. Our study was aimed at expanding the phenotypic, molecular and functional characterization of RSPO1-mutated skin and keratinocytes.ResultsCultured primary keratinocytes from PPK skin of a RSPO1-mutated XX-sex reversed patient displayed highly impaired differentiation and epithelial-mesenchymal transition (EMT)-like phenotype. Interestingly, RSPO1-mutated PPK skin expressed markers of increased proliferation, dedifferentiation and altered cell–cell adhesion. Furthermore, all these signs were more evident in SCC specimens of the patient. Cultured PPK patient’s keratinocytes exhibited increased expression of cell‒matrix adhesion proteins and extracellular matrix remodeling enzymes. Moreover, they showed invasiveness properties in an organotypic skin model in presence of PPK fibroblasts, which behave like cancer-associated fibroblasts. However, the co-culture with normal fibroblasts or treatment with the recombinant RSPO1 protein did not revert or reduce the EMT-like phenotype and invasion capability of PPK keratinocytes. Notably, RSPO1-mutated PPK fibroblasts induced a hyperproliferative and dedifferentiated phenotype of age-matched normal control plantar keratinocytes. Wnt signaling has a key role in both PPK promotion and SCC development. Accordingly, Wnt mediators were differentially expressed in both PPK keratinocytes and skin specimens of RSPO1-mutated patient compared to control.ConclusionsAltogether our data indicate that the absence of RSPO1 in patients with 46XX disorder of sexual development affects the skin microenvironment and epidermal integrity, thus contributing to the risk of SCC tumorigenesis in palmoplantar regions exposed to major frictional stresses.

Oral manifestation of pachyonychia congenita type 1: Jadassohn lewandowsky syndrome

Pachyonychia congenital (PC), is a rare genetic disorder, autosomal dominant, disorder of keratinization. This condition is characterized by cutaneous manifestation mainly hyperkeratosis of skin and mucosae and hypertrophy of nails. In this condition, almost 50% of the patients will have oral leukokeratosis. The case report here is of a 15 years old girl, presented with dystrophic, thickened fingernails and toenails with subungual hyperkeratosis, palmoplantar keratoderma, hyperkeratotic plaques in buccal mucosae. Histological examination shows acanthosis, parakeratosis and ballooning of epithelial cells, these features were consistent leukokeratosis, and has been diagnosed as Pachyonychia Congenita type 1. This is a rare condition hence, has been reported.

Clinical and molecular genetic findings of Crisponi/cold-induced sweating syndrome (CS/CISS) spectrum in patients from Turkey.

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by episodic hyperthermia, arthrogryposis, impaired feeding ability, and respiratory distress. The classic CS/CISS is mainly associated with CRLF1 and, rarely, CLCF1. PERCHING syndrome, previously known as CS/CISS type-3 associated with biallelic pathogenic variants in KLHL7, is notable for its few overlapping manifestations. This study presents genotype-phenotype relationships in CS/CISS-like spectrum associated with CRLF1 and KLHL7. Clinical findings of 19 patients from 14 families and four patients from three families were found in association with six different CRLF1 and three different KLHL7 variants, respectively. c.167T>C and c.713delC of the CRLF1 gene and the c.642G>C of the KLHL7 were novel. The c.708_709delCCinsT allele of CRLF1 was identified in 10 families from the Mardin province of Turkey, underlining that an ancestral haplotype has become widespread. CRLF1-associated phenotypes revealed novel manifestations such as prenatal oligohydramnios, benign external hydrocephalus, previously unreported dysmorphic features emerging with advancing age, severe palmoplantar keratoderma and facial erythema, hypopigmented macules and streaks, and recurrent cardiac arrests. KLHL7 variants presented with glabellar nevus flammeus, blepharophimosis, microcephaly, thin corpus callosum, and cleft palate. Abnormalities of sweating, observed in one patient reported herein, is known to be very rare among KLHL7-related phenotypes.

Evaluation of causative etiological factors for acquired palmoplantar keratoderma

Evaluation of causative etiological factors for acquired palmoplantar keratoderma