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BACKGROUND Germline autosomal dominant and autosomal recessive mutations in PERP encoding p53 effector related to PMP-22 (PERP), a component of epidermal desmosomes, have been associated with a spectrum of keratodermas. Monoallelic nonsense mutations cause Olmsted syndrome with severe periorificial and palmoplantar keratoderma (PPK). Biallelic recessive frameshift and missense mutations are associated with milder forms of the disease, including generalized erythrokeratoderma and PPK. OBJECTIVES To add new insights into the genotype-phenotype correlations as a consequence of PERP mutations and to provide a comprehensive review of the literature. METHODS Among 26 previously unresolved families within a cohort of 180 extended Iranian families with syndromic or nonsyndromic ichthyosis, two families with shared clinical features were examined by whole-exome sequencing (WES) and genome-wide homozygosity mapping (HM). Mycological and dermatopathological studies were performed to further characterize their atypical phenotypic presentations. RESULTS In two unrelated multiplex consanguineous families affected by ichthyosis, two novel biallelic PERP variants, NM_022121.5, c.89T>C, p.Leu30Pro and c.466G>C, p.Gly156Arg, located inside of genomic homozygosity regions of the probands were detected. Interestingly, some patients had areas of scaly psoriasiform plaques on a background of generalized ichthyosis that appeared during active cutaneous fungal infections. Mycological examinations of these lesions revealed infections caused by Candida albicans, Epidermophyton floccosum, or Trichophyton rubrum. Histopathology of the psoriasiform lesions shared some features with psoriasis, which when combined with clinical presentation, led to incorrect diagnoses of guttate psoriasis or pustular psoriasis. CONCLUSIONS PERP variants in ichthyosis patients can confer susceptibility to recalcitrant cutaneous fungal infections. Additionally, patients with episodic psoriasiform dermatitis in the setting of keratoderma should be considered for PERP genotyping and cutaneous fungal examinations.

Functional skin barrier requires sphingolipid homeostasis; 3-ketodihydrosphingosine reductase or KDSR is a key enzyme of sphingolipid anabolism catalyzing the reduction of 3-ketodihydrosphingosine to sphinganine. Biallelic mutations in the KDSR gene may cause erythrokeratoderma variabilis et progressive-4, later specified as PERIOPTER syndrome, emphasizing a characteristic periorifical and ptychotropic erythrokeratoderma. We report another patient with compound heterozygous mutations in KDSR, born with generalized harlequin ichthyosis, which progressed into palmoplantar keratoderma. To determine whether patient-associated KDSR mutations lead to KDSR substrate accumulation and/or unrecognized sphingolipid downstream products in stratum corneum (SC), we analyzed lipids of this and previously published patients with non-identical biallelic mutations in KDSR. In SC of both patients, we identified ‘hitherto’ unobserved skin ceramides with an unusual keto-type sphingoid base in lesional and non-lesional areas, which accounted for up to 10% of the measured ceramide species. Furthermore, an overall shorter mean chain length of free and bound sphingoid bases was observed—shorter mean chain length of free sphingoid bases was also observed in lesional psoriasis vulgaris SC, but not generally in lesional atopic dermatitis SC. Formation of keto-type ceramides is probably due to a bottle neck in metabolic flux through KDSR and a bypass by ceramide synthases, which highlights the importance of tight intermediate regulation during sphingolipid anabolism and reveals substrate deprivation as potential therapy.

Background Autosomal recessive congenital ichthyoses (ARCI) are a genetically heterogeneous group of rare and chronic disorders characterized by generalized skin scaling and hyperkeratosis, erythroderma, and palmoplantar keratoderma. Additional features include ectropion, eclabium, ear deformities, foul-smell, joints contractures and walking problems, recurrent infections, as well as pruritus and pain. No curative therapy is available and disease care mainly relies on daily application of topical emollients and keratolytics to the whole-body surface. Altogether, disease signs and symptoms and treatment modalities have a major impact on quality of life of patients and their caregivers. However, very few studies have evaluated the family disease burden in ARCI. Methods We have performed an Italian multicenter cross-sectional study to assess the secondary disease impact on family members of pediatric and adult patients with ARCI, using a validated dermatology-specific questionnaire, the family dermatology life quality index (FDLQI). Disease severity was assessed by the dermatologist in each center. Results Seventy-eight out of 82 patients who were accompanied by at least one family member filled the FDLQI. Forty-eight (61.5%) patients were aged less than 18 years. The mean FDLQI score was 10.3 (median 10), and the most affected dimensions were (1) time needed for care, (2) extra-housework, and (3) household expenditure. Higher total FDLQI score significantly correlated with more severe disease score (P = 0.003). Features associated with greater family burden included recurrent infections (P = 0.004), foul-smell (P = 0.009), palmoplantar keratoderma (P = 0.041), but also presence of scales on the face (P = 0.039) and ear deformities (P = 0.016). Conclusions Our findings highlight the major socio-economic and psychological burden imposed by ARCI on the QoL of family caregivers. In addition, they show that global evaluation of disease impact also on family members is an essential part of patient-reported outcomes. Finally, our data underline the need to develop specific measures for family support.

Papillon-Lefevere syndrome is a very rare autosomal recessive trait characterized by palmoplantar hyperkeratosis and severe generalized early-onset periodontitis leading to premature loss of primary and permanent dentitions. Various etiopathogenesis factors are associated with syndrome. The palmoplantar keratoderma typically has its onset between the ages of 1 and 4 years and severe periodontitis starts at age of 3-4 years. A dentist plays an important role in early diagnosing and preserving remaining teeth in oral cavity. This case series describes three cases of PLS in siblings with consanguineously married parents. All siblings in the family were affected which makes this a rare case. Keywords: Consanguineous, Palmoplantar keratosis, Periodontitis, Cathepsin­ C gene

Papillon-Lefevre syndrome (PLS) (OMIM: 245000) is a rare autosomal recessive disorder characterized by palmoplantar hyperkeratosis and early onset periodontitis, resulting in the premature loss of the deciduous and permanent teeth. PLS is caused by mutations in the cathepsin C (CTSC) gene (OMIM: 602365), which has been mapped to chromosome 11q14-q21. Genetic analysis can help early and rapid diagnosis of PLS. Here we report on a Chinese PLS pedigree with two affected siblings. We have identified two novel compound heterozygous mutations c.763T>C (p.C255R) and c.1015C>A (p.R339S) in the CTSC gene. The two mutations expand the spectrum of CTSC mutations in PLS.

Background Palmoplantar hyperkeratosis is a cutaneous manifestation that had not been clearly associated with infection by the human T-cell lymphotropic virus, which is a retrovirus that in most cases does not develop clinical pathologies and its symptoms may be undetected. The skin is one of the most affected organs, however until now only seborrheic dermatitis, xerosis/ichthyosis and infective dermatitis associated with HTLV-1 have been described as cutaneous clinical manifestations of this disease. Case presentation We present the case of a 36-year-old male patient with serologically documented HTLV-1 infection, who presented symptoms of diarrhea, malabsorption due to Strongyloides stercoralis, and in whom a physical examination revealed an association with generalized xerosis and palmoplantar keratoderma confirmed by skin biopsy. Other infectious etiologies and malignancy were ruled out. This clinical manifestation was managed with dermal hydration, and skin care which improved the thickened skin and make it less noticeable. Conclusions According to our experience, this is the first reported case of palmoplantar keratoderma associated with a human lymphotropic virus infection. This is a skin manifestation that has not been confirmed in conjunction with HTLV-I before. This implies that palmoplantar keratoderma is a new clinical manifestation of this infection, that should be considered in the initial approach of patients in endemic areas with these dermatological characteristics.

R-spondin (RSPO)1 is a fibroblast-secreted protein that belongs to the R-spondin protein family which is essential for reproductive organ development, epithelial stem cell renewal and cancer induction or suppression. RSPO1 gene mutations cause palmoplantar hyperkeratosis with squamous cell carcinoma (SCC) of the skin, 46XX sex reversal and true hermaphroditism. To characterize RSPO1-deficient skin fibroblasts derived from two patients with mutations in RSPO1, with palmoplantar hyperkeratosis, recurrent SCC and 46XX sex reversal, to provide further insight into disease-related skin tumourigenesis. Fibroblast cultures from non-tumoural palmoplantar skin biopsies were established to evaluate features and properties that may be altered at cancer onset, i.e. proliferation, extracellular matrix contraction and invasion, as well as TGF-β and matrix metalloproteinase (MMP) secretion. Fibroblasts demonstrated increased proliferative potential in vitro, a high level of collagen contraction and invasion by SCC cells, release of high levels of pro-inflammatory and pro-fibrotic TGF-β, and increased expression of MMP1 and MMP3. Analysis of the expression of selected proteins associated with RSPO1-activated pathways confirmed sustained activation of the TGF-β signalling pathway and indicated a loss of TGF-β inhibitory feedback. Also, treatment of fibroblasts with a recombinant RSPO1 protein aggravated this pro-inflammatory phenotype, suggesting caution in designing therapeutic strategies based on restoration of protein function. Our findings indicate that fibroblasts from RSPO1-mutated patients behave similarly to cancer-associated fibroblasts. Chronic inflammation and fibrotic changes in palmoplantar skin may play a role in SCC development and recurrence, possibly by irreversibly activating the tumourigenic phenotype of fibroblasts.

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.

Li Gong,1,2 Shuping Guo,1 Detong Wang,3 Ting Wang,4 Xiaoli Ren,1 Yuting Yuan,1,2 Hongzhou Cui1 1Department of Dermatology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2The First Clinical Medical College of Shanxi Medical University, Taiyuan, People’s Republic of China; 3Tonghua Hospital of Traditional Chinese Medicine, Tonghua, People’s Republic of China; 4Department of Dermatology, Shanxi Hospital of Integrated Traditional and Western Integrated Medicine, Taiyuan, People’s Republic of ChinaCorrespondence: Hongzhou CuiDepartment of Dermatology, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, Shanxi, 030001, People’s Republic of ChinaEmail menjuncui@163.comBackground: Pachyonychia congenita (PC) is a rare, autosomal dominant genodermatosis characterized by palmoplantar keratoderma, nail dystrophy, cystic lesions, follicular hyperkeratosis, mucosal leukokeratoses, hyperhidrosis, hoarseness, and, rarely, natal teeth. Five keratin genes, KRT6A, KRT6B, KRT6C, KRT16 and KRT17, have been found to be associated with PC.Methods: Using polymerase chain reaction and Sanger sequencing techniques, the purpose of the present study was to investigate the clinical features associated with PC and discover disease-associated variants. The KRT6A, KRT16, KRT17, and KRT6B exonic and flanking region sequences were amplified and directly sequenced to detect mutations.Results: Across two independent instances of PC, we identified a previously reported c.1393T>C (p.Tyr465His) mutation in exon 7 of KRT6A, and a novel c.1237G>C (p.Glu413Gln) heterozygous missense mutation in exon 6 of the KRT16 gene.Conclusion: Through phenotype-genotype analysis among PC pedigrees, confirmed diagnoses of PC-K6a and PC-K16 were made in the two patients who presented with symptoms of PC. A new pathogenic mutation site in PC-K16 was potentially discovered.Keywords: KRT6A gene, KRT16 gene, pachyonychia congenital, phenotype-genotype

The current revised task force criteria for diagnosis of arrhythmogenic cardiomyopathy (ACM) includes only morphological criteria for right ventricle with no consideration for left ventricle criteria.1 However, accumulating evidence suggests increasing left ventricle involvement in ACM. One such phenotype is Carvajal syndrome, which is a primary left ventricle ACM that is inherited as a familial cardiocutaneous syndrome consisting of woolly hair, palmoplantar keratoderma, and cardiac involvement. High index of clinical suspicion and advanced imaging based on cardiac magnetic resonance imaging (MRI) are key to making the diagnosis. We describe here cardiac MRI findings and scar pattern that led to the diagnosis of Carvajal syndrome in our patient. Key Teaching Points • Arrhythmogenic left-sided ventricular cardiomyopathy (ALVC) is a rare type of arrhythmogenic cardiomyopathy with a phenotype that is distinct from the traditional arrhythmogenic right ventricular cardiomyopathy. • High index of clinical suspicion and cardiac magnetic resonance imaging are key to the diagnosis of ALVC. • A circumferential/ring-like pattern of epicardial or midmyocardial delayed enhancement pattern is increasingly recognized as a hallmark for clinically suspected ALVC with desmosomal mutation (Carvajal syndrome).

Nagashima-type palmoplantar keratosis (NPPK) is the most prevalent palmoplantar keratoderma (PPK) in East Asia. Homozygous or compound heterozygous loss-of-function mutations in serpin peptidase inhibitor, clade B (ovalbumin), and member 70 (SERPINB7), which encodes members of the serine protease inhibitor superfamily, have been identified as the cause of NPPK. Clinical manifestations of NPPK include well-demarcated erythema, mild to moderate hyperkeratosis on the whole palm, and sole with transgrediens, extending to the dorsal surfaces of the hands and feet, inner wrists, ankles, and the Achilles tendon areas. In this study, we perform a review of relevant clinical cases aimed at elucidating the clinical characteristics, genetic characterization, differential diagnoses, and clinical management of NPPK. A better understanding of the clinical characteristics and pathogenic gene characterization of NPPK will enhance the diagnosis of NPPK, identify related diseases, and inform on the precise therapy and prognosis. Moreover, it will promote the awareness of NPPK in non-Asian regions.

Thirteen members of aquaporin (AQP), a water channel, are expressed in mammals. In this review, we briefly overview these mammalian AQPs, then focus on AQP5, an exocrine gland-type AQP. Namely, we discuss: (1) the mechanism for coupling of AQP5 dynamics with the secretion and restoration cycle of amylase after isoproterenol (IPR) in the parotid gland (PG); (2) roles of parasympathetic nerve for maintaining AQP5 level in the submandibular gland (SMG), and; (3) AQP5 down-regulation in an experimental pathological model by LPS administration in the PG. We then move to the effects of single nucleotide mutation (SNP) found in rats and humans and its affected phenotypes. That is, G308A point mutation found in rat AQP5 cDNA resulted in amino acid substitutions of Gly103 for Asp103, and causes diminished expression of its protein product. In humans, several SNPs in AQP5 are found in European and Chinese families and cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma.

Introduction: Palmoplantar keratodermas (PPKs) is heterogeneous entity of cutaneous disorders, with hyperkeratinisation of stratum corneum over palm and soles. PPKs can be hereditary or acquired. Acquired PPK occurs in later years due to continuous or constant exposure to allergens, irritants and exposure to trauma. Aim: This study undertaken to assess the clinical manifestations related to Palmoplantar keratoderma cases and its impact on quality of life of cases. Materials and Methods: A total of 106 patients with chief complaints of Palmoplantar keratoderma attending outpatient department of DVL were included. Detailed clinical history regarding diseases status was collected. The Patients feedback was taken as impact scores i.e. 3 (Very good), 2 (Good), 1 (Moderate), 0 (Poor). QOL was measured by grading system based on the patient’s feedback. Results: Majority cases were between 2nd to 4th decades (65%). Housewives (30.1%) and daily wage labourers (24.5%) were more commonly affected by acquired PPK. Psoriasis (52.8%) followed by Eczema (15.09%), Pityriasis rubra pilaris (8.4%) and Erythroderma dermatitis (5.6%) are common symptoms associated with PPK. There is a notable impact of PPK on quality of life of patients in 57.4% cases. Conclusion: Acquired PPK is always misdiagnosed because it is nonhereditary. House wives and daily wage workers are commonly affected due to constant exposure to detergents, chemicals and various forms of trauma. Palmoplantar keratodermas has remarkable impact on quality of life of patients. Keywords: Palmoplantar keratoderma (PPK), Psoriasis, Occupation, Prevalence, Quality of life (QOL).

The immune checkpoint inhibitors (ICIs) have transformed the standards of care in cancer treatment and has dramatically improved patient prognoses. As a result of the introduction of these novel treatments several types of adverse events related to ICIs (immune related adverse events ((irAEs)) have been observed and reported. In this case series we describe the clinical course of four patients, with unusual ICI induced toxicities. The first patient was a 59 year-old female who received chemo-immunotherapy (pembrolizumab) for stage 4- lung adenocarcinoma, and developed autonomic neuropathy (AN). The second and third patients were both 63 year-old males who also received chemo-immunotherapy (pembrolizumab) for stage 4-A lung adenocarcinoma. One of those patients developed palmoplantar keratoderma and one developed conjunctivitis, urethritis and arthritis (Reiter syndrome). The fourth patient was an 80 year-old male who received chemo-immunotherapy (pembrolizumab) for stage 3-A squamous cell carcinoma of the lung and developed myasthenia gravis.

Nagashima-type palmoplantar keratosis (NPPK) is a diffuse, non-syndromic (isolated), autosomal recessive palmoplantar keratoderma (PPK) with transgredients. It is characterized by non-progressive mild to moderate transgredient PPK. The mutation in SERPINB7 is reported to underlie the condition. Though many case reports/series have demonstrated various mutations in SERPINB7, the genotype-phenotype correlation in this disorder is still lacking. We herein report two brothers with NPPK. Both patients were found to be compound heterozygous for c.796C>T and c.650_653delCTGT in the SERPINB7 gene. We then summarize the previously reported cases of different mutations in SERPINB7 along with their clinical phenotypes in an attempt to shed some light on this correlation. Further investigations and systematic data collection are still needed to clarify this issue.

BACKGROUND: Hyperkeratotic hand eczema (HHE) is a typical clinical hand eczema subtype with a largely unknown pathophysiology.OBJECTIVE: To investigate histopathology, expression of keratins (K), epidermal barrier proteins, and adhesion molecules in HHE.METHODS: Palmar skin biopsies (lesional and perilesional) were obtained from seven HHE patients and two healthy controls. Moreover, 135 candidate genes associated with palmoplantar keratoderma were screened for mutations.RESULTS: Immunofluorescence staining showed a significant reduction of K9 and K14 in lesional skin. Upregulation was found for K5, K6, K16, and K17 in lesional skin compared with perilesional and healthy palmar skin. Further, upregulation of involucrin and alternating loricrin staining, both in an extracellular staining pattern, was found. Filaggrin expression was similar in lesional, perilesional, and control skin. No monogenetic mutations were found.CONCLUSION: Currently, the phenotype of HHE is included in the hand eczema classification system; however, it can be argued whether this is justified. The evident expression of filaggrin and involucrin in lesional skin does not support a pathogenesis of atopic eczema. The upregulation of K6, K16, and K17 and reduction of K9 and K14 might contribute to the underlying pathogenesis. Unfortunately, comparison with hand eczema studies is not possible yet, because similar protein expression studies are lacking.

Annular epidermolytic ichthyosis is a rare subtype of epidermolytic ichthyosis that is characterized by erythematous, polycyclic, and migratory scaly plaques accompanied by palmoplantar keratoderma. This report presents the case of an 8-year-old girl who developed migratory, erythematous, scaly plaques associated with palmoplantar keratoderma. The initial hypothesis was erythrokeratodermia variabilis et progressiva; however, the finding of epidermolytic hyperkeratosis in histopathological examination led to the diagnosis of annular epidermolytic ichthyosis.

Background: Papillon-Levefre Syndrome (PLS) is a rare genetic disorder with prevalence of 1-4 cases per millions of birth, characterized by the presence of palmar-plantar hyperkeratosis and rapid periodontal destruction of both the primary and secondary dentition. Purpose: This clinical report described such a rare condition with special attention on its diagnostic characterization, various treatment options and Prosthodontic rehabilitation. Case: Five years-old boy accompanied by his mother came to Pediatric Dentistry Specialist Clinic, Universitas Airlangga Dental Hospital - Surabaya with the chief complaint of gradually loss of upper and lower teeth since the patient was 3 years old. Case Management: Removable partial denture was chosen because it was considered as an appliance that can recover the function of mastication, speech and aesthetic patient. Removable partial denture was designed to replace 51, 52, 53, 54, 55, 61, 62, 63, 64, 65, 72, 73, 74, 75, 82, 83, 84 and 85 with retention on 16, 26, 36 and 46, and anterior bite riser on 31 and 41. Conclusion .Removable partial denture is the treatment of choice for children with PLS who are still in the growth period because it can recover mastication and aesthetic functions, have a good aesthetic, and easy maintenance that could done by t he child.

Mitochondria fulfill essential roles in ATP production, metabolic regulation, calcium signaling, generation of reactive oxygen species (ROS), and additional determinants of cellular health. Recent studies have highlighted a role for mitochondria during cell differentiation, including in skin epidermis. The observation of oxidative stress in keratinocytes from Krt16 null mouse skin, a model for pachyonychia congenita (PC)-associated palmoplantar keratoderma, prompted us to examine the role of Keratin (K) 16 protein and its partner K6 in regulating the structure and function of mitochondria. Electron microscopy revealed major anomalies in mitochondrial ultrastructure in late stage, E18.5, Krt6a/Krt6b null embryonic mouse skin. Follow-up studies utilizing biochemical, metabolic, and live imaging readouts showed that, relative to controls, skin keratinocytes null for Krt6a/Krt6b or Krt16 exhibit elevated ROS, reduced mitochondrial respiration, intracellular distribution differences, and altered movement of mitochondria within the cell. These findings highlight a novel role for K6 and K16 in regulating mitochondrial morphology, dynamics, and function and shed new light on the causes of oxidative stress observed in PC and related keratin-based skin disorders.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of predominantly the right ventricular (RV) myocardium. Affected patients typically present as young adults with hemodynamically stable ventricular tachycardia, although pediatric cases are increasingly recognized. These young subjects often have a more severe phenotype with a high risk of sudden cardiac death (SCD) and progression toward heart failure. Diagnosis of ARVC is made by combining multiple sources of information as prescribed by the consensus-based Task Force Criteria. The description of Naxos disease, a fully penetrant autosomal recessive disorder that is associated with ARVC and a cutaneous phenotype of palmoplantar keratoderma and wooly hair facilitated the identification of the genetic cause of ARVC. At present, approximately 60% of patients are found to carry a pathogenic variant in one of five genes associated with the cardiac desmosome. The incomplete penetrance and variable expressivity of these variants however implies an important role for environmental factors, of which participation in endurance exercise is a strong risk factor. Since there currently is no definite cure for ARVC, disease management is directed toward symptom reduction, delay of disease progression, and prevention of SCD. This clinically focused review describes the spectrum of ARVC among children and adolescents, the genetic architecture underlying this disease, the cardio-cutaneous syndromes that led to its identification, and current diagnostic and therapeutic strategies in pediatric ARVC subjects.

Vitamins are an indispensable food source and important owing to the enzyme cofactor and catalytic roles they play in the body. Fat-soluble vitamins A, D, E, K, and B12, are stored in the body and can cause problems with their excessive accumulation. Other vitamins rarely accumulate in the body because they dissolve in water and are excreted through the kidneys. Alcoholism, strict diets, insufficient parental nutrition, and gastrointestinal absorption problems may be included in the causes of vitamin deficiencies. Although clinical findings of vitamin deficiencies display different characteristics depending on the vitamins, the signs that generally occur are cutaneous pigmentation, pigmentation on mucous membranes, palmoplantar keratoderma characterized by fissures, palmar streaking, yellow streaking on the nails, nail layering, and intranail hemorrhage.

Naxos disease is a recessively inherited pattern of arrhythmogenic cardiomyopathy with palmoplantar keratoderma and woolly hair. The causative mutation identified in plakoglobin protein gene indicated a potential role of the desmosomal protein complex as culprit for cardiomyopathy. In the context of a family, the early evident cutaneous features may serve as a clinical screening tool to spot arrhythmogenic cardiomyopathy in subclinical stage. "Myocarditis-like episodes" may step up the disease evolution or mark a transition from concealed to symptomatic cardiomyopathy phase. Arrhythmogenic cardiomyopathy in Naxos disease shows increased penetrance and phenotypic expression but its arrhythmic risk is analogous to dominant forms.

Background Olmsted syndrome is a rare and complex skin disorder affecting 46 (published) infants as of 2012. The infants affected in this case were born premature at 28 weeks' gestation. Infants affected by this syndrome demonstrate numerous plaques on several specific areas of the skin. Common treatments include exfoliation in addition to psoriasis treatments. The extremely fragile nature of the premature infants' skin complicates treatment modalities. Clinical findings The progression of the infants' dermatologic findings and plaque formation is discussed in this case study. Primary diagnosis The primary diagnosis of Olmsted syndrome was made with the assistance of a multidisciplinary team to work through several differential diagnoses presenting with severe forms of palmoplantar keratoderma. Interventions The management of skin plaques in twin premature infants is presented in this case study. An evidence-based approach, utilizing the model of family-centered care, is presented with multidisciplinary involvement and an outline of the specific plan of care for the extensive skin care regimen used. Outcomes An interdisciplinary skin care regimen was created to provide consistency in transition from hospital to home. Using a consistent approach, the plaques were able to be softened and many removed. Continual maintenance is required to manage continual buildup of skin plaques. Practice recommendations Premature infants are at increased risk for infection due to the immaturity of their skin. The complexity of their skin complicates the ability to recognize and care for rare skin disorders. This case study illuminates the practicality of a consistent and evidence-based approach to a complex and rare skin disorder.

Mal de Meleda (MDM) is a rare sub-type of palmoplantar keratoderma (PPK) disease. The primary symptoms of PPK are scleroatrophy, transient keratoderma, scleroatrophic erythema, pseudoainhum around the digits, and perioral erythema. MDM is a pathology with a difficult clinical course. This case study presents two cases of MDM in siblings born out of second-degree consanguinity. The presenting complaint was the peeling of the palmar skin since birth. Both patients were treated with acitretin orally (dose: 10 mg) for three months and tretinoin (topical) for two months. The prognosis was good after three months of treatment.

espanolLa pitiriasis rubra pilaris es una dermatosis infrecuente cuya etiologia se desconoce; se caracteriza por papulas foliculares hiperqueratosicas, placas eritematosas y escamosas que pueden progresar a eritrodermia, con islas de piel sana, y queratodermia palmoplantar. Los subtipos III, IV y V, segun la clasificacion de Griffiths, se observan exclusivamente en ninos. El tratamiento de esta dermatosis constituye un desafio: no existe un tratamiento universal aceptado ya que la tasa de respuesta a diferentes modalidades varia de manera amplia. Se presenta el caso de una pitiriasis rubra pilaris juvenil de tipo III con buena respuesta a etanercept. EnglishPityriasis rubra pilaris is a rare skin disease whose etiology is unknown, characterized by hyperkeratotic follicular papules, scaly plaques that can progress to erythroderma, with islands of sparing, and palmoplantar keratoderma. Subtypes III, IV, and V according to the classification of Griffiths, are observed exclusively in children. The treatment of this dermatosis constitutes a challenge, there is no universally accepted treatment since the response rate to different therapies varies widely. We present the case of a type III juvenile pityriasis rubra with a good response to etanercept.

1. Luis F. Sanchez-Espino, MD*,† 2. Claudia I. Gil-Tellez, MD* 3. Consuelo Cantu-Reyna, MD* 4. Cesar A. Martinez-Longoria, MD* 1. *Instituto de Seguridad Social para los trabajadores del Estado de Nuevo Leon (ISSSTELEON), Hospital San Jose del Tecnologico de Monterrey, Mexico 2. †Department of Pediatrics, Tecnologico de Monterrey, School of Medicine and Health Science, Mexico A 7-month-old boy presents to our clinic with a 4-month history of a progressive and persistent generalized exanthema that began on the trunk and spread to the extremities. The patient is the firstborn of healthy, nonrelated parents with no relevant past medical history. The infant was born prematurely at 34 weeks’ gestation due to preterm labor and had a short and uncomplicated course in the NICU for respiratory distress. Prior to discharge, the perinatal hearing screening test results were abnormal, and he was referred for additional testing. Developmental milestones were not achieved by the end of the first and third months; the infant could not recognize his parents’ voices or smile in response to familiar sounds. Developmental delay persisted throughout his first year, mainly in the fine motor, cognitive, and social skills. However, many of the expected milestones had been reached by 15 months of age, except for some deficit in language and communication skills. During his primary care visits, his weight has ranged between the 3rd and 10th percentiles, whereas his length and head circumference have been normal. The exanthema is initially considered to be of allergic origin, prompting the trial of various hydrolyzed and elemental formulas without improvement. Between 7 and 14 months of age, the eczematous dermatosis is persistent despite treatment with multiple keratolytics, carbamides, steroid, antifungal treatment, and bacteriostatic ointments. At 18 months of age, the physical examination is remarkable for a generalized dermatosis (Figs 1–3) with extensive erythroderma, keratotic plaques, palmoplantar keratoderma, inflammation of the lips, alopecia, and nail dystrophy (Fig 4). There is oral and genital involvement. Laboratory evaluation includes a white blood cell count of 23,400/µL (23.4 × 109/L), with an eosinophil count of 17,000/µL (17.0 × 109/L), and IgE levels of 296 UI/mL. Skin, hair, and scalp biopsies show diffuse …

HMS can have neurologic MS like manifestations. It is urgent to do more research and report probable unknown associations of HMS for its better management.

Background PNP is a malignancy-associated autoimmune mucocutaneous syndrome due to autoantibodies against plakins, desmogleins, and other components of the epidermis and basement membrane of epithelial tissues. PNP-causing malignancies comprise mainly lymphoproliferative and hematologic neoplasms. PNP is extremely rare, especially in children.Methods Here, we present the first case of a child who developed PNP on a PTLD after small bowel transplantation because of a severe genetic protein-losing enteropathy.Results The patient in this case report had a severe stomatitis, striate palmoplantar keratoderma, and lichenoid skin lesions. In addition, she had marked esophageal involvement. She had lung pathology due to recurrent pulmonary infections and ventilator injury. Although we found no evidence of BO, she died from severe pneumonia and respiratory failure at the age of 12 years.Conclusion It is exceptional that, despite effective treatment of the PTLD, the girl survived 5 years after her diagnosis of PNP. We hypothesize that the girl survived relatively long after the PNP diagnosis due to strong T-cell suppressive treatments for her small bowel transplantation.

Nagashima-type palmoplantar keratoderma (NPPK) is characterized by non-progressive, diffuse, and cross-gradient hyperkeratosis caused by mutations in the SERPINB7 gene on chromosome 18q21.33. Chromosome 18q deletion syndrome (18q- syndrome) is a terminal deletion or microdeletion syndrome characterized by intellectual disability and congenital malformations. This paper describes an 18-year-old man with palmoplantar keratoderma and diffuse white matter abnormalities in the brain. Trio-based exome sequencing (ES) revealed a suspected mosaic compound heterozygous mutation for c.796C>T (p.Arg266∗) in exon 8 inherited from the mother and a de novo exons 4–6 deletion of SERPINB7. Additional copy number variant (CNV) analysis of the ES data indicated a heterozygous gross deletion of 18q22.3-q23. The two SERPINB7 gene variants were verified by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). Finally, low-coverage whole-genome sequencing (WGS) confirmed the 18q22.3-q23 deletion and additionally detected a mosaic 18q21.33-q22.3 deletion, together explaining NPPK and the neurological phenotypes of the proband. The gross deletion of all exons of SERPINB7 was revealed for the first time. More rarely, c.796C>T (p.Arg266∗) was likely to be mosaic, while the exon deletion was mosaic. In conclusion, the combination of multiple molecular genetic testing methods provides comprehensive informative molecular findings and promotes the diagnosis of complex diseases, as in this case.

Germline mutations in HRAS cause Costello syndrome (CS), while mosaic mutations in HRAS show a variability of phenotypes, ranging from mild features such as keratinocytic epidermal nevus (KEN), sebaceous nevus (SN), woolly hair nevus (WHN) with KEN, to severe manifestations of CS with cutis laxa. We report two individuals. The first was a 2-year-old boy with woolly hair nevus (WHN) without any other cutaneous involvement, in whom somatic HRAS mutation (c.34G>A; p.Gly12Ser) was identified in his affected scalp and hair follicle specimens. This is the first reported WHN type 1 (no cutaneous involvement) patient caused by somatic HRAS mutation. The other individual was a 12-year-old girl with CS caused by germline HRAS mutation (c.34G>A), that manifested with coarse face, palmoplantar keratoderma, deep palmar and plantar creases, hyperpigmented patches, asymmetry and deformity of lower limbs, atopic dermatitis, as well as mental retardation. Of note, a linear hyperpigmented plaque was observed in her father's lumbosacral region. Although the father refused to provide semen and skin tissue for further examination, this reminds us of possible mosaicism in parents of individuals with germline de novo HRAS mutation and underlines the importance of parental evaluation for prenatal counseling.

Periungual pyogenic granulomas are benign vascular tumors that present as painful, round, spontaneously bleeding lesions composed of rapidly proliferating capillaries and excess tissue. The vast majority of pyogenic granulomas are caused by physical trauma or infectious agents and they may resolve spontaneously. Herein, we highlight a very rare case of periungual pyogenic granulomas induced by the regularly prescribed oral retinoid acitretin during treatment for congenital palmoplantar keratoderma. This unique case showed that it is feasible to continue acitretin therapy in the presence of pyogenic granuloma development if proper dose reduction and topical therapies are utilized. The patient's lesions resolved within two weeks of this protocol's initiation and the pyogenic granulomas did not recur over the course of a six-month follow-up observation period. In addition, we performed a systematic review of the literature using PubMed databases for the clinical features and treatments in other reported acitretin-induced pyogenic granuloma cases; we compiled a comprehensive list of other prescription drugs known to cause pyogenic granulomas up-to-date.

Background Papilon‐Lefevre syndrome (PLS; OMIM 245000) is a rare autosomal recessive disease characterized by aggressive periodontitis and palmoplantar keratoderma. The prevalence of PLS in the general population is one to four cases per million. Although the etiology and pathogenic mechanisms underlying PLS remain largely unclear, existing evidence shows loss‐of‐function mutations of the cathepsin C gene (CTSC; OMIM 602365) could cause PLS. Here we found a novel variant of the CTSC gene in a Chinese PLS family and predicted the effect of the variant on the physic–chemical characters and tertiary structure of the protein. Methods The 1–7 coding exons and exon–intron boundaries of CTSC gene of the proband and her family were amplified and sequenced directly, and Chromas was used to read sequencing files. Furthermore, the PolyPhen‐2, PROVEAN, and Mutation Taster were utilized to predict the pathogenicity of the variant. Besides, the physic–chemical and structural characters of the protein were analyzed by ProtParam, ProtScale, and SWISS‐MODEL. Results Our study identified a novel homozygous variant c.763T>C (p.Cys255Arg) in exon 6 of the CTSC gene, and it was a likely pathogenic variant as predicted by PolyPhen‐2, PROVEAN, and Mutation Taster. Moreover, ProtParam and Protscale revealed the variant increased the isoelectric point and hydrophilicity of the protein, and the SWISS‐MODEL analysis suggested the variant was located in a critical domain for protein activity. Conclusion Our study analyzed a Chinese family with PLS and identified a novel missense variant in the CTSC gene. Besides, this study retrospectively summarized 113 variants of CTSC in the world and highlighted the features of 27 CTSC variants in Chinese PLS patients. In addition, this study paid much particular attention to the relationship between CTSC variants and different phenotypes., Our study identified a novel missense variant in the cathepsin C (CTSC) gene. Besides, we summarized variants of CTSC in the world and analyzed the features of CTSC in Chinese Papilon‐Lefevre syndrome patients. Furthermore, we paid specific attention to the relationship between CTSC variants and different phenotypes.

Mohamad et al. (2020) describe loss-of-function mutations in SERPINA12 as a cause of diffuse, transgradient palmoplantar keratoderma (PPK). This disorder shares similar clinical features with other PPKs caused by protease overactivity, including erythema, peeling, and exacerbation on water exposure. Understanding this disorder may shed further light on the role of proteases and their inhibitors in epidermal physiology.

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

Ichthyosis hystrix, Curth-Macklin type (IHCM) is an extremely rare autosomal dominant dermatosis caused by mutations in the keratin genes, KRT1 or KRT10, which often manifests as extensive, dark, spiky or verrucous plaques and severe palmoplantar keratoderma. We report a novel frameshift truncation mutation, c.1596_1597insAT (p.Gly533Metfs*82) in exon 7 (V2 tail domain) of KRT1, which, by replacing the glycine-serine-rich tail of KRT1 with a series of 75 alanine-rich amino acids, produces a mild IHCM phenotype. The patient with the mutation presented with localized ichthyosis and progressive hyperkeratosis of the palms and soles with no history of blistering.

Topical use of immune response modifiers, such as imiquimod, has increased in dermatology. Although its topical use is well tolerated, it may be associated with exacerbations of generalized cutaneous inflammatory diseases, possibly through the systemic circulation of pro-inflammatory cytokines. This report describes a case of development of pityriasis rubra pilaris, a rare erythematous-papulosquamous dermatosis, in a woman aged 60 years during treatment with imiquimod 5% cream for actinic keratosis. It evolved with erythrodermic conditions and palmoplantar keratoderma, presenting progressive clinical resolution after the introduction of methotrexate. The authors emphasize the importance of recognizing possible systemic reactions associated with the topical use of imiquimod.

The article deals with ethiopathogenetic factors of origin of progredient symmetric erythrokeratodermia of Gottron which is mainly characterized by autosomal dominant mode of inheritance and is classified as a disorder of cornification with extra epidermal cellular proliferation.Clinicopathologic criteria on the basis of which this pathology can be verified are described here, such as: onset of a disease at an early age, strictly divided polycyclic, fixed, hyperkeratotic plaques with a narrow erythematic crown and a clean-cut, sometimes hyper pigmented edge, which are symmetrically located on skin on head, buttocks, limbs and are not prone to quick peripheral growth; large frequency of palmoplantar keratoderma and also histological changes typical of erythrokeratodermia.The article describes a rare clinical case of autosomal-recessive progredient symmetric erythrokeratodermia of Gottron which is distinguished by seasonal changes of skin pathological process — emergence of rash in winter and complete remissions in summer.