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Background: Ectodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare hereditary disorder characterized by defects in teeth, hair, and nails in association with a fusion of the digits. Genetically, the disease phenotypes are caused by homozygous and compound heterozygous variants in NECTIN4 gene. Objective: The main objective of the study was to identify the pathogenic sequence variant(s) for family screening and identification of carriers. Methods: In the present study, the authors have investigated a large consanguineous family of Pakistani origin segregating autosomal recessive EDSS1. All the coding exons of the NECTIN4 gene were directly sequenced using gene-specific primers. Results: The affected individuals presented the classical EDSS1 clinical features including sparse hair, hypoplastic nails with thick flat discolored nail plates, peg-shaped, conical, and widely spaced teeth with enamel hypoplasia, proximal cutaneous syndactyly of fingers and toes. Sequence analysis of the coding region of the NECTIN4 identified a novel nonsense variant [c.163C>T; p.(Arg55*)] in exon-2 of the gene. Computational analysis of protein structure revealed that the variant induced premature termination at Arg55 located in Ig-like V-loop region leading to loss of Ig-C2 type domains and transmembrane region, and most likely Nectin-4 function will be lost. Study limitation: Gene expression studies are absent that would have strengthened the findings of computational analysis. Conclusion: The present study expanded the phenotypic and mutation spectrum of the NECTIN4 gene. Further, the study would assist in carrier testing and prenatal diagnosis of the affected families.

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: Hereditary palmoplantar keratodermas (PPK) represent a heterogeneous group of rare skin disorders with epidermal hyperkeratosis of the palms and soles, with occasional additional manifestations in other tissues. Mutations in at least 69 genes have been implicated in PPK, but further novel candidate genes and mutations are still to be found. Objectives: To identify mutations underlying PPK in a cohort of 64 patients. Methods: DNA of 48 patients was analysed on a custom-designed in-house panel for 35 PPK genes, and 16 patients were investigated by a diagnostic genetic laboratory either by whole-exome sequencing, gene panels or targeted single-gene sequencing. Results: Of the 64 PPK patients, 32 had diffuse (50%), 19 focal (30%) and 13 punctate (20%) PPK. None had striate PPK. Pathogenic mutations in altogether five genes were identified in 31 of 64 (48%) patients, the majority (22/31) with diffuse PPK. Of them, 11 had a mutation in AQP5, five in SERPINB7, four in KRT9 and two in SLURP1. AAGAB mutations were found in nine punctate PPK patients. New mutations were identified in KRT9 and AAGAB. No pathogenic mutations were detected in focal PPK. Variants of uncertain significance (VUS) in PPK-associated and other genes were observed in 21 patients that might explain their PPK. No suggestive pathogenic variants were found for 12 patients. Conclusions: Diffuse PPK was the most common (50%) and striate PPK was not observed. We identified pathogenic mutations in 48% of our PPK patients, mainly in five genes: AQP5, AAGAB, KRT9, SERPINB7 and SLURP1., QC 20220314

We report a 6-year-old girl showing epidermolytic ichthyosis/epidermolytic hyperkeratosis (EI/EH). Targeted Next Generation Sequencing revealed a de novo, previously unidentified KRT1 mutation. The findings of this study expands the clinical and spectrum and genotype-phenotype correlation associated with EI/EH.

Acrokeratoelastoidosis (AKE) is a rare, benign papular keratoderma that presents as keratotic papules on the lateral margins of the palms and soles. It is most commonly inherited in an autosomal dominant fashion, although sporadic cases are also described. We present a sporadic case of AKE in an 11-year-old girl with a past medical history significant for asthma. On literature review, we found three other cases presenting in children with a past medical history of asthma. We suggest a possible association between asthma and sporadic cases of AKE in children. Current understanding of the pathophysiology of AKE and its associated risk factors is limited and no effective treatment exists. Awareness of a possible association with asthma and atopy, careful history recording in young patients presenting with sporadic cases of AKE, and further research may help to delineate the likelihood of an association between AKE and asthma or atopy. Developing a better understanding of the associated factors that may contribute to the disease process may help guide more effective, targeted treatments in the future.

Background: It is important to better understand the role that environmental risk factors play on the development of esophageal cancer in Howel-Evans families. Additionally, there is little published about appropriate esophageal cancer screening practices in families genetically confirmed to have this condition.Methods: Surveys were distributed to 47 addresses of an American family with Howel-Evans syndrome, of which 29 responded and met inclusion criteria. Data was collected about demographics, environmental risk factors, and medical history of participants.Results : We report characteristics of family members with tylosis, rates of esophageal cancer, rates of genetic counseling, and levels of environmental risk factors. Of the survey respondents, 43% reported features of tylosis, 71.4% were male and 28.6% were female and 28.6% reported leukoplakia. Only 21.4% of tylotic family members smoked, 65% drank alcohol, and 28.6% drank well water. More than half (57.1%) of the tylotic individuals had never had an esophagogastroduodenoscopy (EGD) and no one had been diagnosed with esophageal carcinoma. Only 3.4% of respondents had ever received genetic testing for Howel-Evans syndrome, despite genetic confirmation of their relatives.Conclusions: We encourage dermatologists to discuss smoking-cessation, genetic counseling, and early EGD with affected families.

Importance: Crusted (Norwegian) scabies is a severe manifestation of the contagious skin infection caused by Sarcoptes scabiei. Crusted scabies has been well described in patients with known immunocompromised states. Treatment may be complicated by delayed diagnosis and/or inadequate treatment. This infection may not rank highly on one’s differential diagnosis in the absence of an immunocompromised state, highlighting the uniqueness of the case being presented. Several papers describe immunocompromised children with Down syndrome who are infected with crusted scabies. We present a case of infection in an adult with Down syndrome without evidence of an immunocompromised state.Observations: Our patient came to us with a 13-month history of progressively worsening symptoms, the last 4-6 weeks of that time period being most dramatic, despite various treatments. We performed tissue biopsy, culture, and laboratory evaluations, which revealed numerous mites and bacterial superinfection.Conclusions and Relevance: Crusted scabies infection may occur in adult age individuals with Down syndrome regardless of immune status, leading us to encourage practitioners to consider this condition when presented with patients of this population. We also highlight the need for further exploration of disease prevalence in this patient population.

Palmoplantar keratoderma of the Gamborg-Nielsen type (PPK-GN) is a rare autosomal recessive skin disorder described in patients from Sweden. Mal de Meleda (MDM) is also a rare autosomal recessive inherited PPK first reported in 5 families from the island of Meleda. The 2 conditions phenotypically overlap and are characterised by palmoplantar erythematous hyperkeratotic plaques. The genetic background giving rise to PPK-GN has hitherto been unknown, whereas MDM is known to be caused by mutations in the gene encoding secreted Ly-6/uPAR-related protein 1, SLURP-1. In the present study we scrutinised individuals affected by PPK-GN for mutations in the SLURP1 gene and identified 2 different mutations. Fourteen Swedish patients were homozygous for a previously described mutation, c.43T>C, while one individual was a compound heterozygote with one copy of a novel mutation, c.280T>A, in addition to one copy of the c.43T>C mutation. Hereby we confirm that PPK-GN is an allelic variant of MDM.

Since 1994, four cases of epidermal nevus with epidermolytic hyperkeratosis (EH) caused by K10 gene mutations have been reported, although no K1 gene mutation has yet been reported. We detected a K1 gene (KRT1) mutation in epidermal nevus with EH in a 10-year-old Japanese male. The patient showed well-demarcated verrucous, hyperkeratotic plaques mainly on the trunk, covering 15 % of the entire body surface. No hyperkeratosis was seen on the palms or soles. He had no family history of skin disorders. His lesional skin showed typical granular degeneration and, ultrastructurally, clumped keratin filaments were observed in the upper epidermis. Direct sequence analysis of genomic DNA extracted from lesional skin revealed a heterozygous 5’ donor splice site mutation c.591+2T>A in KRT1. This mutation was not detected in genomic DNA samples from patient’s peripheral blood leukocytes or those of other family members. The identical splice mutation was previously reported in a family with palmoplantar keratoderma and mild ichthyosis, and was demonstrated to result in a 22 amino acid deletion p.Val175_Lys196del in the H1 and 1A domains of K1. The present patient is the first reported case of epidermal nevus associated with EH caused by a K1 gene mutation in a mosaic pattern.