Co-existence of atypical tuberculid with lupus vulgaris.

Cutaneous tuberculosis (CTB) is an uncommon form of extra-pulmonary tuberculosis accounting for ≤2% of mycobacterium tuberculosis cases and is more often reported from developing countries. Tuberculid, a cutaneous hypersensitivity reaction to mycobacteria or its fragments, is a another rare cutaneous manifestation seen in association with tuberculosis of other organ systems including tuberculous lymphadenitis, pulmonary tuberculosis, etc. Co-occurrence of a tuberculid with CTB is extremely rare. Herein we report a childhood case of lupus vulgaris, a type of CTB, associated with an atypical presentation of tuberculid.

Cutis marmorata telangiectatica congenita being caused by postzygotic GNA11 mutations.

Cutis marmorata telangiectatica congenita (CMTC) is characterized by coarse-meshed capillary malformations arranged in asymmetrically distributed patches. The disorder may be associated with hyper- or hypoplastic limbs, syndactyly, cleft palate, and glaucoma. Because the disease usually occurs sporadically, the concept of a lethal mutation surviving by mosaicism was proposed about 30 years ago. Here we describe three children with CMTC due to a postzygotic GNA11 mutation c547C > T (p.Arg183Cys), documented in saliva (patient 1) or lesional cutaneous tissue (patients 2 and 3). All three individuals had widespread and asymmetric CMTC which was present from birth and became fainter during the first years of life. Variably associated anomalies included glaucoma, choroidal capillary malformation, and body asymmetry. In previous case reports, postzygotic GNA11 mutations were documented in two cases of phacomatosis cesiomarmorata, being characterized by CMTC coexisting with segmental dermal melanocytosis. Moreover, postzygotic GNA11 mutations were noted in two CMTC patients described under the incorrect diagnosis of "nevus vascularis mixtus". Hence, the present cases convincingly support the concept that CMTC can be caused by mosaic GNA11 mutations and thus belongs to the GNA11-Related Capillary Nevus (GNARCAN) spectrum. In two other bona fide cases of CMTC, however, we were unable to find a mutation in GNA11, which may be explained either by our inability to detect a very low percentage of mutant cells or by genetic heterogeneity of the phenotype.

CEDNIK syndrome with phenotypic variability.

CEDNIK syndrome is a rare autosomal recessive syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma of which 25 cases from 19 families have been reported to date. It is a progressive neurodegenerative disorder caused by the loss-of-function pathogenic variant of the SNAP29 gene encoding a member of the SNARE family of proteins. We describe two female siblings from a Syrian parent-related family with CEDNIK syndrome due to homozygous pathogenic variant in SNAP29 [c.223delG(p.Val75Serf*28)]. Palmoplantar keratoderma, reported as a cardinal sign in CEDNIK syndrome, was absent in both patients as of the last follow-up, and one of our patients had a verrucous venous malformation, a finding that has not been previously reported.

A Prospective Survey of Skin Manifestations in Children With Inborn Errors of Immunity From a National Registry Over 17 Years.

Background and Objectives: Reports on skin manifestations in inborn errors of immunity (IEI) are based on retrospective analysis, small series, or isolated case reports. The present prospective study aimed to determine the spectrum of skin manifestations in children with IEI and their relevance to specific molecular defects. Materials and Methods: The data were obtained from the Kuwait National Primary Immunodeficiency Disorders Registry during the period of 2004-2020. Results: A total of 313 pediatric cases of IEI, 71% diagnosed at molecular level, were registered with a cumulative follow-up period of 29,734 months. Skin manifestations were seen in 40.3% of the patients, and they were among the presenting manifestations in 33%. Patients with skin manifestations were older at both onset and diagnosis ages of IEI symptoms, but this was statistically significant for the latter only. The diagnosis delay was significantly longer in patients with skin manifestations. There was a statistically significant association between having skin manifestations and IEI category, being more common in patients with complement deficiencies, combined immunodeficiencies, and diseases of immune dysregulation. There was no statistically significant association between having skin manifestations and both gender and survival. Skin infections were the most frequent manifestations followed by eczema and autoimmune associations. Among IEI with more than 10 cases, skin lesions were a consistent finding in dedicator of cytokinesis 8 (DOCK8) deficiency, hyper IgE syndrome, ataxia-telangiectasia, and recombination activation gene (RAG)1 deficiency. Conclusions: Skin manifestations are common in IEI patients, and they had significant diagnosis delay and referral to specialists. Improvement of awareness about IEI is needed among pediatricians and dermatologists.

Molecular epidemiology of non-syndromic autosomal recessive congenital ichthyosis in a Middle-Eastern population.

Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification disorder presenting with generalized scaling and varying degrees of erythema. Clinical manifestations range from lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) through the most severe form of ARCI, Harlequin ichthyosis (HI). We used homozygosity mapping, whole-exome and direct sequencing to delineate the relative distribution of pathogenic variants as well as identify genotype-phenotype correlations in a cohort of 62 Middle Eastern families with ARCI of various ethnic backgrounds. Pathogenic variants were identified in most ARCI-associated genes including TGM1 (21%), CYP4F22 (18%), ALOX12B (14%), ABCA12 (10%), ALOXE3 (6%), NIPAL4 (5%), PNPLA1 (3%), LIPN (2%) and SDR9C7 (2%). In 19% of cases, no mutation was identified. Our cohort revealed a higher prevalence of CYP4F22 and ABCA12 pathogenic variants and a lower prevalence of TGM1 and NIPAL4 variants, as compared to data obtained in other regions of the world. Most variants (89%) in ALOX12B were associated with CIE and were the most common cause of ARCI among patients of Muslim origin (26%). Palmoplantar keratoderma associated with fissures was exclusively a result of pathogenic variants in TGM1. To our knowledge, this is the largest cohort study of ARCI in the Middle-Eastern population reported to date. Our data demonstrate the importance of population-tailored mutation screening strategies and shed light upon specific genotype-phenotype correlations.

Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity.

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions.

TP63-related disorders: two case reports and a brief review of the literature.

TP63-related disorders comprise a group of six overlapping autosomal dominant (AD) syndromes caused by heterozygous pathogenic variants in the tumor protein p63 gene (TP63). The present report describes the identification of heterozygous de novo pathogenic variants in the DNA binding domain (DBD) of the TP63 gene in two patients diagnosed with Ectodermal dysplasia-Ectrodactyly-Cleft lip/palate syndrome three (EEC3) and Ankyloblepharon-Ectodermal defects-Cleft lip/palate syndrome (AEC), respectively. The report discusses the phenotypic and genotypic characteristics of these patients and provides a brief review of the TP63-related disorder literature.

Granulomatous reaction following bacillus Calmette-Guérin vaccination: Successful response to clarithromycin.

We report a 3-year-old girl with a delayed nontuberculous granulomatous reaction on a bacillus Calmette-Guérin injection site with dissemination to distant sites who showed a favorable response to clarithromycin used for 12 weeks with no recurrence on a follow-up of more than 2 years.

Spectrum of autoimmune bullous diseases among children in Kuwait.

BACKGROUND: Autoimmune bullous diseases (AIBD) are rare among children. The data describing the overall spectrum and prognosis of pediatric AIBD (pAIBD) are scarce, and there are no established treatment guidelines. OBJECTIVES: The present study examined the spectrum, clinical characteristics, and long-term prognosis of pAIBD in a tertiary care pediatric dermatology unit. METHODS: Retrospective records of all pAIBD cases (<18 years) registered over a span of 28 years were analyzed. RESULTS: Records of 23 cases of pAIBD, including 16 boys and 7 girls, were reviewed. They constituted 8.5% of total AIBD patients from all age groups. Ninety-one percent of patients were of Arab ethnicity. Linear IgA bullous dermatosis was the most prevalent AIBD followed by bullous pemphigoid, bullous lupus erythematosus, and pemphigus variants (pyostomatitis-pyodermatitis vegetans and neonatal pemphigus). The mean age of onset and diagnosis was 6.4 and 7.7 years, respectively. Systemic treatments, including systemic corticosteroids and dapsone, were required in most cases. Intravenous immunoglobulin G (IVIG) was also utilized as second-line therapy. The mean follow-up period was 76 months with 90% of the patients in complete remission. CONCLUSIONS: AIBD pose a great challenge among children both in diagnosis and treatment. This study highlights the ethnic variability and underscores the need for additional similar, international studies to achieve a better understanding of the burden related to pAIBD and help establish treatment guidelines.

Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) manifests with generalized scaling often associated with generalized erythema. Mutations in at least 13 different genes have been reported to cause ARCI. Acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder manifesting with peeling over the distal limbs and dorsal surfaces of hands and feet. APSS is mostly due to mutations in TGM5, encoding transglutaminase 5. Both ARCI and APSS are fully penetrant genetic traits. Here, we describe a consanguineous family in which one patient with mild ARCI was found to carry a homozygous mutation in ALOXE3 (c.1238G > A; p.Gly413Asp). The patient was also found to carry a known pathogenic homozygous mutation in TGM5 (c.1335G > C; p.Lys445Asn) but did not display acral peeling skin. Her uncle carried the same homozygous mutation in TGM5 but carried the ALOXE3 mutation in a heterozygous state and showed clinical features typical of APSS. Taken collectively, these observations suggested that the ALOXE3 mutation suppresses the clinical expression of the TGM5 variant. We hypothesized that ALOXE3 deficiency may affect the expression of a protein capable of compensating for the lack of TGM5 expression. Downregulation of ALOXE3 in primary human keratinocytes resulted in increased levels of corneodesmosin, which plays a critical role in the maintenance of cell-cell adhesion in the upper epidermal layers. Accordingly, ectopic corneodesmosin expression rescued the cell-cell adhesion defect caused by TGM5 deficiency in keratinocytes as ascertained by the dispase dissociation assay. The present data thus provide evidence for phenotypic suppression in a human hereditary skin disorder.

Loss-of-function variants in C3ORF52 result in localized autosomal recessive hypotrichosis.

PURPOSE: Localized autosomal recessive hypotrichosis (LAH) has been associated with pathogenic variants in DSG4, encoding a desmosomal protein as well as in LIPH and LPAR6, encoding respectively lipase H, which catalyzes the formation of 2-acyl-lysophosphatidic acid (LPA), and lysophosphatidic acid receptor 6, a receptor for LPA. LPA promotes hair growth and differentiation. In this study we aimed at delineating the genetic basis of LAH in patients without pathogenic variants in these three genes. METHODS: Variant analysis was conducted using exome and direct sequencing. We then performed quantitative reverse transcription polymerase chain reaction (RT-qPCR), immunofluorescence staining, immunoblotting, enzymatic, and coimmunoprecipitation assays to evaluate the consequences of potential etiologic variants. RESULTS: We identified homozygous variants in C3ORF52 in four individuals with LAH. C3ORF52 was found to be coexpressed with lipase H in the inner root sheath of the hair follicle and the two proteins were found to directly interact. The LAH-causing variants were associated with decreased C3ORF52 expression and resulted in markedly reduced lipase H-mediated LPA biosynthesis. CONCLUSION: LAH can be caused by abnormal function of at least three proteins which are necessary for proper LPA biosynthesis.