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.

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.

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.

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.

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.

Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23.

SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24-q32. By using whole-exome sequencing in a further Palestinian-Jordanian SPG23 pedigree, we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (dual serine-threonine and tyrosine protein kinase) in all four affected family members. DSTYK is located within the established linkage region and we also found the same mutation in the previously reported pedigree and another Israeli pedigree (total of ten affected individuals from three different families). The mutation removes the last two exons and part of the 3' UTR of DSTYK. Skin biopsies revealed reduced DSTYK protein levels along with focal loss of melanocytes. Ultrastructurally, swollen mitochondria and cytoplasmic vacuoles were also noted in remaining melanocytes and some keratinocytes and fibroblasts. Cultured keratinocytes and fibroblasts from an affected individual, as well as knockdown of Dstyk in mouse melanocytes, keratinocytes, and fibroblasts, were associated with increased cell death after ultraviolet irradiation. Keratinocytes from an affected individual showed loss of kinase activity upon stimulation with fibroblast growth factor. Previously, dominant mutations in DSTYK were implicated in congenital urological developmental disorders, but our study identifies different phenotypic consequences for a recurrent autosomal-recessive deletion mutation in revealing the genetic basis of SPG23.

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.

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.

Neutrophilic Panniculitis in a child with MYSM1 deficiency.

Neutrophilic panniculitis (NP) with myelodysplasia has been described in adults but not in children. We report a case of NP associated with myelodysplasia in a child with MYSM1 deficiency, a newly described syndrome with primary immunodeficiency (PI), bone marrow failure, and developmental aberrations.

Chronic cutaneous graft-versus-host disease in children: A report of 14 patients from a tertiary care pediatric dermatology clinic.

BACKGROUND/OBJECTIVES: Allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option for many life-threatening disorders in children. Chronic graft-versus-host disease (cGVHD) is a significant complication of HSCT, and its treatment is challenging. Skin is the most common organ affected in cGVHD, with protean manifestations posing a challenge in diagnosis and management. The objective was to have a better understanding of the spectrum of chronic cutaneous GVHD (cc-GVHD) in children. METHODS: Hospital records of 14 children with cc-GVHD, registered over 9 years, were reviewed. RESULTS: All the patients had received HSCT from related donors. Median duration between HSCT and onset of cc-GVHD was 7.5 months. Eighty-six percent of the patients had a prior history of aGVHD, and 14% had de novo onset of cc-GVHD. Of 14 patients, 71% had classic cc-GVHD. Overlap syndrome was observed in 29%. Tandem occurrence of multiple morphologies was noticed in 6 (43%) patients. Of classic cc-GVHD, lichen planus-like cc-GVHD was most common (57%) followed by scleroderma-like (29%) and poikiloderma (7%). Rare variants included eczema-like (14%) and psoriasis-like (7%) cc-GVHD. Mucosal involvement was seen in 78.6% of the patients, nail involvement in 50%, and hair abnormalities in 43%. After a median follow-up of 4.8 years, complete remission was observed in 50% and mortality in 14%. CONCLUSION: The study signifies the diverse nature of cc-GVHD and indicates the need for multicenter surveys including larger number of patients to have proper insight into and develop treatment guidelines for cc-GVHD in children.

Mutations in GRHL2 result in an autosomal-recessive ectodermal Dysplasia syndrome.

Grainyhead-like 2, encoded by GRHL2, is a member of a highly conserved family of transcription factors that play essential roles during epithelial development. Haploinsufficiency for GRHL2 has been implicated in autosomal-dominant deafness, but mutations have not yet been associated with any skin pathology. We investigated two unrelated Kuwaiti families in which a total of six individuals have had lifelong ectodermal defects. The clinical features comprised nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia. In addition, three individuals had sensorineural deafness, and three had bronchial asthma. Taken together, the features were consistent with an unusual autosomal-recessive ectodermal dysplasia syndrome. Because of consanguinity in both families, we used whole-exome sequencing to search for novel homozygous DNA variants and found GRHL2 mutations common to both families: affected subjects in one family were homozygous for c.1192T>C (p.Tyr398His) in exon 9, and subjects in the other family were homozygous for c.1445T>A (p.Ile482Lys) in exon 11. Immortalized keratinocytes (p.Ile482Lys) showed altered cell morphology, impaired tight junctions, adhesion defects, and cytoplasmic translocation of GRHL2. Whole-skin transcriptomic analysis (p.Ile482Lys) disclosed changes in genes implicated in networks of cell-cell and cell-matrix adhesion. Our clinical findings of an autosomal-recessive ectodermal dysplasia syndrome provide insight into the role of GRHL2 in skin development, homeostasis, and human disease.

Systematised naevus sebaceus resulting from post-zygotic mutation in HRAS.

Naevus sebaceus has recently been shown to result from post-zygotic mutations in HRAS, KRAS or occasionally NRAS. We present details of a neonate with extensive naevus sebaceus in whom we identified a pathogenic mutation in HRAS (c.37G > C; p.Gly13Arg), but only in lesional skin DNA, consistent with a mosaic RASopathy. This case highlights the clinicopathological and molecular findings of this naevoid disorder as well as the key issues in the clinical assessment and management of such patients.

Cutaneous Lupus Erythematosus in Children: Experience from a Tertiary Care Pediatric Dermatology Clinic.

BACKGROUND/OBJECTIVES: The manifestations of cutaneous lupus erythematosus (CLE) and their relevance to systemic disease are well characterized in adults, but data are limited in children. The objective of the current study was to examine the spectrum of CLE and its relationship to systemic disease in children from a tertiary care pediatric dermatology clinic. MATERIALS AND METHODS: An analysis of 26 children with CLE registered consecutively over 14 years was performed. RESULTS: Ninety-six percent of the patients were of Arab ethnicity. They included seven (27%) cases with neonatal lupus erythematosus (LE) (71% females and 29% males). Of the other 19 children with CLE, 95% were female. The mean and median age at diagnosis was 11 years. Eighty-nine percent of the patients fulfilled the criteria for systemic LE. All patients had LE-specific lesions and 83% had LE-nonspecific manifestations. Atypical initial presentations were recorded in 28% of the patients, and 22% of the patients had the rare LE variants. Of the LE-specific manifestations, acute CLE was seen in 83%, subacute in 44%, and chronic in 22%. Autoimmune associations were recorded in 44% and a positive family history of autoimmune diseases in 61%. CONCLUSION: This study highlights a striking female predominance, higher risk of systemic disease in children presenting with CLE, higher prevalence of atypical presentation and rare CLE variants, and underrepresentation of discoid LE in children and signifies the need for more surveys to delineate the spectrum of pediatric CLE in different parts of the world.