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.

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.

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.

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.

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.

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.

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.

Clinical subtypes and molecular basis of epidermolysis bullosa in Kuwait.

BACKGROUND: Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous blistering skin disease, but in countries such as Kuwait, there are very limited data on the clinical and molecular pathology of EB. To improve understanding of EB in Kuwait, we report the experience of a local tertiary referral center over a 17.5 year period (January 2000-June 2017) in establishing clinical and molecular diagnoses. METHODS: Review of hospital records and diagnostic reports. Individual cases were diagnosed by combinations of clinical assessment, skin biopsy (immunohistochemistry and transmission electron microscopy), Sanger sequencing of EB genes, and whole exome sequencing. RESULTS: Fifty-four families with EB were registered with the clinic over this period, 41 of whom (84 patients) participated in diagnostic studies. Thirty-seven of these 41 families had consanguineous marriages; 34 had recessive forms of EB, while only seven had dominant subtypes. Recurrent mutations were observed in epidermal dystonin, transglutaminase 5, and type VII collagen. CONCLUSIONS: The prevalence of EB in Kuwait is approximately three times that of internationally cited rates with an over-representation of autosomal recessive variants. Establishing the molecular basis of EB in Kuwait with accurate diagnostic subtyping provides a basis for determining healthcare requirements and improving patient management of EB.

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.

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.

Phacomatosis pigmentovascularis: Report of four new cases.

Phacomatosis pigmentovascularis is a rare group of syndromes characterized by the co-existence of a vascular nevus and a pigmentary nevus with or without extracutaneous systemic involvement. The existing classifications of phacomatosis pigmentovascularis are based on phenotypic characteristics. We report four new cases of phacomatosis pigmentovascularis, three with phacomatosis cesioflammea demonstrating phenotypic variability, and one with phacomatosis cesiomarmorata. Extracutaneous manifestations were observed in three patients (75%) that included central nervous system involvement in three, bilateral congenital glaucoma in two, and cardiovascular system involvement in one. The molecular basis of phacomatosis pigmentovascularis is yet to be elucidated. Whether the various subtypes of phacomatosis pigmentovascularis are separate molecular entities or phenotypic variants of the same disease needs to be settled.

Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas-Papas and CHAND syndromes.

Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas-Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non-affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingly, however, our patients did not have cleft lip/palate, a common feature encountered in Bartsocas-Papas syndrome. Whereas in Bartsocas-Papas syndromes missense mutations are usually located within the serin/threonin kinase of RIPK4, the mutation detected in our family resides just outside of the kinase domain, which could explain the milder phenotype. Our data raise the question if CHAND syndrome indeed is a distinct entity. Alternatively, CHAND and Bartsocas-Papas syndrome might be allelic disorders or RIPK4 mutations could confer varying degrees of phenotypic severity, depending on their localization within or outside functionally important domains. Our findings indicate that making an accurate diagnosis based only on the prevailing clinical symptoms is challenging.

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.

Noninfectious cutaneous granulomas in primary immunodeficiency disorders: report from a national registry.

: The association of noninfectious cutaneous granulomas with primary immunodeficiency disorders (PIDs) is a rare but well-recognized phenomenon. With the recent advent of new classification and broadening of the list of PIDs, there is now ever-growing number of PIDs having being reported with noninfectious cutaneous granulomas or granulomatous tissue reactions. The authors observed 4 patients with cutaneous granulomas associated with PIDs that constitute 2% of total PIDs registered with them. In this report, the authors describe these 4 patients with cutaneous granulomas/granulomatous skin reactions associated one each with common variable immunodeficiency, Omenn syndrome, combined immunodeficiency, and Blau syndrome (BS), and briefly review the literature on various clinicopathological patterns of cutaneous granulomas with possible underlying pathogenetic mechanisms responsible for such tissue reactions in patients with PID.

Impact of next generation sequencing on diagnostics in a genetic skin disease clinic.

Individuals with inherited skin diseases often pose one of the most difficult diagnostic challenges in dermatology. The hunt for the underlying molecular pathology may involve candidate gene screening or linkage analysis, which is usually determined by the initial history, the physical findings and laboratory tests. Recent technical advances in DNA sequencing, however, are shifting the diagnostic paradigm. Notably, next-generation sequencing allows a more comprehensive approach to diagnosing inherited diseases, with potential savings of both time and money. In the setting of a paediatric dermatology genetics clinic in Kuwait, we therefore performed whole-exome sequencing on seven individuals without a priori detailed knowledge of the patients' disorders: from these sequencing data, we diagnosed X-linked hypohidrotic ectodermal dysplasia (two cases), acrodermatitis enteropathica, recessive erythropoietic protoporphyria (two siblings) and localized recessive dystrophic epidermolysis bullosa (two siblings). All these groups of disorders are clinically and genetically heterogeneous, but the sequencing data proved inherently useful in improving patient care and avoiding unnecessary investigations. Our observations highlight the value of whole-exome sequencing, in combination with robust bioinformatics analysis, in determining the precise molecular pathology and clinical diagnosis in patients with genetic skin disorders, notably at an early stage in the clinical evaluation of these often complex disorders and thereby support a new paradigm for future diagnostics.

Febrile ulceronecrotic Mucha-Habermann disease (pityriasis lichenoides et varioliformis acuta fulminans) associated with parvovirus infection.

Febrile ulceronecrotic Mucha-Habermann disease is a rare fulminant variant of pityriasis lichenoides et varioliformis acuta, characterized by a rapidly progressive course with predominant ulceronecrotic lesions associated with fever and systemic manifestations. It carries a great morbidity and is potentially fatal. The exact pathogenesis is not clear, and it has been proposed to be the result of hypersensitivity reaction to an infection. We report a patient with febrile ulceronecrotic Mucha-Habermann disease in a 12-year-old boy in whom the condition was most likely precipitated by parvovirus infection, and he showed a favorable response to a combination of prednisolone with narrow band ultraviolet B (NB-UVB) phototherapy.