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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., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Although dermatologic conditions bring relatively few people to the Emergency Department, hospitalized patients, especially older people, often suffer from skin problems that contribute to their morbidity., Aims: We wanted to identify the frequency, clinical course, treatment and influence on hospitalization of dermatologic conditions in patients hospitalized in internal and geriatric departments in Galilee Medical Center. We concentrated on two groups of adults, aged 40-65 years (adult group) and above 65 years (elderly group), in order to understand differences in the cause of referral, type of diagnosis and mode of treatment., Methods: We performed a retrospective review of 82 hospitalized patients who were referred for dermatological consultation between May-September 2013. Of the 82 patients, 47.6% made up the 'adult' group and 52.4% the 'elderly' group; 62.2% of patients were independent, 18.3% partially independent and 19.5% needed nursing care., Results: Skin infections (38.3%), allergy (mostly drug induced) (23.5%) and trophic disorders (18.5%) were the most common diagnoses. 'Elderly' were less often referred to dermatological consultation than 'adults' (44.3% vs. 55.7%, respectively); skin infections were more common in the 'elderly' (44.8% vs. 55.7%). Nursing care patients (19.5%) were least referred to dermatological consultation, but severity of skin condition (the number of diagnoses and number of treatments per patient) was greater in nursing care patients., Conclusions: The clinical course between the independent and nursing care patients varies in the number of requests, the different type of diagnoses, the severity of the conditions and the number of treatments provided., Discussion: Our study emphasizes the importance of skin examination by a dermatologist, considering the high number of referrals for dermatological consultations. On the other hand, there was a significant difference between the 'elderly' and 'adult' groups, with fewer referrals for dermatological consultations by the medical staff in the 'elderly' group. Our results resemble those in the literature, having identified the most common skin problems in two groups of hospitalized patients.

Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging characterization of seven patients followed by homozygosity mapping and linkage analysis were performed. Next generation sequencing, bioinformatics, and segregation analyses followed, to determine a loss of function sequence variation in the phospholipase A 2 -activating protein encoding gene (PLAA). Expression and functional studies of the encoded protein were performed and included measurement of prostaglandin E 2 and cytosolic phospholipase A 2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E 2 levels were measured in different tissues. The novel phenotype of our patients segregated with a homozygous loss-of-function sequence variant, causing the substitution of leucine at position 752 to phenylalanine, in PLAA, which causes disruption of the protein's ability to induce prostaglandin E 2 and cytosolic phospholipase A 2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E 2 The non-functional phospholipase A 2 -activating protein and the associated neurological phenotype, reported herein for the first time, join other complex phospholipid defects that cause leukoencephalopathies in humans, emphasizing the importance of this axis in white matter development and maintenance., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Autosomal recessive congenital ichthyosis (ARCI) is the term given to a complex and heterogeneous group of cornification disorders associated with mutations in at least eight distinct genes. Mutation distribution and prevalence rates are instrumental for the design of diagnostic strategies in ARCI but have not yet been systematically explored in the Israeli population. Previous data suggest that the demographic features specific to Middle Eastern populations, such as a high frequency of consanguineous marriages, may have an effect on the molecular epidemiology of genodermatoses., Methods: We systematically assessed all families with ARCI presenting at our clinics over a period of 9 years, using a combination of homozygosity mapping, direct sequencing and PCR-restriction fragment length polymorphism assays., Results: In total, 20 families with ARCI were assessed, and causative mutations were identified in 7 genes: TGM1 (30% of patients), ALOX12B (20%), ABCA12 (5%), CYP4F22 (10%), ALOXE3 (10%), LIPN (5%) and NIPAL4 (5%) Two families (10%) had mutations mapped to an ARCI-associated locus on 12p11.2-q13, while no mutation was found for one additional kindred. In the subgroup of families of Arab Muslim origin, mutations were identified most frequently in ALOX12B and TGM1 (31%), whereas the other subgroups displayed a subtype distribution very similar to that previously reported in western populations., Conclusions: The present data point to the need for population-tailored mutation screening strategies in genetically heterogeneous genodermatoses, based on the relative prevalence of the disease subsets., (© 2013 British Association of Dermatologists.)

The XPD protein plays a pivotal role in basal transcription and in nucleotide excision repair (NER) as one of the ten known components of the transcription factor TFIIH. Mutations in XPD can result in the DNA repair-deficient diseases xeroderma pigmentosum (XP), trichothiodystrophy (TTD), cerebro-oculo-facial-skeletal syndrome, and in combined phenotypes such as XP/Cockayne syndrome and XP/TTD. We describe here an 18-year-old individual with mild sun sensitivity, no neurological abnormalities and no tumors, who carries a p.R683Q mutation in one allele, and the novel p.R616Q mutation in the other allele of the XPD gene. We also describe four patients from one family, homozygous for the identical p.R683Q mutation in XPD, who exhibit mild skin pigmentation and loss of tendon reflexes. Three homozygous patients presented with late-onset skin tumors, and two with features of premature aging and moderate cognitive decline. Cells from the compound heterozygous individual and from one of the patients homozygous for p.R683Q exhibited similar responses to UV irradiation: reduced viability and defective overall removal of UV-induced cyclobutane pyrimidine dimers, implying deficient global genomic NER. Cells from the compound heterozygous subject also failed to recover RNA synthesis after UV, indicating defective transcription-coupled NER. Mutations affecting codon 616 in XPD generally result in functionally null proteins; we hypothesize that the phenotype of the heterozygous patient results solely from expression of the p.R683Q allele. This study illustrates the importance of detailed follow up with sun sensitive individuals, to ensure appropriate prophylaxis and to understand the mechanistic basis of the implicated hereditary disease., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The routine diagnosis of genodermatoses is significantly complicated by the fact that in this group of disorders, clinical manifestations may result from mutations in unrelated genes (genetic heterogeneity) and mutations in the same gene often lead to dissimilar clinical signs (phenotypic heterogeneity)., Methods: In this study, we applied the principles of homozygosity mapping as a screening method before formal mutational analysis in an attempt to facilitate the molecular diagnosis of genodermatoses in consanguineous families. The method was evaluated in a retrospective fashion in 4 families previously assessed with junctional epidermolysis bullosa and in a prospective manner in 11 families with congenital recessive ichthyosis., Results: The method was found to be efficient in directing the molecular analysis to one of the 4 genes commonly involved in the pathogenesis of junctional epidermolysis bullosa or in identifying cases of congenital recessive ichthyosis caused by mutations in TGM1. We found that this diagnostic strategy results in a 5-fold decrease in the cost of mutation analysis., Limitations: The proposed diagnostic strategy is applicable to consanguineous families only and, therefore, cannot be used in outbred populations., Conclusion: Our results indicate that homozygosity mapping may serve as a useful adjunct in the molecular diagnosis of junctional epidermolysis bullosa or congenital recessive ichthyosis in inbred populations. This study emphasizes the usefulness in human genetics of diagnostic strategies tailored to the demographic features of target populations.

Bacterial skin infections are very common and trigger destruction of the skin integrity. Impetigo is a consequence of group A beta-hemolytic streptococcus or Staphylococcus aureus infection. The clinical presentation in general is very typical and empiric treatment is usually successful. In cases of close contacts such as between classmates, athletes, or soldiers, the prompt recognition and appropriate treatment of the infection may stop an epidemic. We report a group of six soldiers who shared the same military equipment (physical shields) during hand-to-hand combat training. All of the soldiers had skin lesions and two of them suffered from systemic symptoms. Group A beta-hemolytic streptococcus and S. aureus were cultured from the impetiginous lesions. All patients recovered after systemic and/or local antibiotic treatments. These cases emphasize the need for the maintenance of proper hygiene throughout the training program to prevent spread of the disease and the importance of rapid diagnosis by bacteriological identification.

Congenital recessive ichthyoses represent a vast and markedly heterogeneous group of diseases that have been mapped to at least seven distinct chromosomal loci. In this study, we ascertained two consanguineous families presenting with congenital ichthyosis. Using homozygosity mapping, we identified a 6.5 cM homozygous region on 12p11.2-q13 shared by all affected individuals. Multipoint logarithm of odds ratio (LOD) score analysis placed the new locus between markers D12S345 and D12S390 with a maximum LOD score of 4.79 at marker CH12SSR13. This region harbors PPHLN1, encoding periphilin 1, a protein involved in the cornification process. No deleterious mutations were identified within the coding region of this gene, suggesting the existence of another gene associated with epidermal differentiation on 12p11.2-q13.

We report three female patients suffering from toxic epidermal necrolysis, with 30% to 70% epidermal detachment. Alleged causative agents were dipyrone, dibenzazepine, and allopurinol. All patients were treated by intravenous immunoglobulins (IVIG) and survived without further complications, although poor prognostic factors such as concomitant diabetes, large areas of epidermal detachment, and pancytopenia were present. We report these cases with emphasis on the concept that prompt diagnosis, withdrawal of causative drugs, and immediate treatment are imperative for the favorable outcome of the disease. Our patients can be added to the list of those patients who were successfully treated by IVIG, as indicated in this review of the literature.

The histological findings in the first diagnostic biopsy of 50 patients with Kaposi's sarcoma (KS) were classified and were related to the clinical course. Forty-one patients had the "classic KS," of whom 31 had a benign course and 10 an aggressive disease. Nine patients had iatrogenically induced KS. Histologically the following subtypes were found: mixed type in 18 patients, spindle type in 16, early type in 14, and hemangiomatous and lymphangiomatous types in one each. We did not find any statistical relationship between the histological subtypes, degree of nuclear atypia, number of mitoses, and density of the inflammatory cell infiltrates in the KS lesions, and the clinical types and course of the disease. The results of this study do not support the possibility of a prognostic importance regarding the histological features of the early lesions in patients with classic or iatrogenic Kaposi's sarcoma.

Pseudoainhum is an infrequent complication in the autosomal-recessive keratodermas. We describe two related families in which the diagnosis of mal de Meleda keratoderma has been confirmed by mode of inheritance and ultrastructural findings. One family member, a 9-year-old girl, developed pseudoainhum which threatened the viability of her little fingers. This responded to treatment with etretinate. The treatment dilemma posed by keratoderma-induced pseudoainhum in children, i.e. the concern over the possible skeletal toxic effects of long-term etretinate treatment vs. the risks and outcome of surgery, is discussed.

Neutral lipid storage disease with ichthyosis (NLSDI) is an inherited metabolic disorder characterized by accumulation of neutral lipids, in a wide variety of cells, by a still unknown mechanism. Previous studies have shown normal cholesterol content in NLSDI granulocytes, fibroblasts and skin cells. Monocyte-derived macrophages possess an additional pathway of cholesterol uptake, which is not shared by these cells and which is not regulated by intracellular cholesterol levels. This pathway is thought to play a rôle in the process of atherosclerosis. Three NLSDI patients were studied. The serum levels of triglycerides, cholesterol, high-density lipoprotein cholesterol, and apolipoproteins A-I and B were within normal limits in all three patients. The intracellular levels of free and esterified cholesterol were measured in the monocyte-derived macrophages of one patient and found to be normal, while the triglyceride concentrations were twice as high as normal. The cholesterol esterification rates, which serve as a sensitive indicator of intracellular changes in cholesteryl ester levels, were normal in the monocyte-derived macrophages of all three patients. These findings provide further evidence that cholesterol metabolism is not disturbed in NLSDI, and it may be inferred that in this respect these patients are not at increased risk for atherosclerosis.

The diagnosis of bite by the brown recluse spider, Loxosceles reclusus, is rarely based on absolute identification of the insect because the victims are usually bitten while sleeping or dressing. More often, the history, clinical findings and course of the bite lead to the diagnosis. For early confirmation up to 24 hours after the bite, the passive hemagglutination test can be used. For older lesions, the in-vitro lymphocyte transformation test is useful, but is available in only a few medical centers. Treatment of the bite of the brown recluse spider varies from conservative to more active approaches. Resting, local cooling, systemic antibiotics to prevent infection and mild anti-inflammatory drugs may be given. In the more active approach oral corticosteroids are added in the first 72 hours to the antibiotics, especially in massive bites with necrotic centers greater than 2 cm in diameter, or when there is systemic loxoscelism. Recently, good results have been reported with Avlosulfon (dapsone), which is claimed to cure necrotic cutaneous ulcerations, presumably by reducing the activity of polymorphonuclear leukocytes. Other treatments include specific antivenin, (of limited use because it must be administered shortly after the bite), and surgery to prevent spreading of the venom. We describe 3 cases of brown spider bite with typical clinical presentations in adults aged 20-40 years. 2 were treated with corticosteroids and antibiotics and 1 with Avlosulfon and prednisone, all within 72 hours of the bite. 2 recovered completely within a few days, but the third treated with prednisone and antibiotics, developed an ulcer which healed only after several months of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)