Clinical and molecular features in a cohort of Middle Eastern patients with epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane. Based on the level of separation within the dermal-epidermal junction, EB is sub-classified into four major types including EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB (KEB) with 16 EB-associated genes reported to date. METHODS: We ascertained a cohort of 151 EB patients of various Middle Eastern ethnic backgrounds. RESULTS: The cohort was comprised of EBS (64%, 97/151), DEB (21%, 31/151), JEB (12%, 18/151), and KEB (3%, 5/151). KRT14 and KRT5 variants were most common among EBS patients with 43% (42/97) and 46% (45/97) of EBS patients carrying mutations in either of these two genes, respectively. Truncal involvement was more common in KRT14-associated EBS as compared to EBS due to KRT5 mutations (p < .05). Mutations in COL17A1 and laminin 332-encoding genes were identified in 55% (10/18) and 45% (8/18) of JEB patients. Scarring alopecia, caries, and EB nevi were most common among JEB patients carrying COL17A1 mutations as compared to laminin 332-associated JEB (p < .05). Abnormal nails were evident in most DEB and JEB patients while poikiloderma was exclusively observed in KEB (p < .001). CONCLUSIONS: EB patients of Middle Eastern origin were found to feature specific phenotype-genotype correlations of relevance to the diagnosis and genetic counseling of patients in this region.

Monitoring oral propranolol for infantile hemangiomata.

Treating infantile hemangiomas with oral propranolol may be initiated in accordance with various protocols some require hospitalization. However, different adverse events have been reported during treatment, thus it is of special importance to find a protocol which is both safe and feasible. We performed a retrospective cohort study of all cases of infantile hemangiomas treated with oral propranolol at our institute between January 2010 and February 2020. Pretreatment evaluation consisted of pediatric cardiologist evaluation including electrocardiography and echocardiography. The propranolol starting dosage was 0.5 mg/kg bid; 2 weeks later the dosage was escalated to 1 mg/kg bid. During the initiation and escalation visits, heart rate and blood pressure were measured before and every hour for a total of 3 h, and blood glucose level was measured within the first hour of treatment. A total of 131 children were treated during the study period. Scalp, facial and genital region infantile hemangiomas were more prevalent in regard to their relative body surface area. No symptomatic bradycardia, hypotension, hypoglycemia, or any other adverse events were documented; few patients had asymptomatic bradycardia and hypotension, which were more common in infants below 6-months of age. Only one patient had asymptomatic hypoglycemia, not requiring any intervention. Initiation and escalation of propranolol treatment for infantile hemangiomas proved to be safe, and without symptomatic adverse effects. However, considering the young age of the patients and the possible asymptomatic adverse reactions, we recommend the following simple protocol as presented, for pretreatment evaluation and short monitoring during treatment initiation and dose escalation.

Superimposed type 2 segmental atopic dermatitis: case series and review of the literature.

Generalized acquired dermatoses can seldom manifest more prominently or exclusively along the lines of Blaschko. Six individuals with segmental atopic dermatitis (AD) have been reported to date. We present three additional cases of segmental cutaneous manifestations superimposed on generalized AD, and review the relevant literature.

The relationship between atopy and allergic contact dermatitis in Israeli patients.

Introduction: Whether individuals with atopic diseases have a different risk of contact allergy compared to those who are non-atopic is controversial and data are conflicting. Aim: To explore the association between atopy and allergic contact dermatitis (ACD). Material and methods: This retrospective cross-sectional study included 301 patients referred to a tertiary clinic to evaluate ACD. Demographic details including personal and familial mucosal or cutaneous atopic status were recorded. Patch tests were tailored to their clinical presentations and relevant exposures. Results: At least 1 positive patch test reaction was observed in 177 patients (59% of the study cohort), of which 52% had a history of atopic diseases, compared with 44% of patients with a negative patch test result (p = 0.2). Additionally, 147 patients had an atopic background, of which 92 (62%) had ≥ 1 positive patch test result, compared with 55% of non-atopic patients (p = 0.2). Nickel sulphate was the most common contact allergen (13.4% of the patch test reactions). Conclusions: We identified a positive tendency for atopic diseases among individuals with ACD and vice versa. Our study supports the aggregate data from previous studies despite the non-significant differences between the study and control groups. However, further research performed in larger populations of patients is necessary to evaluate the real association between atopy and ACD on a solid basis. Our results indicate the necessity of systematic patch testing in patient setups with atopic background and chronic dermatitis.

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.

Laboratory monitoring during antifungal treatment of paediatric tinea capitis.

Griseofulvin and terbinafine are considered effective first-line therapies for tinea capitis (TC). Haematological dyscrasias and hepatic injury are possible adverse effects with both drugs. There is a debate in the literature regarding the necessity of laboratory monitoring during griseofulvin and terbinafine treatment. We aimed at assessing the prevalence and severity of haematological and hepatic laboratory test abnormalities in a paediatric cohort of African immigrants in Tel-Aviv with TC who were treated with Terbinafine or Griseofulvin. We conducted a retrospective study of all TC cases diagnosed and treated at the paediatric dermatology clinic, Tel-Aviv Medical centre, between June 2013 and March 2019. Epidemiologic, clinical and laboratory data were collected. Our cohort included 321 patients of whom 225 (70%) were treated with Griseofulvin and 96 (30%) with Terbinafine. We identified a total of 64 (20%) patients with haematological or hepatic laboratory test abnormalities that in most cases (96.3%) were considered as mild. No difference in laboratory abnormalities prevalence was identified between the griseofulvin and terbinafine groups (21.3% and 16.6%, respectively). Only one patient treated with Griseofulvin revealed significantly increased levels of hepatic aminotransferases that required discontinuation of treatment. Mild elevation in hepatic transaminases is relatively common among paediatric patients treated with systemic antifungal treatment for TC. However, significant laboratory abnormalities are extremely rare and may be diagnosed and addressed early through periodic laboratory tests monitoring.

Treatment of port wine stain with Tixel-induced rapamycin delivery following pulsed dye laser application.

Although pulsed dye laser (PDL) is considered the gold standard treatment for port wine stains (PWS), post PDL revascularization is one of the main causes of incomplete regression and recurrence. Recently, topical sirolimus have been shown to improve treatment outcome probably through minimizing post-laser revascularization. We sought to evaluate the added value of the Tixel drug delivery system (DDS) to the PDL and topical rapamycin treatment for PWS. This case series includes three teenager patients with previously treated PWS with PDL. Upon enrollment, every stain was divided into A and B halves for treatment assignments to the following regimens: (A) PDL + DDS + rapamycin; (B) PDL + rapamycin. Subjects were instructed to apply rapamycin topically over the PWS twice daily for the entire treatment period. Assessment of the treatment and adverse reactions as well as photographs was performed at baseline and before every PDL treatment. There were clinically significant differences in blanching responses favoring PWS receiving PDL + DDS + rapamycin as compared to PDL + rapamycin alone. Transient hyperpigmentation was noted in one patient. Two patients developed mild transient irritation and dermatitis following the treatment on both halves. The use of drug delivery system combined with topical rapamycin has no remarkable adverse effects, improves the results of PDL treatment for port wine stains, and can reduce the total number of required PDL sessions.

An enhanced transcutaneous delivery of botulinum toxin for the treatment of Hailey-Hailey disease.

Successful treatment of Hailey-Hailey disease with intradermal botulinum toxin injections has been previously reported. The main disadvantages of this treatment are the excruciating pain and the risk of infections due to the numerous injections. We sought to evaluate the clinical effectiveness and safety profile of a novel approach using an energy-based device (Tixel, Novoxel, and Israel), followed by the topical application of botulinum toxin Type A for the treatment of Hailey-Hailey disease. A retrospective study of all cases of histologically diagnosed cases of Hailey-Hailey disease treated with Tixel device followed by topical application of botulinum toxin between 2018 and 2019 was performed. Epidemiologic, clinical, and treatment data, including effectiveness score and safety, were reviewed. The study included eight patients, of whom seven patients (87.5%) showed good or partial response. No systemic or local adverse effects were reported. There was no difference in effectivity between different body areas. Response to treatment ranged between patients with an average duration of 7.125 months after the second treatment. Tixel treatment followed by topical application of botulinum toxin can be considered in the treatment of Hailey-Hailey disease. This approach is less invasive, less painful, and yet effective as well as safe.

Enhanced Percutaneous Delivery of Beta-Blockers Using Thermal Resurfacing Drug Delivery System for Topical Treatment of Infantile Hemangiomas.

BACKGROUND: Infantile hemangiomas (IHs) are the most common vascular tumors in children. In the past few years, topical beta-blockers (bBs) have been reported to be an effective treatment of superficial IHs. OBJECTIVE: We sought to evaluate the clinical effectiveness and safety profile of enhanced percutaneous delivery of bBs for the treatment of IH. METHODS: A retrospective study of all cases of IHs treated with enhanced percutaneous delivery of bBs between 2018 and 2019 was performed. Epidemiologic, clinical, and treatment data, including effectiveness score and safety, were reviewed. RESULTS: The study included 11 patients with a total of 11 IHs. Of the total number of IHs, 7 (63.7%) showed a good response to treatment and 4 (36.3%) had a partial response; thus all patients (100%) had good or partial response to treatment. No systemic or local adverse effects were reported. LIMITATIONS: This is an uncontrolled retrospective study. CONCLUSION: Enhanced percutaneous delivery of bBs is a safe and efficient topical therapy for IH.

Griseofulvin vs terbinafine for paediatric tinea capitis: When and for how long.

Outbreaks of tinea capitis (TC) can be a source of medical and economic burden for healthcare systems; Griseofulvin and terbinafine are considered to be effective first-line treatments for TC. In order to compare the efficacy of griseofulvin and terbinafine for the treatment of TC in a paediatric population of African immigrants in the Tel Aviv area, we conducted a retrospective cohort study of all cases of TC diagnosed and treated between March 2016 and February 2018 at a dedicated TC paediatric dermatology clinic at the Tel Aviv Medical Center (which serves as a referral centre for the paediatric refugee population in the Tel Aviv metropolitan area). Epidemiologic, clinical and laboratory data were collected, and 304 patients were included. Trichophyton violaceum (TV), Trichophyton soudanense (TS) and Microsporum audouinii (MA) were the prominent causative organisms. Treatment with griseofulvin suspension for 12 weeks was compared with (a) griseofulvin suspension for 8 weeks and with (b) terbinafine tablets for 4 weeks. There was no statistically significant difference between the groups regarding age, sex, country of birth, ethnicity and the causative organism. Twelve weeks of griseofulvin treatment had a statistically significant better cure rate than 4 weeks of terbinafine. Treatment was significantly more effective when TC was due to infections with MA and TS as compared with TV. No statistically significant difference was observed between 12- and 8-week treatment with griseofulvin.

Fractional ablative carbon dioxide laser followed by topical sodium stibogluconate application: A treatment option for pediatric cutaneous leishmaniasis.

BACKGROUND: Leishmaniasis is a protozoan zoonotic parasitic infection with cutaneous, mucocutaneous, and visceral manifestations. Israel is endemic for cutaneous leishmaniasis, which is a self-limited disease but is associated with scarring, which is often a source of psychological and social burden for patients. Scars can be especially devastating for children and teenagers. A wide range of physical and medical approaches is used to treat cutaneous leishmaniasis, among which intralesional injections of sodium stibogluconate rank among the most frequently used. Unfortunately, despite being effective, this therapeutic modality can be very painful. Fractional ablative laser creates a controlled mesh-like pattern of tissue ablation in the skin that promotes dermal remodeling and collagen production while at the same time facilitating enhanced delivery of topically applied medications. METHODS: Patients were treated with fractional ablative carbon dioxide laser followed by immediate topical application of sodium stibogluconate. All children were diagnosed with cutaneous leishmaniasis prior to treatment initiation.. RESULTS: Ten children were treated. One leishmania tropica-positive girl failed to respond. The other nine patients achieved clinical cure and demonstrated good to excellent final cosmesis. Self-rated patient satisfaction and tolerance were high No adverse effects were observed or reported during treatment. CONCLUSION: Fractional ablative carbon dioxide laser followed by topical sodium stibogluconate application appears to be a safe and promising treatment for cutaneous leishmaniasis infection in children. Future controlled studies are required to validate these findings and compare this technique with traditional approaches.

Predicting neurofibromatosis type 1 risk among children with isolated café-au-lait macules.

BACKGROUND: Although isolated cafe-au-lait macules (CALMs) are a common skin finding, they are an early feature of neurofibromatosis type 1 (NF1). OBJECTIVE: We sought to develop an algorithm determining the risk of children with CALMs to have constitutional NF1. METHODS: We conducted a retrospective study of patients with isolated CALMs. Diagnosis of NF1 was based on detecting NF1 mutation in blood or fulfilling clinical criteria. RESULTS: In all, 170 of 419 (41%) and 21 of 86 (24%) children with isolated CALMs who underwent molecular testing and clinical follow-up, respectively, were given a diagnosis of NF1. Presence of fewer than 6 CALMs at presentation or atypical CALMs was associated with not having NF1 (P < .001). An algorithm based on age, CALMs number, and presence of atypical macules predicted NF1 in both cohorts. According to the algorithm, children older than 29 months with at least 1 atypical CALM or less than 6 CALMs have a 0.9% (95% confidence interval 0%-2.6%) risk for constitutional NF1 whereas children younger than 29 months with 6 or more CALMs have a high risk (80.4%, 95% confidence interval 74.6%-86.2%). LIMITATIONS: The study was designed to detect constitutional NF1 and not NF1 in mosaic form. CONCLUSIONS: A simple algorithm enables categorization of children with isolated CALMs as being at low or high risk for having NF1.

Tinea capitis outbreak among paediatric refugee population, an evolving healthcare challenge.

Outbreaks of tinea capitis (TC) represent a major medical and economic burden. Population migrations have become a phenomenon of increasing relevance for medical conditions management. Given the recent massive arrival of immigrants, we sought to determine epidemiologic trends for TC among paediatric populations at the Tel Aviv Medical Center. We conducted a retrospective study of all TC cases diagnosed between 2010 and 2014 in a paediatric dermatology unit of a tertiary medical centre, serving as a referral centre for the paediatric refugee population from the great Tel Aviv area. Epidemiologic, clinical and treatment data including effectiveness and safety were reviewed. In all, 145 children met the inclusion criteria. Trend analyses showed increases in TC rates over the study period. Incidence rates were higher in boys than in girls. Children of African origin had the highest TC incidence rates as compared with other ethnic groups. Trichophyton violaceum and Microsporum audouinii were the predominant causative organisms. Treatment with griseofulvin was satisfactory in all cases. There was a significant increase in TC incidence rates in the Tel Aviv area over the study period. TV and MA were the predominant organisms. These trends may be a result of poor living conditions and crowded school premises.

To Treat Molluscum Contagiosum or Not-Curettage: An Effective, Well-Accepted Treatment Modality.

BACKGROUND/OBJECTIVES: Molluscum contagiosum (MC) is a common viral disease primarily affecting children. The objective was to compare the effectiveness of curettage as a treatment modality for MC with no treatment. METHODS: We performed a retrospective study of 2,022 children with MC between 2008 and 2012. Epidemiologic, clinical, and treatment data, including effectiveness, safety, and satisfaction, were reviewed. RESULTS: Fifty-six percent of the children were 2 to 5 years of age. The duration of the infection was 1 to 2 years for 51%, less than 1 year for 32%, and more than 2 years for 17% of the children. Seventy percent of the children were self-referrals; 86% had had a previous examination and 76% of those had been advised not to treat the infection. The disease was mild (22%), moderate (64%), or severe (14%). A total of 1,879 patients underwent curettage; 70% were cured after one treatment and 26% after two treatments. Satisfaction was high: 97% of children and parents. CONCLUSION: Active treatment should be offered despite the fact that MC is self-limiting. Curettage in an appropriate setting is very effective, with high patient satisfaction and fast cure rates.

Childhood Pemphigus Foliaceus with Exclusive Immunoglobulin G Autoantibodies to Desmocollins.

Pemphigus refers to a group of potentially fatal blistering skin diseases that are often due to the deleterious effects of autoantibodies directed against desmosomal antigens. Although desmogleins have been mainly implicated as autoantigens in pemphigus, a steadily growing body of evidence suggests that other desmosomal proteins may be causally involved as well. Antibodies directed against desmocollin-3 have been shown to play a direct role in the pathogenesis of several types of pemphigus. Here we describe the case of a child with localized pemphigus foliaceus and immunoglobulin G (IgG) reactivity exclusively directed to desmocollins. The present report suggests that autoantibodies against nondesmoglein antigens may play a role in the pathogenesis of superficial pemphigus, in addition to pemphigus vulgaris, paraneoplastic pemphigus, and IgA pemphigus.

Cognitive profile of school-age children and teenagers with hypohidrotic ectodermal dysplasia (HED).

Anhidrotic/hypohidrotic ectodermal dysplasia (HED) is the most common of the ectodermal dysplasias characterized by a triad of absent or reduced sweat, hypodontia and misshapen teeth, and missing or sparse hair. As the central nervous system is primarily ectodermal in origin, it has long been a concern that HED may be associated with developmental delay and/or intellectual disabilities. While published reviews report abnormalities in mental or motor development in 15-25% of HED-affected patients, there is no report in the literature including a systematic assessment of intellectual abilities in a cohort of patients with this rare disorder. During yearly health care updates, many of our clinic families report attention difficulties in young HED patients without evidence of a significant impact on school performance. In an exploratory study to identify and quantify intellectual abnormalities that may be associated with HED, we performed a psychological examination of 23 HED patients by means of the Wechsler Intelligence Scales, WPPSI-III, and WISC-IV. The interpretation of the tests shows no significant impairment in the achievements of the sample group compared with normative values (full scale scores, and index scale scores of the WISC-IV). At an individual level, the HED-affected patients were characterised by higher scores on the Verbal Comprehension Index, on Perceptual Reasoning and Working Memory Indices, and lower scores on the Processing Speed Index. As all of the Indices were within normal limits for the study population, in the absence of major mental/motor disabilities these findings support the mainstream education of HED-affected children.

Infantile myofibromatosis: a series of 28 cases.

BACKGROUND: Infantile myofibromatosis (IM) is a rare disorder of fibroblastic/myofibroblastic proliferation in children. OBJECTIVES: We sought to document common and unusual characteristics of patients with IM. METHODS: This was a retrospective study of 28 children diagnosed with histopathologically confirmed IM between 1992 and 2012. Epidemiologic, clinical, and treatment data were reviewed. RESULTS: IM was more frequent in boys (60.8%). Skin lesions were congenital in 64.3% of cases. The solitary form accounted for 50% of cases. Most nodules were painless, arising in cutaneous or subcutaneous tissue. The multicentric form accounted for 39% of cases; the skin, subcutaneous tissue, or muscle was involved in 97.8% of cases, and the bones in 50% of cases. The generalized form had a mortality rate of 33% (one-third of cases). Multicentric and generalized forms regressed spontaneously; severe local complications were observed, and late recurrent nodules developed in a few cases. LIMITATIONS: The retrospective review and the ascertainment of patients (from the departments of obstetrics and pediatrics) may have introduced bias in the analysis of severity of the different forms of IM. CONCLUSION: The diagnosis of IM must be confirmed histopathologically because the clinical presentation can be misleading. The prognosis is usually good, although local morbidity can occur. The generalized and multicentric forms merit long-term follow-up.

Incidence rate of alopecia areata in Israel: A 15-year analysis of population-based data and the emergence of young male adults as the most at-risk group.

Incidence rate and temporal trends in alopecia areata (AA) vary worldwide. As a common disorder with a major impact on life quality, there is a continuous need for comprehensive epidemiological characterization and global updates of the disease burden. We sought to perform an epidemiologic characterization of AA patients and to explore temporal trends across different subgroups using long-term health data. A retrospective population-based study was conducted in a large healthcare organization in Israel. Data were analyzed for all patients with AA between 2005 and 2019. A total of 30 805 patients for 29 504 798 person-years were identified during the study period, representing an overall incidence rate of 104.4 cases per 100 000 person-years. Young adults and patients of middle socioeconomic status had the highest incidence rate compared to the whole cohort. Incidence rates in females were lower than in males (incidence rate ratio 0.72, 95% confidence interval 0.71-0.74). In a temporal trends analysis, the yearly incidence rate for the whole cohort was stable throughout the study period. Males between the ages of 18 and 30 had a significant increase in incidence during the study years, where the incidence rate increased from 119.54 to 162.36 per 100 000 person-years. Despite the limitation of lack of analysis by subgroups of disease severity and other personal data, our study clearly indicates that young male adults of middle socioeconomic status emerge as the most at risk associated with AA over a decade and a half. In an effort to delineate risk factors for this gender gap, different stressors are speculated as triggers.