RESUMEN
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.
Asunto(s)
Trastornos de la Pigmentación/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Eliminación de Secuencia , Paraplejía Espástica Hereditaria/genética , Vitíligo/genética , Secuencia de Aminoácidos , Animales , Apoptosis/genética , Pueblo Asiatico/genética , Cromosomas Humanos Par 1/genética , Exones , Facies , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Ligamiento Genético , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Homocigoto , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Masculino , Melanocitos/citología , Melanocitos/metabolismo , Ratones , Células 3T3 NIH , Linaje , Trastornos de la Pigmentación/diagnóstico , Paraplejía Espástica Hereditaria/diagnóstico , Vitíligo/diagnóstico , Adulto JovenRESUMEN
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.
Asunto(s)
Fisura del Paladar/genética , Proteínas de Unión al ADN/genética , Displasia Ectodérmica/genética , Genes Recesivos/genética , Discapacidad Intelectual/genética , Mutación/genética , Piel/patología , Sindactilia/genética , Factores de Transcripción/genética , Western Blotting , Niño , Proteínas de Unión al ADN/metabolismo , Exones/genética , Femenino , Humanos , Masculino , Linaje , Fenotipo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Piel/metabolismo , Síndrome , Factores de Transcripción/metabolismoRESUMEN
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.
Asunto(s)
Nevo/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias de las Glándulas Sebáceas/genética , Humanos , Recién Nacido , Masculino , MutaciónRESUMEN
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.
Asunto(s)
Lupus Eritematoso Cutáneo/epidemiología , Adolescente , Enfermedades Autoinmunes/complicaciones , Niño , Femenino , Humanos , Lupus Eritematoso Cutáneo/patología , Lupus Eritematoso Sistémico/complicaciones , Masculino , Factores de Riesgo , Centros de Atención TerciariaRESUMEN
: 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.
Asunto(s)
Granuloma/etiología , Granuloma/patología , Síndromes de Inmunodeficiencia/complicaciones , Enfermedades de la Piel/etiología , Enfermedades de la Piel/patología , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Sistema de RegistrosRESUMEN
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.
Asunto(s)
Dermatología/métodos , Exoma , Secuenciación de Nucleótidos de Alto Rendimiento , Enfermedades de la Piel/genética , Adolescente , Secuencia de Bases , Preescolar , Biología Computacional , Femenino , Predisposición Genética a la Enfermedad , Genoma Humano , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Análisis de Secuencia de ADNRESUMEN
Mycosis fungoides (MF) is rare in children and adolescents. This study was aimed to determine the clinicoepidemiologic features of juvenile onset (≤18 yrs) MF in Kuwait. Thirty-six children and adolescents (≤18 yrs) with MF registered in a referral photobiology unit for cutaneous lymphomas between July 1991 and June 2009 were included in this study. Children and adolescents were observed to constitute 16.6% of the total number of patients with MF, with 97% of patients of Arab ethnicity. The age-adjusted incidence rate of MF in children and adolescents among the total population was 0.29/100,000 persons/year. Among 36 Arab children and adolescents, boys outnumbered girls by 1.25:1. Mean and median age at onset of disease was 9 years, and age at diagnosis was 13 years. Patch stage disease was the most common clinical variant (75%) with 56% with pure hypopigmented MF-variant. The majority of patients (75%) had stage IB (TNM and B staging) disease. The study highlights a high prevalence and incidence of juvenile MF in Kuwait with a predominantly hypopigmented presentation.
Asunto(s)
Micosis Fungoide/epidemiología , Micosis Fungoide/patología , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patología , Adolescente , Distribución por Edad , Edad de Inicio , Biopsia , Niño , Preescolar , Femenino , Humanos , Incidencia , Kuwait/epidemiología , Masculino , Sistema de Registros/estadística & datos numéricos , Distribución por SexoRESUMEN
BACKGROUND: Fungal infections constitute a major health problem all over the world. Signs and symptoms induced by various dermatophytic infections are difficult to distinguish clinically from each other. So, characterization by in vitro culture is required for appropriate diagnosis and treatment as well as to study the epidemiological characteristics in a region. OBJECTIVES: The present retrospective work was aimed to study the spectrum of fungal infections of the skin, nails and hairs in the Capital area of Kuwait over a span of 5 years and to compare the results with those reported earlier from this region and other parts of the world. PATIENTS/MATERIALS: The study was conducted on 2,730 patients referred from dermatology outpatients to mycology laboratory suspected to have fungal infection over a 5-year period. Identification of dermatophyte isolates obtained was done by conventional microscopic examination in all patients, whereas culture techniques were performed for 1,593 of them. RESULTS: Among 2,730 patients, 1,437 were men and 1,293 were women with a men to women ratio of 1.1:1. The age ranged from 3 months to 70 years (mean age 28.5 years). The clinical diagnosis of these patients was as follows: onychomycosis; tinea corporis; tinea capitis; tinea pedis; tinea cruris; tinea manum and tinea versicolor. Potassium hydroxide (KOH) examination showed positive results in 39% of all cases, whereas positive cultures were obtained in 29% of cultured specimens. Among dermatophytes, six species were isolated: Trichophyton mentagrophytes (39%), Microsporum canis (16%), Trichophyton rubrum (10%), Epidermophyton floccosum (6.2%), Trichophyton violaceum (2.4%) and Trichophyton verrucosum (0.4%). Trichophyton mentagrophytes was isolated from all body sites. Candida and Aspergillus niger were isolated on cycloheximide-free cultures in cases with onychomycosis. CONCLUSIONS: Cutaneous fungal infections including dermatophytes remain prevalent in this part of the world. The most common isolate was T. mentagrophytes followed by Candida species. The least isolate was T. verrucosum. Species identification in relation to factors such as time, place and population is warranted in order to implement treatment regimens and to propose potential control measures.
Asunto(s)
Dermatomicosis/epidemiología , Adolescente , Adulto , Anciano , Animales , Arthrodermataceae/clasificación , Arthrodermataceae/aislamiento & purificación , Niño , Preescolar , Femenino , Cabello/microbiología , Humanos , Incidencia , Lactante , Kuwait/epidemiología , Masculino , Persona de Mediana Edad , Uñas/microbiología , Estudios Retrospectivos , Piel/microbiología , Adulto JovenRESUMEN
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.
Asunto(s)
Epidermólisis Ampollosa/diagnóstico , Epidermólisis Ampollosa/genética , Piel/patología , Biopsia , Moléculas de Adhesión Celular/genética , Colágeno Tipo VII/genética , Consanguinidad , Desmoplaquinas/genética , Distonina/genética , Epidermólisis Ampollosa/patología , Exoma , Femenino , Genes Dominantes , Genes Recesivos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Integrina beta4/genética , Queratina-14/genética , Queratina-5/genética , Kuwait , Masculino , Transglutaminasas/genética , gamma Catenina/genética , KalininaRESUMEN
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.
Asunto(s)
Síndromes Neurocutáneos/diagnóstico por imagen , Femenino , Humanos , Lactante , Síndromes Neurocutáneos/terapiaRESUMEN
OBJECTIVE: To assess the level of control and prevalence of type 2 diabetes in King Abdulaziz Housing City (Iskan) population of Saudi Arabia. MATERIALS AND METHODS: Retrospective cross-sectional study conducted in a primary-care setting. All Type 2 diabetics referred to our diabetes center between January 2011 and January 2015 were identified, and their computerized records reviewed. Glycated hemoglobin levels (HbA1c), low-density lipoprotein (LDL), blood pressure (BP), and the albumin-creatinine ratio (ACR) were noted and the patients categorized accordingly. Demographic data (age and gender) were also documented. Inactive patients (not seen for more than 2 years) were excluded. RESULTS: The overall prevalence of type 2 diabetes for all age groups in ISKAN population was 3.25%. About 56% of the diabetics were female and 70% were aged between 18 and 59 years. The rate of uncontrolled diabetes was 59.3%. Males were more likely to have uncontrolled diabetes (odds ratio: 1.44, CI: 1.17-1.76, P = 0.0004). Forty percent of the diabetics had an LDL above target (≥2.6 mmol/l) while 25.9% had uncontrolled hypertension (BP ≥ 140/90). Of those who had an ACR test done within the last year (59.3%), the rate of micro- and macro-albuminuria was 8.8% and 2.5%, respectively. CONCLUSIONS: The overall prevalence of type 2 diabetes in our community seems lower than the previously reported national figures. An alarming number of diabetics in our population have an uncontrolled disease. More stringent diabetes annual review and recall program is needed to control diabetes and reduce complications.
Asunto(s)
Enfermedades del Cabello/genética , Mutación , Uñas Malformadas/congénito , Desiminasas de la Arginina Proteica/genética , Trombospondinas/genética , Preescolar , Salud de la Familia , Femenino , Predisposición Genética a la Enfermedad , Cabello/anomalías , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Kuwait , Masculino , Uñas Malformadas/genética , Linaje , Fenotipo , Arginina Deiminasa Proteína-Tipo 3RESUMEN
BACKGROUND: Mycosis fungoides (MF) is an indolent, most common type of cutaneous T-cell lymphoma (CTCL) with an average estimated incidence of 0.5 cases per 100,000 persons per year in the western world. Although various clinical and epidemiological features are well delineated in the western population, the data is scarce from our region. OBJECTIVES: To study the clinicoepidemiological features of MF from Kuwait. SETTING: A referral photobiology unit for cutaneous lymphomas in a national dermatology department in collaboration with three other dermatology departments in Kuwait and Kuwait cancer center. PATIENTS AND METHODS: One hundred and ninety-three cases of MF registered between July 1991 and June 2006 were included for this study. RESULTS: Eighty-six percent of our MF cases were of Arab ethnicity. Males outnumbered the females by 2:1 ratio. Mean age at diagnosis was 35.20 ± 14.37 years, and 16% of the patients were diagnosed by the age 20 years. The annual incidence rate (IR) of MF in Kuwait was observed to be 0.43 cases per 100,000 persons with a significantly higher IR among Arabs as compared to non-Arab Asians (RR = 4.4; 95% CI = 2.9-6.6). A successive rise in the IR of MF was noticed with the advancing age. The annual IR among males was more or less comparable to that of females. Skin patches were the most prevalent skin lesions (67%) at diagnosis, and 22% of the patients had a pure hypopigmented variant. Patients with hypopigmented MF were observed to have younger mean age at diagnosis (27.60 ± 12.42 years) as compared to other MF cases (38.14 ± 14.37 years) (P = 0.000). Ninety-two percent of the patients had the early stage (IA, IB, and IIA) of disease. CONCLUSIONS: Our patients with MF were observed to have a relatively younger age at diagnosis, with a high proportion of patients diagnosed by the age 20 years. Arabs were observed to have a higher annual IR of MF as compared to non-Arab Asians. Hypopigmented MF is prevalent in our population. The study highlights the ethnic and/or regional variations in the clinicoepidemiological characteristics of MF.