RESUMEN
Epidermolytic ichthyosis (EI) is a type of congenital ichthyosis, characterized by erythema and blistering at birth followed by hyperkeratosis. EI is caused by pathogenic variants in the genes KRT1 and KRT10, encoding the proteins keratin 1 (KRT1) and keratin 10 (KRT10), respectively, and is primarily transmitted by autosomal-dominant inheritance, although recessive inheritance caused by nonsense variants in KRT10 is also described. The keratins form a network of intermediate filaments and are a structural component of the cytoskeleton, giving strength and resilience to the skin. We present three cases of mild EI caused by pathogenic KRT10 variations in the L12 linker domain. To our knowledge, this is the first time L12 linker domain pathogenic variants are identified in KRT10 for EI. The aim of this study was to identify gene variants for patients with EI in KRT1 or KRT10. To establish the pathogenicity of the found variations in KRT10, we evaluated all patients and available family members clinically. Genetic analyses were performed using Sanger sequencing. Vectors containing wild-type or mutated forms of KRT10 were transfected into HaCaT cells and analyzed by high-resolution confocal microscopy. Genetic analysis of KRT10 identified a heterozygous de novo variant c.910G>A p.(Val304Met) in family 1, a familial heterozygous variant c.911T>C p.(Val304Ala) in family 2, and a familial heterozygous variant c.917T>C p.(Met306Thr) in family 3. All identified missense variants were located in the L12 linker domain of KRT10. In vitro study of aggregate formation of the missense variants in KRT10 only showed a very mild and not quantifiable aggregate formation in the KRT10 network, compared with the wild-type sequence. We report three different novel missense variants in the L12 linker domain of KRT10 in patients with an atypical, milder form of EI resembling peeling skin syndrome.
Asunto(s)
Hiperqueratosis Epidermolítica , Queratina-10 , Linaje , Adulto , Preescolar , Femenino , Humanos , Masculino , Células HaCaT , Heterocigoto , Hiperqueratosis Epidermolítica/genética , Hiperqueratosis Epidermolítica/patología , Hiperqueratosis Epidermolítica/diagnóstico , Queratina-1/genética , Queratina-10/genética , Mutación Missense , Dominios Proteicos/genética , Piel/patología , Recién NacidoAsunto(s)
Ictiosis Lamelar , Humanos , Aciltransferasas , Genes Recesivos , Ictiosis Lamelar/genética , Mutación , FosfolipasasRESUMEN
We report the unique case of a 3-year-old girl who presented with linear erythematosquamous lesions following the lines of Blaschko, suggestive of genetic mosaicism in the skin. Single-candidate gene analyses were performed on DNA from blood, excluding Conradi-Hünermann-Happle syndrome, erythrokeratodermia variabilis and a mosaic presentation of pityriasis rubra pilaris. With whole-exome sequencing (WES) on DNA from the patient's blood, a heterozygous missense mutation in exon 25 of the ABCA12 gene was detected. By manually scrutinizing the WES data, another low-percentage pathogenic frameshift mutation was found in the adjacent exon 26 of the same gene. This frameshift mutation was confirmed with Sanger sequencing in DNA isolated from a lesional skin biopsy. A subsequent cloning experiment was performed to prove that the patient is compound heterozygous for both mutations in the affected skin, explaining the blaschkoid ichthyosiform erythrodermic phenotype. The patient's phenotype was elucidated by the combination of a germline mutation and an acquired postzygotic mutation in ABCA12, resulting in the diagnosis of a mosaic manifestation of autosomal recessive congenital ichthyosis. Postzygotic compound allelic loss in autosomal recessive disorders is extremely rare and will not appear as the typical phenotype of the known germline mutation-associated disease. This is the first report of a proven biallelic mosaic presentation of an autosomal recessive genodermatosis, and we propose the term 'recessive mosaicism' for this kind of manifestation. What's already know about this topic? Specific mutations in the ABCA12 lipid transporter are known to cause different phenotypes like harlequin ichthyosis, congenital ichthyosiform erythroderma and lamellar ichthyosis. In mosaicism, two or more cell populations that are genetically different arise postzygotically in the developing embryo. In the skin, mosaicism can present itself in different patterns of affected skin, often caused by a dominant genetic mutation. What does this study add? We report a unique patient with blaschkoid congenital ichthyosiform erythroderma due to biallelic mutations, one inherited germline missense mutation and the other a postzygotic frameshift mutation in the ABCA12 gene. This study describes the diagnostic approach and applied research that can be used if one encounters a similar diagnostic dilemma with manifestations suspected for genetic mosaicism. We propose the term 'recessive mosaicism' for this kind of mosaic presentation of an autosomal recessive genodermatosis.
Asunto(s)
Eritrodermia Ictiosiforme Congénita , Ictiosis Lamelar , Transportadoras de Casetes de Unión a ATP/genética , Preescolar , Femenino , Humanos , Ictiosis Lamelar/genética , Mosaicismo , MutaciónRESUMEN
Schnitzler's syndrome is an auto-inflammatory disorder which is characterized by two mandatory features: an urticarial rash and a monoclonal gammopathy. Although the pathophysiology of this syndrome is not yet fully understood, a role for interleukin-1 seems apparent. While this presumed link between interleukin-1 and the monoclonal gammopathy is not yet elucidated, a mutual factor in pathophysiology however seems likely. Here we present a novel hypothesis of a shared pathophysiologic mechanism between Schitzler's syndrome and monoclonal gammopathy.
Asunto(s)
Enfermedades Autoinflamatorias Hereditarias/fisiopatología , Síndrome de Schnitzler/fisiopatología , Animales , Enfermedades Autoinflamatorias Hereditarias/metabolismo , Humanos , Interleucina-1/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Síndrome de Schnitzler/metabolismoRESUMEN
Basal cell naevus syndrome (BCNS) is associated with germline mutations in the PTCH1 gene. Postzygotic mosaicism can also cause BCNS. Here we describe two patients, one with multiple basal cell carcinomas (BCCs) and one with clinical BCNS, who had no PTCH1 mutation in DNA extracted from blood. In both patients, we performed genetic analysis on different BCCs, revealing the presence of a shared PTCH1 mutation in all tumours. Our findings show that in patients with symptoms of BCNS and initial absence of a PTCH1 mutation in blood, genetic profiling of BCCs can detect postzygotic mosaicism. What's already known about this topic? Basal cell naevus syndrome (BCNS) is associated with germline mutations in the PTCH1 gene, but it can also be caused by low-grade postzygotic mosaicism in PTCH1. What does this study add? In patients suspected of having BCNS or patients with multiple basal cell carcinomas (BCCs) with a special distribution on the body and no mutation detected in blood, it is worthwhile to search for a shared PTCH1 mutation in their BCCs as this can detect postzygotic mosaicism. This information is important to ensure proper surveillance programmes, choose the right therapy and provide adequate genetic counselling.
Asunto(s)
Síndrome del Nevo Basocelular/genética , Mosaicismo , Receptor Patched-1/genética , Neoplasias Cutáneas/genética , Adulto , Síndrome del Nevo Basocelular/sangre , Síndrome del Nevo Basocelular/patología , Biopsia , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Humanos , Piel/patología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patologíaAsunto(s)
Alopecia/genética , Colangitis Esclerosante/genética , Claudina-1/deficiencia , Codón sin Sentido/genética , Ictiosis/genética , Trastornos Leucocíticos/genética , Enfermedades de los Conductos Biliares/diagnóstico , Niño , Claudina-1/efectos de los fármacos , Claudina-1/genética , Consanguinidad , Diagnóstico Diferencial , Femenino , Humanos , Hepatopatías/diagnósticoRESUMEN
Basal cell naevus syndrome (BCNS) is an autosomal dominant disorder most commonly caused by a germline mutation in the Drosophila homologue of patched-1 gene (PTCH1). Here we describe a patient with clinical signs of BCNS, caused by postzygotic mosaicism of a PTCH1 mutation. We performed restriction fragment length polymorphism analysis and Droplet Digital polymerase chain reaction to determine the degree of mosaicism in different tissues of this patient. Our case shows that a relatively low-grade mosaicism can lead to clinical signs reminiscent of those caused by a germline mutation. This finding has important implications for genetic counselling and therefore is pivotal to recognize for dermatologists, as well as for clinical geneticists and clinical laboratory geneticists.
Asunto(s)
Síndrome del Nevo Basocelular/genética , Mutación de Línea Germinal/genética , Mosaicismo , Receptor Patched-1/genética , Femenino , Humanos , Adulto JovenAsunto(s)
Folículo Piloso/patología , Síndromes Neoplásicos Hereditarios/sangre , Síndromes Neoplásicos Hereditarios/patología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patología , Piel/patología , Enzima Desubiquitinante CYLD/genética , Femenino , Humanos , Mutación , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/ultraestructura , Adulto JovenAsunto(s)
Enfermedad de Darier/genética , Adulto , Enfermedad de Darier/patología , Femenino , Humanos , Fenotipo , Sri LankaRESUMEN
BACKGROUND: A recent noninferiority randomized controlled trial (RCT) indicated that imiquimod can be considered as superior to methylaminolevulinate photodynamic therapy (MAL-PDT) in the treatment of superficial basal cell carcinoma (sBCC). Knowledge of treatment effectiveness in subgroups of patients is of great value in clinical practice to select the most effective treatment for an individual patient with sBCC. OBJECTIVES: To explore whether the relative treatment effect of MAL-PDT and imiquimod is consistent across subgroups defined by patient and tumour characteristics. METHODS: Data were derived from a single-blinded, noninferiority, multicentre RCT comparing MAL-PDT, topical imiquimod and fluorouracil (ISRCTN79701845). Treatment success was defined as free of tumour recurrence at 12-month follow-up. Subgroup analyses were performed for subgroups defined by sex, age, tumour location and tumour size. RESULTS: Two hundred and two patients received MAL-PDT and 198 received imiquimod. The superiority of imiquimod vs. MAL-PDT was observed in subgroups of females, sBCC on the trunk and large tumours with risk differences in favour of imiquimod of 18·4% [95% confidence interval (CI) 7·8-29·0%], 21·0% (95% CI 10·9-31·1%) and 18·9% (95% CI 7·1-30·7%), respectively. Higher probability of treatment success for imiquimod vs. MAL-PDT was consistently found in all other subgroups with the exception of sBCC localized on the lower extremities in older patients. In the latter subgroup, the risk difference at the expense of imiquimod was -57·3% (95% CI -81·7% to -32·9%). CONCLUSIONS: Imiquimod remains the first-choice treatment for sBCC in terms of effectiveness. In older patients with sBCC on the lower extremities MAL-PDT might be preferred. Results should be interpreted carefully as subgroup analyses were exploratory and not driven by prior hypotheses.
Asunto(s)
Ácido Aminolevulínico/análogos & derivados , Aminoquinolinas/administración & dosificación , Antineoplásicos/administración & dosificación , Carcinoma Basocelular/tratamiento farmacológico , Fármacos Fotosensibilizantes/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Administración Cutánea , Adulto , Anciano , Anciano de 80 o más Años , Ácido Aminolevulínico/administración & dosificación , Femenino , Humanos , Imiquimod , Masculino , Persona de Mediana Edad , Pomadas , Fotoquimioterapia/métodos , Método Simple Ciego , Resultado del TratamientoRESUMEN
BACKGROUND: Variegate porphyria (VP) is due to a partial deficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in the haem biosynthetic pathway. Clinically, VP is characterized by photosensitivity and acute neurovisceral attacks that can manifest separately or together in affected individuals. The disease is inherited in an autosomal dominant fashion with incomplete penetrance and PPOX gene mutations associated with VP are usually unique to patients and their families. In South Africa, however, VP is highly prevalent as the result of a founder mutation, designated p.R59W. Previous genealogical and haplotype studies showed a link between South African and Dutch carriers of p.R59W and it was suggested that this mutation was introduced to South Africa by Dutch settlers at the end of the 17th century. OBJECTIVES: To perform extended haplotype analysis in six South African and Dutch VP families with the p.R59W mutation. METHODS: Haplotyping of 13 microsatellite markers flanking the PPOX gene on chromosome 1q22-23 and five informative single nucleotide polymorphisms within and around the gene. RESULTS: A core haplotype cosegregated in all families studied. CONCLUSIONS: Our data deliver further confirmation that the South African and Dutch VP families carrying mutation p.R59W shared a common ancestor.
Asunto(s)
Cromosomas Humanos Par 1/genética , Flavoproteínas/genética , Haplotipos/genética , Proteínas Mitocondriales/genética , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Porfiria Variegata/genética , Protoporfirinógeno-Oxidasa/genética , Frecuencia de los Genes/genética , Heterocigoto , Humanos , Repeticiones de Microsatélite/genética , Países Bajos/etnología , Linaje , Sudáfrica/etnologíaAsunto(s)
Dermatitis Exfoliativa/genética , Mutación , Trastornos de la Pigmentación/genética , Transglutaminasas/genética , Análisis Mutacional de ADN , Europa (Continente) , Salud de la Familia , Haplotipos , Homocigoto , Humanos , Modelos Genéticos , Enfermedades de la Piel/congénito , Enfermedades Cutáneas Vesiculoampollosas/genéticaAsunto(s)
Aneurisma/genética , Carcinoma Basocelular/genética , Cromosomas Humanos X/genética , Ligamiento Genético , Histiocitoma Fibroso Benigno/genética , Hipotricosis/genética , Neoplasias Cutáneas/genética , Aneurisma/patología , Carcinoma Basocelular/patología , Familia , Haplotipos , Histiocitoma Fibroso Benigno/patología , Humanos , Hipotricosis/patología , Linaje , Neoplasias Cutáneas/patologíaRESUMEN
Gap junctions are intercellular channels which are permeable to ions and small molecules up to about 1 kDa in size. They are prominent in the skin, but their precise function there is largely unknown. Mutations in skin-expressed gap junction genes disrupt epidermal growth and differentiation. A relatively minor epidermal connexin, connexin 26 (Cx26), is associated with a wide variety of phenotypes, each specifically associated with a particular amino acid residue. How the different mutations in GJB2 lead to such distinctive phenotypes is poorly understood. Analysis of new GJB2 mutations can shed new light on pathogenesis and the apparently vital role of Cx26 in maintaining epidermal integrity.
Asunto(s)
Conexinas/genética , Mutación Missense , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Adulto , Conexina 26 , Uniones Comunicantes/genética , Deformidades Congénitas de la Mano/genética , Deformidades Congénitas de la Mano/patología , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Humanos , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/patología , Masculino , FenotipoRESUMEN
BACKGROUND: Focal dermal hypoplasia (FDH) is an X-linked dominant disorder caused by nonsense mutations and deletions in the PORCN gene coding for a transmembrane endoplasmic reticulum protein required for Wingless signalling. Symptoms consist mainly of linear atrophic skin defects, skeletal deformities and, in many cases, mental retardation. Osteopathia striata is a nearly constant feature. Approximately 90% of patients are women. A few instances of father-to-daughter transmission and a number of sporadic male cases presumably as a result of somatic mosaicism have been recorded. OBJECTIVES: The aim of this study was to demonstrate the presence of somatic mosaicism for PORCN mutations in a male patient. METHODS: We sequenced the PORCN gene in different tissues from a boy with symptoms of FDH. RESULTS: We demonstrate post-zygotic mosaicism for a novel deletion in the PORCN gene. CONCLUSIONS: A novel PORCN deletion, present in a post-zygotic mosaic, causes focal dermal hyplasia in a male patient.