RESUMEN
Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n = 41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development.
Asunto(s)
Síndrome de Costello/genética , Anomalías Craneofaciales/embriología , Anomalías Craneofaciales/genética , Sistema de Señalización de MAP Quinasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Anomalías Múltiples/embriología , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Hipoplasia del Esmalte Dental/embriología , Hipoplasia del Esmalte Dental/genética , Displasia Ectodérmica/embriología , Displasia Ectodérmica/genética , Facies , Insuficiencia de Crecimiento/embriología , Insuficiencia de Crecimiento/genética , Femenino , Hiperplasia Gingival/embriología , Hiperplasia Gingival/genética , Cardiopatías Congénitas/embriología , Cardiopatías Congénitas/genética , Humanos , Masculino , Maloclusión/embriología , Maloclusión/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Mutación , Fosfatidilinositol 3-Quinasas/genética , Diente/embriología , Anomalías Dentarias/embriología , Anomalías Dentarias/genética , Adulto JovenRESUMEN
Hypohidrotic ectodermal dysplasia (HED) is the most common type of ectodermal dysplasia (ED), which encompasses a large group of syndromes that share several phenotypic features such as missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. X-linked hypohidrotic ectodermal dysplasia (XL-HED) is associated with mutations in ectodysplasin (EDA1). Hypohidrosis due to hypoplastic sweat glands and thin, sparse hair are phenotypic features that significantly affect the daily lives of XL-HED individuals and therefore require systematic analysis. We sought to determine the quality of life of individuals with XL-HED and to quantify sweat duct and hair phenotypes using confocal imaging, pilocarpine iontophoresis, and phototrichogram analysis. Using these highly sensitive and non-invasive techniques, we demonstrated that 11/12 XL-HED individuals presented with a complete absence of sweat ducts and that none produced sweat. We determined that the thin hair phenotype observed in XL-HED was due to multiple factors, such as fewer terminal hairs with decreased thickness and slower growth rate, as well as fewer follicular units and fewer hairs per unit. The precise characterization of XL-HED phenotypes using sensitive and non-invasive techniques presented in our study will improve upon larger genotype-phenotype studies and the assessment of future therapies in XL-HED.
Asunto(s)
Dermatología/métodos , Displasia Ectodermal Anhidrótica Tipo 1/etiología , Cabello/patología , Glándulas Sudoríparas/patología , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Ectodisplasinas/genética , Humanos , Iontoforesis/métodos , Masculino , Microscopía Confocal/métodos , Fenotipo , Pilocarpina , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Hypohidrotic ectodermal dysplasia (HED) is the most prevalent type of ectodermal dysplasia (ED). ED is an umbrella term for a group of syndromes characterized by missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. The X-linked recessive (XL), autosomal recessive (AR), and autosomal dominant (AD) types of HED are caused by mutations in the genes encoding ectodysplasin (EDA1), EDA receptor (EDAR), or EDAR-associated death domain (EDARADD). Patients with HED have a distinctive facial appearance, yet a quantitative analysis of the HED craniofacial phenotype using advanced three-dimensional (3D) technologies has not been reported. In this study, we characterized craniofacial morphology in subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED) by use of 3D imaging and geometric morphometrics (GM), a technique that uses defined landmarks to quantify size and shape in complex craniofacial morphologies. We found that the XLHED craniofacial phenotype differed significantly from controls. Patients had a smaller and shorter face with a proportionally longer chin and midface, prominent midfacial hypoplasia, a more protrusive chin and mandible, a narrower and more pointed nose, shorter philtrum, a narrower mouth, and a fuller and more rounded lower lip. Our findings refine the phenotype of XLHED and may be useful both for clinical diagnosis of XLHED and to extend understanding of the role of EDA in craniofacial development.