RESUMEN
Retinoic acid receptor beta (RARB) variants are heavily linked to pathologies of neural crest cell migration. The purpose of this report is to present a 23-month-old male with the previously described R387C RARB gain-of-function variant whose gastrointestinal issues and long-term constipation lead to the discovery of colonic hypoganglionosis. This case further delineates the pattern of malformation associated with RARB variants. The findings are also consistent with the known etiology of aganglionic colon due to failed neural crest cell migration.
Asunto(s)
Enfermedades Funcionales del Colon/diagnóstico , Enfermedades Funcionales del Colon/etiología , Estreñimiento/diagnóstico , Estreñimiento/etiología , Predisposición Genética a la Enfermedad , Variación Genética , Receptores de Ácido Retinoico/genética , Alelos , Exoma , Humanos , Lactante , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Mutación con Pérdida de Función , Masculino , Radiografía , Secuenciación del ExomaRESUMEN
We report a patient with aplasia cutis congenita, Duane anomaly, hip dysplasia, and other anomalies who had a de novo missense variant in UBA2, which encodes for a protein involved in the SUMOylation pathway. It has previously been suggested that UBA2 haploinsufficiency underlies scalp defects in the 19q13.11 deletion syndrome. We propose that disturbance of the SUMOylation pathway, mediated by pathogenic variants in UBA2, is a novel mechanism for aplasia cutis congenita and other phenotypic abnormalities. © 2017 Wiley Periodicals, Inc.
Asunto(s)
Anomalías Múltiples/genética , Síndrome de Retracción de Duane/genética , Displasia Ectodérmica/genética , Luxación de la Cadera/genética , Mutación Missense , Enzimas Activadoras de Ubiquitina/genética , Anomalías Múltiples/diagnóstico , Preescolar , Síndrome de Retracción de Duane/diagnóstico , Displasia Ectodérmica/diagnóstico , Exoma , Facies , Femenino , Estudios de Asociación Genética , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Luxación de la Cadera/diagnóstico , Humanos , Fenotipo , Radiografía , Sumoilación , Tomografía Computarizada por Rayos X , Enzimas Activadoras de Ubiquitina/metabolismoRESUMEN
Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery.
Asunto(s)
Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Mutación , Hidrolasas Diéster Fosfóricas/genética , Seudoxantoma Elástico/genética , Pirofosfatasas/genética , Calcificación Vascular/genética , Estrías Angioides/genética , Secuencia de Bases , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Seudoxantoma Elástico/patología , Estudios Retrospectivos , Encuestas y Cuestionarios , Calcificación Vascular/patologíaRESUMEN
Mutations in genes encoding cardiac sarcomeric proteins are thought to be a very rare cause of hypertrophic cardiomyopathy (HCM) in infants and young children. We report on genetic and histopathological findings in a 3-month-old infant presenting with severe progressive HCM arising from a mutation in the gene encoding the essential light chain of myosin (MYL3). The patient was found to have a novel, paternally inherited pathogenic c.530 A>G mutation in exon 5 of the MYL3 gene. His father was asymptomatic. Although, MYL3 mutations have been previously associated with adult-onset HCM, it has not been seen in infantile forms. As such, this case adds to the emerging evidence demonstrating that familial disease associated with mutations in cardiac sarcomere protein genes may have an important role in infants and children with HCM. In addition, this case highlights the marked phenotypic heterogeneity associated with sarcomeric protein mutations both within and between families.