RESUMEN
This study aims to evaluate the etiology of pediatric sensorineural hearing loss (SNHL). A total of 423 children with SNHL were evaluated, with the focus on the determination of causative genetic and acquired etiologies of uni- and bilateral SNHL in relation to age at diagnosis and severity of the hearing loss. We found that a stepwise diagnostic approach comprising of imaging, genetic, and/or pediatric evaluation identified a cause for SNHL in 67% of the children. The most common causative finding in children with bilateral SNHL was causative gene variants (26%), and in children with unilateral SNHL, a structural anomaly of the temporal bone (27%). The probability of finding an etiologic diagnosis is significantly higher in children under the age of 1 year and children with profound SNHL.Conclusions: With our stepwise diagnostic approach, we found a diagnostic yield of 67%. Bilateral SNHL often has a genetic cause, whereas in unilateral SNHL structural abnormalities of the labyrinth are the dominant etiologic factor. The diagnostic yield is associated with the age at detection and severity of hearing loss: the highest proportion of causative abnormalities is found in children with a young age at detection or a profound hearing loss. What is Known: ⢠Congenital sensorineural hearing loss is one of the most common congenital disorders ⢠Determination of the cause is important for adequate management and prognosis and may include radiology, serology, and DNA analysis What is New: ⢠Using a stepwise diagnostic approach, causative abnormalities are found in 67% both in uni- and bilateral SNHL, with the highest diagnostic yield in very young children and those suffering from profound hearing loss ⢠Bilateral SNHL often has a genetic cause, whereas in unilateral SNHL structural abnormalities of the labyrinth are the dominant etiologic factor.
Asunto(s)
Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/etiología , Adolescente , Audiometría , Niño , Preescolar , Femenino , Marcadores Genéticos , Pruebas Genéticas , Pérdida Auditiva Bilateral/diagnóstico , Pérdida Auditiva Bilateral/etiología , Pérdida Auditiva Unilateral/diagnóstico , Pérdida Auditiva Unilateral/etiología , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos XRESUMEN
This study focuses on further characterization of the audiovestibular phenotype and on genotype-phenotype correlations of DFNB77, an autosomal recessive type of hearing impairment (HI). DFNB77 is associated with disease-causing variants in LOXHD1, and is genetically and phenotypically highly heterogeneous. Heterozygous deleterious missense variants in LOXHD1 have been associated with late-onset Fuchs corneal dystrophy (FCD). However, up to now screening for FCD of heterozygous carriers in DFNB77 families has not been reported. This study describes the genotype and audiovestibular phenotype of 9 families with DFNB77. In addition, carriers within the families were screened for FCD. Fifteen pathogenic missense and truncating variants were identified, of which 12 were novel. The hearing phenotype showed high inter- and intrafamilial variation in severity and progression. There was no evidence for involvement of the vestibular system. None of the carriers showed (pre-clinical) symptoms of FCD. Our findings expand the genotypic and phenotypic spectrum of DFNB77, but a clear correlation between the type or location of the variant and the severity or progression of HI could not be established. We hypothesize that environmental factors or genetic modifiers are responsible for phenotypic differences. No association was found between heterozygous LOXHD1 variants and the occurrence of FCD in carriers.
Asunto(s)
Proteínas Portadoras/genética , Distrofia Endotelial de Fuchs/genética , Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/genética , Adolescente , Adulto , Audiometría , Niño , Preescolar , Femenino , Distrofia Endotelial de Fuchs/fisiopatología , Estudios de Asociación Genética , Genotipo , Pérdida Auditiva Sensorineural/fisiopatología , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Linaje , FenotipoRESUMEN
The BCAP31 gene is located between SLC6A8, associated with X-linked creatine transporter deficiency, and ABCD1, associated with X-linked adrenoleukodystrophy. Recently, loss-of-function mutations in BCAP31 were reported in association with severe developmental delay, deafness and dystonia. We characterized the break points in eight patients with deletions of SLC6A8, BCAP31 and/or ABCD1 and studied the genotype-phenotype correlations. The phenotype in patients with contiguous gene deletions involving BCAP31 overlaps with the phenotype of isolated BCAP31 deficiency. Only deletions involving both BCAP31 and ABCD1 were associated with hepatic cholestasis and death before 1 year, which might be explained by a synergistic effect. Remarkably, a patient with an isolated deletion at the 3'-end of SLC6A8 had a similar severe phenotype as seen in BCAP31 deficiency but without deafness. This might be caused by the disturbance of a regulatory element between SLC6A8 and BCAP31.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Colestasis Intrahepática/genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genética , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/mortalidad , Adrenoleucodistrofia/patología , Adulto , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/mortalidad , Encefalopatías Metabólicas Innatas/patología , Niño , Preescolar , Colestasis Intrahepática/mortalidad , Colestasis Intrahepática/patología , Creatina/deficiencia , Creatina/genética , Eliminación de Gen , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/mortalidad , Discapacidad Intelectual/patología , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/genética , Discapacidad Intelectual Ligada al Cromosoma X/mortalidad , Discapacidad Intelectual Ligada al Cromosoma X/patología , Fenotipo , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/deficienciaRESUMEN
BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.
Asunto(s)
Encefalopatías Metabólicas Innatas/genética , Creatina/deficiencia , Creatina/metabolismo , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteínas del Tejido Nervioso/genética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/deficiencia , Adulto , Niño , Creatina/genética , Genes Ligados a X , Pruebas Genéticas , Genotipo , Humanos , Masculino , Fenotipo , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genética , Estudios RetrospectivosRESUMEN
The creatine transporter defect is an X-linked cause of mental retardation. We investigated the clinical features and pattern of X-inactivation in a Dutch cohort of eight female heterozygotes. We show that symptoms of the creatine transporter defect (mental retardation, learning difficulties, and constipation) can be present in female heterozygotes. We further show that the diagnosis in females is not straightforward: (i) The creatine/creatinine ratio in urine was elevated only in three of eight females. (ii) Although as a group the females had a significantly decreased cerebral creatine concentration, individual females had creatine concentrations overlapping with normal controls. (iii) Skewed X-inactivation was found in the cultured fibroblasts, in favour of either the mutated or the wild-type allele, leading to either deficient or normal results in the creatine uptake studies in fibroblasts. Thus, screening by these tests is unreliable for the diagnosis. In addition, we found no consistent skewing of the X-inactivation in peripheral tissues indicating that there is no selection against the creatine transporter defect. We conclude that testing for creatine transporter defect should be considered in females with (mild) mental retardation. Screening by DNA analysis of the SLC6A8 gene is recommended.
Asunto(s)
Heterocigoto , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteínas del Tejido Nervioso/genética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genética , Inactivación del Cromosoma X/genética , Adulto , Anciano , Células Cultivadas , Creatina/metabolismo , Femenino , Humanos , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Persona de Mediana Edad , Mutación , Países Bajos , Pruebas NeuropsicológicasRESUMEN
Mucopolysaccharidosis IIIC (MPS IIIC, Sanfilippo C syndrome) is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT). We performed a clinical study on 29 Dutch MPS IIIC patients and determined causative mutations in the recently identified HGSNAT gene. Psychomotor development was reported to be normal in all patients during the first year of life. First clinical signs were usually noted between 1 and 6 years (mean 3.5 years), and consisted of delayed psychomotor development and behavioral problems. Other symptoms included sleeping and hearing problems, recurrent infections, diarrhoea and epilepsy. Two sisters had attenuated disease and did not have symptoms until the third decade. Mean age of death was 34 years (range 25-48). Molecular analysis revealed mutations in both alleles for all patients except one. Altogether 14 different mutations were found: two splice site mutations, one frame shift mutation due to an insertion, three nonsense mutations and eight missense mutations. Two mutations, p.R344C and p.S518F, were frequent among probands of Dutch origin representing 22.0% and 29.3%, respectively, of the mutant alleles. This study demonstrates that MPS IIIC has a milder course than previously reported and that both severity and clinical course are highly variable even between sibs, complicating prediction of the clinical phenotype for individual patients. A clear phenotype-genotype correlation could not be established, except that the mutations p.G262R and p.S539C were only found in two sisters with late-onset disease and presumably convey a mild phenotype.
Asunto(s)
Acetiltransferasas/deficiencia , Acetiltransferasas/genética , Mucopolisacaridosis III/enzimología , Mucopolisacaridosis III/genética , Mutación , Acetiltransferasas/química , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , ADN/genética , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Modelos Moleculares , Mucopolisacaridosis III/clasificación , Mucopolisacaridosis III/fisiopatología , Mutación Missense , Países Bajos , FenotipoRESUMEN
There is a growing awareness that inborn errors of metabolism can be a cause of non-immune hydrops fetalis. The association between congenital disorders of glycosylation (CDG) and hydrops fetalis has been based on one case report concerning two sibs with hydrops fetalis and CDG-Ik. Since then two patients with hydrops-like features and CDG-Ia have been reported. Two more unrelated patients with CDG-Ia who presented with hydrops fetalis are reported here, providing definite evidence that non-immune hydrops fetalis can be caused by CDG-Ia. The presence of congenital thrombocytopenia and high ferritin levels in both patients was remarkable. These might be common features in this severe form of CDG. Both patients had one severe mutation in the phosphomannomutase 2 gene, probably fully inactivating the enzyme, and one milder mutation with residual activity, as had the patients reported in literature. The presence of one severe mutation might be required for the development of hydrops fetalis. CDG-Ia should be considered in the differential diagnosis of hydrops fetalis and analysis of PMM activity in chorionic villi or amniocytes should also be considered.
Asunto(s)
Anomalías Múltiples/genética , Glicosilación , Hidropesía Fetal/genética , Fosfotransferasas (Fosfomutasas)/genética , Procesamiento Proteico-Postraduccional/genética , Codón sin Sentido , Resultado Fatal , Femenino , Ferritinas/sangre , Mutación del Sistema de Lectura , Glicoproteínas/metabolismo , Cardiopatías Congénitas/genética , Humanos , Hidropesía Fetal/diagnóstico por imagen , Hipoalbuminemia/congénito , Hipoalbuminemia/genética , Recién Nacido , Focalización Isoeléctrica , Masculino , Mutagénesis Insercional , Mutación Missense , Derrame Pericárdico/congénito , Fosfotransferasas (Fosfomutasas)/deficiencia , Trombocitopenia/congénito , Trombocitopenia/genética , Transferrina/análisis , Ultrasonografía PrenatalRESUMEN
OBJECTIVE: To evaluate the clinically relevant abnormalities as visualized on CT and MR imaging in children with symmetric and asymmetric bilateral sensorineural hearing loss (SNHL), in relation to age and the severity of hearing loss. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral otology and audiology center. PATIENTS AND DIAGNOSTIC INTERVENTIONS: From January 2006 until January 2016, a total of 207 children diagnosed with symmetric and asymmetric bilateral SNHL were included. They underwent CT and/or MR imaging for the evaluation of the etiology of their hearing loss. MAIN OUTCOME MEASURES: Radiologic abnormalities associated with SNHL. RESULTS: 302 scans were performed in 207 children (median age of 0.8 years old) with bilateral SNHL. The most frequently identified cause of bilateral SNHL was a malformation of the labyrinth. The combined diagnostic yield of CT and MR imaging was 32%. The diagnostic yield of MR (34%) was considerably higher than that of CT (20%). We found a higher rate of abnormalities in children with profound hearing loss (41%) compared to milder hearing loss (8-29%), and in asymmetric SNHL (52%) compared to symmetric SNHL (30%). CONCLUSION: Imaging is essential in the etiologic evaluation of children with bilateral SNHL. The highest diagnostic yield is found in children with bilateral asymmetric SNHL or profound SNHL. Based on our findings, MR is the primary imaging modality of choice in the etiological evaluation of children with bilateral SNHL because of its high diagnostic yield.
Asunto(s)
Pérdida Auditiva Bilateral/diagnóstico por imagen , Pérdida Auditiva Sensorineural/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Tomografía Computarizada por Rayos X/métodos , Adolescente , Niño , Preescolar , Estudios de Cohortes , Oído Interno/anomalías , Femenino , Pérdida Auditiva Bilateral/etiología , Pérdida Auditiva Sensorineural/etiología , Humanos , Lactante , Masculino , Estudios RetrospectivosRESUMEN
OBJECTIVE: Evaluation of causal abnormalities identified on CT and MR imaging in children with unilateral sensorineural hearing loss (USNHL), and the association with age and severity of hearing loss. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral otology/audiology center. PATIENTS AND DIAGNOSTIC INTERVENTIONS: 102 children diagnosed with USNHL between 2006 and 2016 were included. They underwent CT and/or MR imaging for the evaluation of the etiology of their hearing loss. MAIN OUTCOME MEASURES: Radiologic abnormalities of the inner ear and brain associated with USNHL. RESULTS: Using CT and/or MR imaging, causal abnormalities were identified in 49%, which is higher than previously reported (25-40%). The most frequently affected site was the labyrinth (29%), followed by the cochlear nerve (9%) and brain (7%). No significant difference in the number or type of abnormalities was found for the degree of hearing loss or age categories. CONCLUSIONS: Imaging is essential in the etiologic analysis of USNHL because of the high prevalence of causative abnormalities that can be identified with radiology, irrespective of the patients' age or degree of hearing loss. CT and MR imaging are complementary imaging options. The ideal imaging algorithm is controversial. Based on our findings, we conclude that there is limited additional diagnostic value of simultaneous dual modality imaging over sequential diagnostics. We therefore perform a stepwise radiological workup in order to maximize the diagnostic yield while minimizing impact and costs. If the primary imaging modality does not identify a cause for USNHL, performing the alternative imaging modality should be considered. LEVEL OF EVIDENCE: Retrospective cohort study 2b.
Asunto(s)
Encéfalo/patología , Oído Interno/patología , Pérdida Auditiva Sensorineural/etiología , Imagen por Resonancia Magnética/métodos , Tomografía Computarizada por Rayos X/métodos , Adolescente , Audiometría , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Estudios de Cohortes , Oído Interno/diagnóstico por imagen , Femenino , Pérdida Auditiva Sensorineural/diagnóstico por imagen , Humanos , Lactante , Masculino , Países Bajos , Prevalencia , Estudios Retrospectivos , Centros de Atención TerciariaRESUMEN
BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. METHODS: A NGS gene panel was analysed in 24 patients with EL. RESULTS: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. CONCLUSION: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.
Asunto(s)
Desplazamiento del Cristalino/genética , Pruebas Genéticas/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Análisis de Secuencia de ADN/métodos , Proteínas ADAMTS/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Desplazamiento del Cristalino/diagnóstico , Reacciones Falso Positivas , Femenino , Pruebas Genéticas/normas , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Humanos , Lactante , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Análisis de Secuencia de ADN/normasAsunto(s)
Encéfalo/patología , Insomnio Familiar Fatal/genética , Insomnio Familiar Fatal/patología , Insomnio Familiar Fatal/fisiopatología , Priones/genética , Población Negra , Western Blotting , Egipto , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Países Bajos , Linaje , Mutación Puntual , Proteínas PriónicasRESUMEN
Duplications leading to functional disomy of chromosome Xq28, including MECP2 as the critical dosage-sensitive gene, are associated with a distinct clinical phenotype in males, characterized by severe mental retardation, infantile hypotonia, progressive neurologic impairment, recurrent infections, bladder dysfunction, and absent speech. Female patients with Xq duplications including MECP2 are rare. Only recently submicroscopic duplications of this region on Xq28 have been recognized in four females, and a triplication in a fifth, all in combination with random X-chromosome inactivation (XCI). Based on this small series, it was concluded that in females with MECP2 duplication and random XCI, the typical symptoms of affected boys are not present. We present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene, both isolated and as the result of a translocation, and compare them with the previously reported cases of small duplications in females. The collected data indicate that the associated phenotype in females is distinct from males with similar duplications, but the clinical effects may be as severe as seen in males.
Asunto(s)
Anomalías Múltiples/diagnóstico , Duplicación Cromosómica , Cromosomas Humanos X/genética , Discapacidad Intelectual/genética , Proteína 2 de Unión a Metil-CpG/genética , Fenotipo , Anomalías Múltiples/genética , Niño , Bandeo Cromosómico , Femenino , Estudios de Asociación Genética , Humanos , Linaje , Inactivación del Cromosoma XRESUMEN
Bifurcation of the femur and tibial agenesis are rare anomalies and have been described in both the Gollop-Wolfgang Complex and the tibial agenesis-ectrodactyly syndrome. We report on two patients with bifurcation of the femur and tibial agenesis. Hand ectrodactyly was seen in one of these patients. Both patients had unusual additional anomalies. The first patient had in addition proximal focal femoral deficiency, the other patient had a tracheo-esophageal fistula and pyloric stenosis. Clinical and genetic aspects are discussed.