RESUMO
BACKGROUND: Male EBP disorder with neurologic defects (MEND) syndrome is an X-linked disease caused by hypomorphic mutations in the EBP (emopamil-binding protein) gene. Modifier genes may explain the clinical variability among individuals who share a primary mutation. METHODS: We studied four males (Patient 1 to Patient 4) exhibiting a descending degree of phenotypic severity from a family with MEND syndrome. To identify candidate modifier genes that explain the phenotypic variability, variants of homeostasis cholesterol genes identified by whole-exome sequencing (WES) were ranked according to the predicted magnitude of their effect through an in-house scoring system. RESULTS: Twenty-seven from 105 missense variants found in 45 genes of the four exomes were considered significant (-5 to -9 scores). We found a direct genotype-phenotype association based on the differential accumulation of potentially functional gene variants among males. Patient 1 exhibited 17 variants, both Patients 2 and 3 exhibited nine variants, and Patient 4 exhibited only five variants. CONCLUSION: We conclude that APOA5 (rs3135506), ABCA1 (rs9282541), and APOB (rs679899 and rs12714225) are the most relevant candidate modifier genes in this family. Relative accumulation of the deficiencies associated with variants of these genes along with other lesser deficiencies in other genes appears to explain the variable expressivity in MEND syndrome.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Apolipoproteína A-V , Apolipoproteína B-100 , Colesterol , Exoma , Polimorfismo Genético , Síndrome de Waardenburg , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteína A-V/genética , Apolipoproteína A-V/metabolismo , Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Colesterol/genética , Colesterol/metabolismo , Feminino , Estudos de Associação Genética , Homeostase/genética , Humanos , Masculino , Fenótipo , Índice de Gravidade de Doença , Síndrome de Waardenburg/genética , Síndrome de Waardenburg/metabolismo , Síndrome de Waardenburg/patologiaRESUMO
BACKGROUND: It is important that multiple genetic diagnoses are not missed. This case report describes the clinical features and management of a patient with co-inheritance of Waardenburg syndrome type 4 or Waardenburg-Shah syndrome, an extremely rare disease, and homozygous sickle cell disease not uncommon in the Caribbean. This case is unusual as it may be the first documented case of the co-inheritance of both these diseases. Given the commonality of sickle cell and related hemoglobinopathies, such combined disorders are likely to be under-reported. Importantly, reporting this case will add to the medical literature as it will raise awareness of the phenotypic manifestations of this disorder. CASE PRESENTATION: A 54-year-old Afro-Caribbean woman had a delayed diagnosis of homozygous sickle cell disease at 7 years of age by hemoglobin electrophoresis. The complications of sickle cell disease she experienced included bone pain, a chronic right leg ulcer, avascular necrosis of her left hip, and symptomatic cholelithiasis. This diagnosis was preceded by an earlier diagnosis of Waardenburg syndrome. The basis for the diagnosis of Waardenburg-Shah syndrome was the presence of pigmentary disturbances of her eyes (hypoplastic blue irides), congenital sensorineural hearing loss, and Hirschsprung's disease. She was mute and complained of chronic constipation which required disimpaction on several occasions. She attended a school for the deaf and communicated via writing. A Duhamel procedure bypassing her rectum was performed at age 9. She died following an admission for acute chest syndrome complications. CONCLUSION: Sickle cell disease can be diagnosed by newborn screening but, as in this case, may have a delayed presentation. The delay in diagnosis of homozygous sickle cell disease illustrates that other genetic disorders should be considered in patients who already have a diagnosis of one Mendelian disorder but show atypical features.
Assuntos
Anemia Falciforme/complicações , Anemia Falciforme/genética , Doença de Hirschsprung/complicações , Doença de Hirschsprung/genética , Síndrome de Waardenburg/complicações , Síndrome de Waardenburg/genética , Diagnóstico Tardio , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
This paper deals with the molecular investigation of Waardenburg syndrome (WS) in a sample of 49 clinically diagnosed probands (most from southeastern Brazil), 24 of them having the type 1 (WS1) variant (10 familial and 14 isolated cases) and 25 being affected by the type 2 (WS2) variant (five familial and 20 isolated cases). Sequential Sanger sequencing of all coding exons of PAX3, MITF, EDN3, EDNRB, SOX10 and SNAI2 genes, followed by CNV detection by MLPA of PAX3, MITF and SOX10 genes in selected cases revealed many novel pathogenic variants. Molecular screening, performed in all patients, revealed 19 causative variants (19/49â¯=â¯38.8%), six of them being large whole-exon deletions detected by MLPA, seven (four missense and three nonsense substitutions) resulting from single nucleotide substitutions (SNV), and six representing small indels. A pair of dizygotic affected female twins presented the c.430delC variant in SOX10, but the mutation, imputed to gonadal mosaicism, was not found in their unaffected parents. At least 10 novel causative mutations, described in this paper, were found in this Brazilian sample. Copy-number-variation detected by MLPA identified the causative mutation in 12.2% of our cases, corresponding to 31.6% of all causative mutations. In the majority of cases, the deletions were sporadic, since they were not present in the parents of isolated cases. Our results, as a whole, reinforce the fact that the screening of copy-number-variants by MLPA is a powerful tool to identify the molecular cause in WS patients.
Assuntos
Variações do Número de Cópias de DNA , Mutação , Síndrome de Waardenburg/genética , Brasil , Éxons , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Mosaicismo , Análise de Sequência de DNA , Deleção de SequênciaRESUMO
Reports of terminal and interstitial deletions of the long arm of chromosome 2 are rare in the literature. Here, we present a case report concerning a Chinese boy with a 47,XYY karyotype and a de novo deletion comprising approximately 5 Mb between 2q35 and q36.1, along with syndactyly, type III Waardenburg syndrome, and congenital heart disease. High-resolution chromosome analysis to detect copy number variations was carried out using an Affymetrix microarray platform, and the genes affected by the patient's deletion, including IHH, were determined. However, no copy number changes were observed in his healthy parents. The present case exhibited novel syndactyly features, broadening the spectrum of clinical findings observed in individuals with 2q interstitial deletions. Our data, together with previous observations, suggest that IHH haploinsufficiency is the principal pathogenic factor in the syndactyly phenotype in this study, and that different types of variations at the IHH locus may cause divergent disease phenotypes. This is the first report of the involvement of IHH haploinsufficiency in syndactyly phenotype.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Dedos/anormalidades , Cardiopatias Congênitas/genética , Sindactilia/genética , Síndrome de Waardenburg/genética , Povo Asiático/genética , Criança , Proteínas Hedgehog/genética , Humanos , Cariótipo , MasculinoRESUMO
Tietz syndrome and Waardenburg syndrome type 2A are allelic conditions caused by MITF mutations. Tietz syndrome is inherited in an autosomal dominant pattern and is characterized by congenital deafness and generalized skin, hair, and eye hypopigmentation, while Waardenburg syndrome type 2A typically includes variable degrees of sensorineural hearing loss and patches of de-pigmented skin, hair, and irides. In this paper, we report two unrelated families with MITF mutations. The first family showed an autosomal dominant pattern and variable expressivity. The second patient was isolated. MITF gene analysis in the first family demonstrated a c.648A>C heterozygous mutation in exon 8 c.648A>C; p. (R216S), while in the isolated patient, an apparently de novo heterozygous c.1183_1184insG truncating mutation was demonstrated in exon 10. All patients except one had bilateral reduced ocular anteroposterior axial length and a high hyperopic refractive error corresponding to posterior microphthalmos, features that have not been described as part of the disease. Our results suggest that posterior microphthalmos might be part of the clinical characteristics of Tietz/Waardenburg syndrome type 2A and expand both the clinical and molecular spectrum of the disease. © 2016 Wiley Periodicals, Inc.
Assuntos
Fator de Transcrição Associado à Microftalmia/genética , Microftalmia/genética , Mutação , Fenótipo , Síndrome de Waardenburg/genética , Alelos , Substituição de Aminoácidos , Criança , Pré-Escolar , Éxons , Fácies , Heterozigoto , Humanos , Masculino , Microftalmia/diagnóstico , Exame Físico , Síndrome de Waardenburg/diagnósticoRESUMO
Fundamento: El síndrome de Waardenburg es una enfermedad genética caracterizada por anomalías de la pigmentación y sordera neurosensorial. Se describen varios tipos clínicos, con gran heterogeneidad genética, la mayoría de los casos publicados presentan un patrón de herencia autosómico dominante, aunque se describen otras formas de herencia. Objetivo: Mostrar una familia con varios miembros afectados representativa de expresividad variable. Presentación de caso: Se presenta una familia con siete enfermos donde predomina la hipoacusia de grado variable al igual que las alteraciones de la pigmentación de la piel, el pelo y el iris. El adecuado diagnóstico y asesoramiento genético, unido a la oportuna intervención con el implante coclear ha permitido la incorporación adecuada en la enseñanza normal a estos enfermos. Conclusiones: Es importante el diagnóstico oportuno para realizar acciones con la finalidad de mejorar la calidad de vida y la correcta incorporación social de estos pacientes.
Background: The syndrome of Waardenburg is a genetic illness characterized by anomalies of the pigmentation and neurosensory deafness. Several clinical types are described, with great genetic heterogeneity; most of the published cases present a pattern of autos’omico dominant inheritance, although other inheritance forms are described Objective: To show a representative family with several affected members of variable expression. Case presentation: A family is presented with seven sick persons where the hypo acoustic of variable grade prevail the same as the alterations of the pigmentation of the skin, the hair and the iris. The appropriate diagnose and genetic advice, together to the opportune intervention with the cochlear implants has allowed the adapted incorporation in the normal teaching to these sick persons Conclusions: It is important the opportune diagnosis to carry out actions with the purpose of improving the quality of life and the correct social incorporation of these patients.
Assuntos
Humanos , Síndrome de Waardenburg/genética , FamíliaRESUMO
OBJETIVO: Descrever as características clínicas e imaginológicas de duas famílias com a síndrome de Waardenburg, sendo uma do tipo I e outra do tipo II, enfatizando as manifestações oftalmológicas, bem como o padrão de herança genética. MÉTODO: Realizou-se um estudo clínico envolvendo as duas famílias afetadas pela síndrome de Waardenburg, sendo, através dos heredogramas, determinado o padrão de herança genética presente. Também foram realizadas análises oftalmológicas abordando a medida da acuidade visual, a presença de distopia cantorum (telecanto), a avaliação da coloração da íris e o mapeamento de retina, além de exames otológicos e dermatológicos. RESULTADOS: O heredograma da família afetada pela síndrome de Waardenburg tipo I revelou um modo autossômico dominante de transmissão. A condição estava presente em 85,71% dos pacientes. A distopia cantorum foi a alteração mais frequente, seguida pela mecha branca na pele da fronte, hipopigmentação da íris e da retina e surdez neurossensorial. A família com síndrome de Waardenburg tipo II apresentou 33,33% dos familiares com a alteração. Nenhum membro apresentou distopia cantorum e hipopigmentação de íris. Três pacientes apresentaram surdez neurossensorial (12,5%), associada ao topete branco e manchas acrômicas confluentes pelo corpo. CONCLUSÃO: O presente estudo mostra a importância do oftalmologista no auxílio do diagnóstico desta rara condição genética, uma vez que inclui alterações oftalmológicas como telecanto, hipopigmentação da íris e retina. A distopia cantorum é o principal critério diagnóstico para diferenciar o tipo I do II e deve ser feita por oftalmologista treinado. As famílias encontram-se em acompanhamento multiprofissional, tendo recebido orientações genéticas e os cuidados referentes à proteção ocular.
PURPOSE: To describe the clinical and imaginological features of two families with Waardenburg syndrome: type I and II, with emphasis on ophthalmic manifestations, as well as the pattern of genetic inheritance. METHODS: We conducted a clinical study involving two families affected by Waardenburg syndrome, and through the pedigree, determined the present pattern of genetic inheritance. Analyses were performed including the measurement of visual acuity, the presence of dystopia cantorum (telecanthus), evaluation of iris color and retinal mapping, as well as dermatological and otological examinations. RESULTS: The pedigree of the family affected by the Waardenburg syndrome type I showed an autosomal dominant mode of transmission. The syndrome was present at 85.71% of patients. The dystopia cantorum was the most frequent feature, followed by the white streak on the skin of the forehead, hypopigmentation of the iris and retina and deafness. The Waardenburg syndrome family type II had 33.33% of family members affected by the syndrome. No member had dystopia cantorum and hypopigmentation of the iris. Three patients had sensorineural hearing loss (12.5%), associated with white forelock and achromatic spots confluent by the body. CONCLUSION: This study shows the importance of the ophthalmologist in aiding the diagnosis of this rare genetic condition, since it includes ocular disorders such as telecanthus, hypopigmentation of the iris and retina. The cantorum dystopia is the main diagnostic criterion to differentiate type I and II syndrome and should be done by a trained ophthalmologist. The families are in medical monitoring, receiving genetic guidelines and care related to eye protection.
Assuntos
Adulto , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oftalmopatias Hereditárias/diagnóstico , Iris/anormalidades , Síndrome de Waardenburg/diagnóstico , Oftalmopatias Hereditárias/genética , Predisposição Genética para Doença , Linhagem , Acuidade Visual , Síndrome de Waardenburg/genéticaRESUMO
PURPOSE: To describe the clinical and imaginological features of two families with Waardenburg syndrome: type I and II, with emphasis on ophthalmic manifestations, as well as the pattern of genetic inheritance. METHODS: We conducted a clinical study involving two families affected by Waardenburg syndrome, and through the pedigree, determined the present pattern of genetic inheritance. Analyses were performed including the measurement of visual acuity, the presence of dystopia cantorum (telecanthus), evaluation of iris color and retinal mapping, as well as dermatological and otological examinations. RESULTS: The pedigree of the family affected by the Waardenburg syndrome type I showed an autosomal dominant mode of transmission. The syndrome was present at 85.71% of patients. The dystopia cantorum was the most frequent feature, followed by the white streak on the skin of the forehead, hypopigmentation of the iris and retina and deafness. The Waardenburg syndrome family type II had 33.33% of family members affected by the syndrome. No member had dystopia cantorum and hypopigmentation of the iris. Three patients had sensorineural hearing loss (12.5%), associated with white forelock and achromatic spots confluent by the body. CONCLUSION: This study shows the importance of the ophthalmologist in aiding the diagnosis of this rare genetic condition, since it includes ocular disorders such as telecanthus, hypopigmentation of the iris and retina. The cantorum dystopia is the main diagnostic criterion to differentiate type I and II syndrome and should be done by a trained ophthalmologist. The families are in medical monitoring, receiving genetic guidelines and care related to eye protection.
Assuntos
Oftalmopatias Hereditárias/diagnóstico , Iris/anormalidades , Síndrome de Waardenburg/diagnóstico , Adulto , Pré-Escolar , Oftalmopatias Hereditárias/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Acuidade Visual , Síndrome de Waardenburg/genéticaRESUMO
Waardenburg syndrome is a hereditary auditory-pigmentary syndrome. The major features include pigmentary disturbances and congenital deafness. Clinical findings are extremely variable, not only at the authors' institution but also in the literature. The authors describe four patients who presented with various clinical features and different genetic pedigree penetration.