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1.
Klin Padiatr ; 231(2): 80-86, 2019 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-30870874

RESUMO

Recurrent myocarditis is rare with only few reports having been published for paediatric cases. Repeated use of extracorporeal membrane oxygenation is also uncommon. In this paper we will present a very rare case of a 7-year old girl with recurrent fulminant myocarditis with heart failure requiring cardiopulmonary resuscitation and mechanical circulatory support with extracorporeal membrane oxygenation. Both episodes were precipitated by a viral upper respiratory tract infection, and in both cases the cardiac function eventually completely recovered. The second episode of fulminant myocarditis was particularly complex with markedly elevated markers of myocardiocytolysis, multiorgan dysfunction and the need for prolonged mechanical circulatory support. Nevertheless, the patient made a remarkable recovery. A comprehensive diagnostic workup pointed towards an aberrant immune response as the likely cause of the girl's susceptibility for fulminant myocarditis.


Assuntos
Reanimação Cardiopulmonar , Oxigenação por Membrana Extracorpórea/métodos , Insuficiência Cardíaca/terapia , Miocardite/terapia , Criança , Feminino , Coração Auxiliar , Humanos , Pediatria/métodos , Resultado do Tratamento
2.
PLoS One ; 13(1): e0188578, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29293505

RESUMO

Hereditary hearing loss (HL) is a common sensory disorder, with an incidence of 1-2 per 1000 newborns, and has a genetic etiology in over 50% of cases. It occurs either as part of a syndrome or in isolation and is genetically very heterogeneous which poses a challenge for clinical and molecular diagnosis. We used exome sequencing to seek a genetic cause in a group of 56 subjects (49 probands) with HL: 32 with non-syndromic non-GJB2 HL and 17 with syndromic HL. Following clinical examination and clinical exome sequencing, an etiological diagnosis was established in 15 probands (15/49; 30%); eight (8/17;47%) from the syndromic group and seven (7/32; 21%) from the non-syndromic non-GJB2 subgroup. Fourteen different (half of them novel) non-GJB2 variants causing HL were found in 10 genes (CHD7, HDAC8, MITF, NEFL, OTOF, SF3B4, SLC26A4, TECTA, TMPRSS3, USH2A) among 13 probands, confirming the genetic heterogeneity of hereditary HL. Different genetic causes for HL were found in a single family while three probands with apparent syndromic HL were found to have HL as a separate clinical feature, distinct from the complex phenotype. Clinical exome sequencing proved to be an effective tool used to comprehensively address the genetic heterogeneity of HL, to detect clinically unrecognized HL syndromes, and to decipher complex phenotypes in which HL is a separate feature and not part of a syndrome.


Assuntos
Perda Auditiva/genética , Sequenciamento Completo do Exoma , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Genótipo , Perda Auditiva/diagnóstico , Humanos , Masculino , Fenótipo , Síndrome , Adulto Jovem
3.
Am J Hum Genet ; 101(5): 844-855, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100094

RESUMO

A series of simplex cases have been reported under various diagnoses sharing early aging, especially evident in congenitally decreased subcutaneous fat tissue and sparse hair, bone dysplasia of the skull and fingers, a distinctive facial gestalt, and prenatal and postnatal growth retardation. For historical reasons, we suggest naming the entity Fontaine syndrome. Exome sequencing of four unrelated affected individuals showed that all carried the de novo missense variant c.649C>T (p.Arg217Cys) or c.650G>A (p.Arg217His) in SLC25A24, a solute carrier 25 family member coding for calcium-binding mitochondrial carrier protein (SCaMC-1, also known as SLC25A24). SLC25A24 allows an electro-neutral and reversible exchange of ATP-Mg and phosphate between the cytosol and mitochondria, which is required for maintaining optimal adenine nucleotide levels in the mitochondrial matrix. Molecular dynamic simulation studies predict that p.Arg217Cys and p.Arg217His narrow the substrate cavity of the protein and disrupt transporter dynamics. SLC25A24-mutant fibroblasts and cells expressing p.Arg217Cys or p.Arg217His variants showed altered mitochondrial morphology, a decreased proliferation rate, increased mitochondrial membrane potential, and decreased ATP-linked mitochondrial oxygen consumption. The results suggest that the SLC25A24 mutations lead to impaired mitochondrial ATP synthesis and cause hyperpolarization and increased proton leak in association with an impaired energy metabolism. Our findings identify SLC25A24 mutations affecting codon 217 as the underlying genetic cause of human progeroid Fontaine syndrome.


Assuntos
Envelhecimento/genética , Antiporters/genética , Doenças do Desenvolvimento Ósseo/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas Mitocondriais/genética , Mutação/genética , Adenina/metabolismo , Trifosfato de Adenosina/metabolismo , Citosol/metabolismo , Feminino , Morte Fetal , Fibroblastos/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Potencial da Membrana Mitocondrial/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Simulação de Dinâmica Molecular , Oxigênio/metabolismo , Fosfatos/metabolismo , Síndrome
4.
Hum Mutat ; 38(11): 1477-1484, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28726266

RESUMO

Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period.


Assuntos
Artrogripose/diagnóstico , Artrogripose/genética , Genes Letais , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Artrogripose/mortalidade , Biópsia , Análise Mutacional de DNA , Evolução Fatal , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Raízes Nervosas Espinhais/ultraestrutura , Sequenciamento Completo do Exoma
6.
Cell ; 168(5): 830-842.e7, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28235197

RESUMO

De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.


Assuntos
Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Doenças Genéticas Inatas/embriologia , Doenças Genéticas Inatas/genética , Instabilidade Genômica , Mutação , Pontos de Quebra do Cromossomo , Duplicação Cromossômica , Replicação do DNA , Desenvolvimento Embrionário , Feminino , Gametogênese , Humanos , Masculino
7.
BMC Med Genet ; 17(1): 81, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27846804

RESUMO

BACKGROUND: The objective of reported study was to evaluate the clinical utility of prenatal microarray testing for submicroscopic genomic imbalances in routine prenatal settings and to stratify the findings according to the type of fetal ultrasound anomaly. METHODS: From July 2012 to October 2015 chromosomal microarray testing was performed in 218 fetuses with varying indications for invasive prenatal diagnosis: abnormal karyotype, ultrasound anomalies, pathogenic variant in previous pregnancy or carriership in a parent. RESULTS: The detection rate in the group of fetuses with ultrasound anomalies was 10,0% for pathogenic copy number variants (CNVs), five of them being larger than 8 Mb and expected to be seen on prenatal karyotype. If only those pathogenic CNVs below the classical karyotype resolution are considered, chromosomal microarray testing provided an additional 7,7% diagnostic yield in here reported series. When stratified according to the ultrasound anomalies, the highest percentage of pathogenic CNVs were detected in the group of fetuses with multiple congenital anomalies (16,7%) and lowest in the group of isolated in utero growth restriction (6,3%). In the group of cases with isolated increased nuchal translucency we identified a small interstitial deletion of 16p24.1 involving FOXF1 gene. Prenatal aCGH also provided important insights into cases with seemingly balanced chromosomal rearrangements found on prenatal karyotype, where additional pathogenic CNV were discovered. CONCLUSION: Prenatal chromosomal microarray testing significantly increases the diagnostic yield when compared with conventional karyotyping. The highest added value is shown in prenatal diagnostics in fetuses with abnormal ultrasound results. Variants of unknown significance and risk factor CNVs present important challenges and should be discussed with parents in advance, therefore pretest counseling prior to prenatal testing is very important.


Assuntos
Anormalidades Múltiplas/genética , Hibridização Genômica Comparativa/métodos , Anormalidades Múltiplas/patologia , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Cariótipo , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Diagnóstico Pré-Natal , Ultrassonografia Pré-Natal
8.
Ther Apher Dial ; 20(3): 318-21, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27312922

RESUMO

Hajdu-Cheney syndrome (HJCYS) is a rare, autosomal dominant, skeletal disorder caused by mutations in the NOTCH2 signaling pathway for which genetic testing has recently become available. Renal abnormalities are associated in at least 10% of cases. We present an 8-year-old Caucasian boy, born with multiple dysmorphic features consistent with HJCYS. Imaging of the urinary tract revealed bilateral cystic dysplastic kidneys with associated vesicoureteral reflux. Renal function has been impaired since birth and deteriorated progressively to end-stage renal disease (ESRD) by the age of two and a half years, when peritoneal dialysis was initiated and only recently renal transplantation was performed. Additional congenital abnormalities and multisystem involvement in HJCYS further complicated management, and he developed refractory anemia. Molecular diagnosis was confirmed by identification of a truncating mutation in exon 34 of NOTCH2. Although, renal abnormalities are considered an integral part of the HJCYS, published reports on ESRD are scarce. In those few published cases, where ESRD was recognized, renal failure developed either in late adolescence or adulthood. This is the first report of early ESRD occurring in a child. Patients with HJCYS may need chronic renal replacement therapy even in early childhood. The management of these children can be challenging given the multisystemic manifestations of HJCYS.


Assuntos
Síndrome de Hajdu-Cheney/fisiopatologia , Falência Renal Crônica/etiologia , Receptor Notch2/genética , Criança , Progressão da Doença , Éxons , Síndrome de Hajdu-Cheney/diagnóstico , Síndrome de Hajdu-Cheney/genética , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/genética , Masculino , Mutação
9.
Genet Med ; 18(11): 1102-1110, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27031083

RESUMO

PURPOSE: Genome-wide sequencing approaches are increasingly being used in place of disease gene panel sequencing approaches. Despite the well-recognized benefits of these approaches, they also carry with them an increased burden of analyzing overwhelmingly large gene targets and an increased possibility of detecting incidental findings. METHODS: We propose a novel approach for design of individualized phenotype gene panels using the set of signs and symptoms observed and selecting relevant genes on the basis of known phenotype-gene associations. RESULTS: We used results of diagnostic exome sequencing in 405 cases submitted to our institution to show retrospectively that using the phenotype gene panel increases the sensitivity of masked exome analysis (increase from 25.4 to 29.7% in overall diagnostic yield). We also show that such a strategy enables the possibility of masked analysis of genome-wide sequencing data in patients with poorly defined and multifaceted clinical presentations. Ultimately, we show that this approach enables control over the incidental findings rate (0.25% in phenotype gene panels). Finally, we provide a Web tool for customized phenotype panel creation (available at http://www.kimg.eu/generator). CONCLUSION: In conclusion, we present a novel approach to a phenotype-driven diagnostic process of genome scale sequencing data that harnesses the sensitivity of these approaches while restricting the analysis to genes relevant to clinical presentation in patient.Genet Med 18 11, 1102-1110.


Assuntos
Exoma/genética , Marcação de Genes/métodos , Estudos de Associação Genética , Genoma Humano , Feminino , Variação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Achados Incidentais , Masculino , Análise de Sequência de DNA
10.
Am J Med Genet A ; 170(6): 1573-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27028100

RESUMO

Thanatophoric dysplasia is a type of short-limbed neonatal dwarfism that is usually lethal in the perinatal period. It is characterized by short limbs, a narrow, bell-shaped thorax, macrocephaly with a prominent forehead, and flattened vertebral bodies. These malformations result from autosomal dominant mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. In this report, we describe a novel FGFR3 insertion mutation in a fetus with shortened limbs, curved femurs, and a narrow thorax. The diagnosis of thanatophoric dysplasia type 1 was suspected clinically, and FGFR3 sequencing showed a c.742_743insTGT variant, which predicts p.R248delinsLC. In vivo studies in zebrafish demonstrated that this mutation resulted in the overexpression of zebrafish Fgfr3, leading to the over-activation of downstream signaling and dorsalized embryos. To date, no insertions or deletions in FGFR3 have been reported to cause thanatophoric dysplasia types 1 or 2; therefore, this represents the first report to describe such a mutation. © 2016 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Mutagênese Insercional , Fenótipo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/deficiência , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Displasia Tanatofórica/diagnóstico , Displasia Tanatofórica/genética , Aborto Induzido , Alelos , Animais , Autopsia , Éxons , Feminino , Feto , Expressão Gênica , Genótipo , Humanos , Mutação , Gravidez , Peixe-Zebra
11.
Eur J Paediatr Neurol ; 19(2): 251-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25557349

RESUMO

BACKGROUND: Recent studies have shown that recessive mutations in the TBC1D24 gene cause a variety of epilepsy syndromes, DOORS syndrome and nonsyndromic deafness. METHODS/RESULTS: We report on two siblings with hypotonia, early-onset epileptic encephalopathy, and severe developmental delay. The patients presented with clonic and myoclonic jerks within 1 h after birth. The seizures were resistant to treatment. Audiologic examination showed bilateral sensorineural hearing loss in both siblings. Genetic analysis revealed compound heterozygous mutations in the TBC1D24 gene: a novel missense mutation c.32A > G (p.Asp11Gly) in exon 2 and a frameshift mutation c.1008delT (p.His336Glnfs*12) in exon 4. CONCLUSION: This report supports previous observations that mutations in TBC1D24 cause diverse phenotypes. In fact, early-onset epileptic encephalopathy with sensorineural hearing loss is an additional phenotype observed in patients with recessive TBC1D24 mutations.


Assuntos
Encefalopatias/genética , Proteínas de Transporte/genética , Epilepsia/genética , Mutação/genética , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/etiologia , Eletroencefalografia , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/etiologia , Epilepsia Tônico-Clônica/complicações , Epilepsia Tônico-Clônica/etiologia , Evolução Fatal , Feminino , Mutação da Fase de Leitura/genética , Genes Recessivos/genética , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/genética , Humanos , Lactente , Recém-Nascido , Masculino , Hipotonia Muscular/complicações , Hipotonia Muscular/etiologia , Mutação de Sentido Incorreto/genética , Irmãos
12.
Neurology ; 81(11): 992-8, 2013 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-23935176

RESUMO

OBJECTIVE: We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs). METHODS: We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara syndrome (OS) and 150 with West syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing. RESULTS: We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay. CONCLUSIONS: Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.


Assuntos
Encéfalo/patologia , Encéfalo/fisiopatologia , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Espasmos Infantis , Eletroencefalografia , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Espasmos Infantis/genética , Espasmos Infantis/patologia , Espasmos Infantis/fisiopatologia
13.
Am J Med Genet A ; 161A(7): 1682-5, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23687080

RESUMO

The chromosome 6p21.3 microdeletion phenotype was recently identified through array comparative genomic hybridization. The main features are developmental delay with severe speech impairment, seizures, and behavioral abnormalities. Three patients have been reported with deletion sizes ranging from 100 to 800 kb. We report on a 9-year-old boy with an apparently de novo, 50 kb deletion, and global developmental delay, severe speech impairment, and generalized epilepsy well-controlled by medication. There were four genes identified in this deletion, of which SYNGAP1 is considered to be responsible for speech impairment and epilepsy. We compared the clinical features of this patient with previously reported patients with 6p21.3 and patients with SYNGAP1 mutations. © 2013 Wiley Periodicals, Inc.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 6 , Epilepsia/genética , Deficiência Intelectual/genética , Distúrbios da Fala/genética , Proteínas Ativadoras de ras GTPase/genética , Criança , Deficiências do Desenvolvimento/genética , Epilepsia/tratamento farmacológico , Humanos , Masculino
14.
Epilepsia ; 53(6): e106-10, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22429196

RESUMO

Recent study has shown that mutations in the alpha-II-spectrin (SPTAN1) gene cause early onset intractable seizures, severe developmental delay, diffuse hypomyelination, and widespread brain atrophy. We report a Slovene girl with hypotonia, lack of visual attention, early onset epileptic encephalopathy, and severe developmental delay. The patient presented with segmental myoclonic jerks at the age of 6 weeks, and infantile spasms at the age of 3.5 months. Her seizures were resistant to treatment. Multiple electroencephalography recordings showed deterioration of the background activity, followed by multifocal abnormalities before progressing to hypsarrhythmia. Ophthalmologic examination revealed bilateral dysplastic, coloboma-like optic discs. Brain magnetic resonance imaging showed diffusely reduced white matter and brainstem volumes with hypomyelination. A de novo heterozygous in-frame deletion was detected in SPTAN1: c.6619_6621delGAG (p.E2270del). This report supports the causative relationship between SPTAN1 mutations and early onset intractable seizures with severe hypomyelination and widespread brain volume reduction. Coloboma-like optic discs might be an additional feature observed in patients with SPTAN1 mutations.


Assuntos
Proteínas de Transporte/genética , Doenças Desmielinizantes/etiologia , Proteínas dos Microfilamentos/genética , Mutação/genética , Doenças do Nervo Óptico/etiologia , Doenças do Nervo Óptico/patologia , Espasmos Infantis , Doenças Desmielinizantes/patologia , Eletroencefalografia , Feminino , Angiofluoresceinografia , Humanos , Lactente , Imagem por Ressonância Magnética , Bainha de Mielina/patologia , Doenças do Nervo Óptico/genética , Espasmos Infantis/complicações , Espasmos Infantis/genética , Espasmos Infantis/patologia
15.
Brain ; 134(Pt 1): 143-56, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20952379

RESUMO

Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.


Assuntos
Arginina-tRNA Ligase/genética , Encéfalo/patologia , Endorribonucleases/genética , Adolescente , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Imagem por Ressonância Magnética , Masculino , Mutação , Atrofias Olivopontocerebelares/genética , Atrofias Olivopontocerebelares/patologia
18.
Am J Med Genet A ; 143A(21): 2612-5, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17935252

RESUMO

We report on a family with LEOPARD syndrome which was molecularly proven (p.Thr468Met in PTPN11) in a father and his adult son. The father had multiple lentigines dispersed equally over his body; the son was similarly affected except for the left part of thorax, back and left arm, which were completely devoid of lentigines and only showed a few nevi. In addition, the son was found to have a mosaic karyotype, 47,XYY/46,XY, in lymphocytes. Skin biopsies from the pigmented and unpigmented forearm showed that mainly a 47,XYY karyotype was present in the pigmented skin and mainly a 46,XY karyotype in the unpigmented skin. In both fibroblast cultures the PTPN11 mutation was present, and no additional mutation could be detected. We discuss the various possible explanations for this phenotype, which include the possibility of coincidence; revertant mosaicism; silencing of a second PTPN11 mutation; gene(s) located on a sex chromosome influencing the phenotype; and epigenetic influences. We favor that the co-occurrence of a sex chromosome mosaicism and mosaicism for skin symptoms in a single patient with LEOPARD syndrome is coincidence, but that mosaicism for LEOPARD skin symptoms in itself may well be more frequent and needs additional studies. Each of the above-hypothesized mechanisms may then remain possible.


Assuntos
Síndrome LEOPARD/genética , Mosaicismo , Pele/patologia , Cariótipo XYY/genética , Adolescente , Humanos , Síndrome LEOPARD/diagnóstico , Masculino , Mutação Puntual , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética
19.
Eur J Med Genet ; 50(5): 338-45, 2007 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17684005

RESUMO

Immune deficiency can be part of CHARGE syndrome but often receives only limited attention. We present two patients with CHARGE syndrome confirmed CHD7 mutations who had severe T-cell deficiency, and review 15 CHARGE patients from the literature with immunological problems. Most of them had severe T-cell deficiency, although the spectrum also included mild T-cell deficiency and isolated humoral immune deficiency. We conclude that immunodeficiency can form an important symptom in CHARGE syndrome although the frequency and exact nature are still insufficiently known. We propose to evaluate immune functions in all CHARGE syndrome patients, to estimate the frequency and nature of the accompanying immunodeficiency, and to obtain better data regarding prognosis and management.


Assuntos
Anormalidades Múltiplas/imunologia , Anormalidades Múltiplas/genética , Atresia das Cóanas/genética , Atresia das Cóanas/imunologia , Códon sem Sentido , Coloboma/genética , Coloboma/imunologia , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Transtornos do Crescimento/genética , Transtornos do Crescimento/imunologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/imunologia , Humanos , Recém-Nascido , Masculino , Fenótipo , Síndrome , Linfócitos T/imunologia
20.
Fertil Steril ; 84(5): 1522-5, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16275261

RESUMO

The aim of the study was to define the relevance of deletions and duplications within the DAZ gene cluster to male factor infertility in a population of 90 infertile men and a control of 50 fertile men using real-time polymerase chain reaction (PCR). We conclude that partial deletions of the DAZ genes are associated with oligozoospermia but not with azoospermia; however, an increased number of DAZ genes does not seem to be a statistically significant risk factor for spermatogenic failure.


Assuntos
Dosagem de Genes/genética , Infertilidade Masculina/genética , Proteínas de Ligação a RNA/genética , Cromossomos Humanos Y/genética , Proteína 1 Suprimida em Azoospermia , Deleção de Genes , Duplicação Gênica , Alemanha , Humanos , Masculino , Família Multigênica/genética
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