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1.
Hum Mutat ; 40(12): 2270-2285, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31206972

RESUMO

Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC.

2.
Prenat Diagn ; 38(1): 33-43, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29096039

RESUMO

OBJECTIVE: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. METHOD: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. RESULTS: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. CONCLUSION: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.


Assuntos
Anormalidades Congênitas/genética , Doenças Genéticas Inatas/diagnóstico , Pais , Diagnóstico Pré-Natal/métodos , Sequenciamento Completo do Exoma , Feminino , Genes Recessivos , Humanos , Masculino , Gravidez
3.
Am J Hum Genet ; 101(6): 1021-1033, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29220674

RESUMO

ACTB encodes ß-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, ß-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic ß-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, ß-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.


Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Deficiências do Desenvolvimento/genética , Haploinsuficiência/genética , Actinas/biossíntese , Adolescente , Adulto , Idoso , Animais , Ciclo Celular/genética , Proliferação de Células/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Coloboma/genética , Facies , Feminino , Mutação da Fase de Leitura/genética , Deleção de Genes , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Malformações do Desenvolvimento Cortical/genética , Camundongos , Interferência de RNA , RNA Interferente Pequeno/genética , Adulto Jovem
4.
Am J Med Genet A ; 173(10): i, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28921853

RESUMO

The cover image, by Rani A. Bashir et al., is based on the Original Article Lin-Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders, DOI: 10.1002/ajmg.a.38355.


Assuntos
Craniossinostoses/patologia , Histona Acetiltransferases/genética , Mutação , Fenótipo , Craniossinostoses/genética , Humanos , Síndrome
5.
Am J Med Genet A ; 173(10): 2596-2604, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28696035

RESUMO

We report two patients with sagittal craniosynostosis, hypoplastic male genitalia, agenesis of the corpus callosum, thyroid abnormalities, and dysmorphic features which include short palpebral fissures and retrognathia. The clinical presentation of both patients was initially thought to be suggestive of Lin-Gettig syndrome (LGS), a multiple malformation syndrome associated with craniosynostosis that was initially reported in two brothers in 1990, with a third patient reported in 2003. Our first patient was subsequently found through exome sequencing to have a de novo mutation in KAT6B, c.4572dupT, p.(Thr1525Tyrfs*16). The second patient was ascertained as possible LGS, but KAT6B mutation testing was pursued clinically after the identification of the KAT6B mutation in Patient 1, and identified a de novo mutation, c.4205_4206delCT, p.(Ser1402Cysfs*5). The phenotypic spectrum of KAT6B mutations has been expanding since identification of KAT6B mutations in genitopatellar syndrome (GPS) and Say Barber Biesecker Young Simpson (SBBYS) syndrome patients. We show that craniosynostosis, which has not been previously reported in association with KAT6B mutations, may be part of the genitopatellar/Say Barber Biesecker Young Simpson spectrum. These two patients also further demonstrate the overlapping phenotypes of genitopatellar and SBBYS syndromes recently observed by others. Furthermore, we propose that it is possible that one or more of the previous cases of LGS may have also been due to mutation in KAT6B, and that LGS may actually be a variant within the KAT6B spectrum and not a distinct clinical entity.


Assuntos
Craniossinostoses/genética , Craniossinostoses/patologia , Histona Acetiltransferases/genética , Mutação , Fenótipo , Adulto , Humanos , Lactente , Recém-Nascido , Masculino , Síndrome
6.
Am J Med Genet A ; 173(10): 2731-2735, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28696078

RESUMO

Weaver syndrome is a rare overgrowth syndrome with distinct facial features in young children and variable learning disability. Heterozygous missense mutations in EZH2 are present in over 90% of patients with Weaver syndrome but the exact mechanism by which EZH2 mutations cause Weaver syndrome is unknown. We report an 11-year-old boy with a de novo 1.2-Mb deletion at 7q36.1 including EZH2 who has tall stature, significant intellectual disability, and some physical features of Weaver syndrome. Emerging evidence in the literature indicates that Weaver syndrome EZH2 mutations may result in loss of function of the gene and our report suggests that haploinsufficiency of EZH2 may replicate the clinical phenotype of Weaver syndrome.


Assuntos
Estatura/genética , Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Haploinsuficiência , Deficiência Intelectual/genética , Adulto , Criança , Feminino , Humanos , Masculino , Fenótipo
8.
Am J Hum Genet ; 98(5): 981-992, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27108798

RESUMO

Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions.


Assuntos
Aniridia/etiologia , Aniridia/patologia , Ataxia Cerebelar/etiologia , Ataxia Cerebelar/patologia , Genes Dominantes/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Deficiência Intelectual/etiologia , Deficiência Intelectual/patologia , Mutação/genética , Adolescente , Adulto , Animais , Células Cultivadas , Criança , Feminino , Humanos , Receptores de Inositol 1,4,5-Trifosfato/química , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Camundongos , Microscopia Confocal , Pessoa de Meia-Idade , Linhagem , Conformação Proteica
9.
Pract Neurol ; 16(2): 111-21, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26864574

RESUMO

Identifying the underlying cause of epilepsy often helps in choosing the appropriate management, suggests the long-term prognosis and clarifies the risk of the same condition in relatives. Epilepsy has many causes and a small but significant proportion of affected people have an identifiable genetic cause. Here, we discuss the role of genetic testing in adults with epilepsy, focusing on dysmorphic features noticeable on physical examination that might provide a strong clue to a specific genetic syndrome. We give illustrative examples of recognisable facial 'gestalt'. An astute clinician can recognise such clues and significantly shorten the process of making the underlying diagnosis in their patient.


Assuntos
Epilepsia/diagnóstico , Epilepsia/genética , Face/anormalidades , Feminino , Testes Genéticos , Humanos , Masculino , Síndrome
10.
Pediatr Nephrol ; 31(12): 2257, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-26891726

RESUMO

A case is presented of a neonate born at 32 weeks of gestation with intra-uterine growth retardation. The renal scan performed at 31 weeks showed oligohydramnios but normal kidneys. The neonate was oliguric from birth and required early peritoneal dialysis. Her urine showed heavy proteinuria, and the plasma albumin was very low. Post-natal ultrasonography showed large bright kidneys with reduced corticomedullary differentiation but no dysplastia; arterial and venous flow was normal on Doppler ultrasound. The quiz discusses the differential diagnosis with particular reference to whether this picture represents acute kidney injury with expected improvement or chronic kidney disease. Further questions discuss mechanisms of renal failure in this situation. Finally, with reference to previous case reports and series, a correlation between a specific mutation and this severe phenotype is proposed.


Assuntos
Lesão Renal Aguda/complicações , Insuficiência Renal Crônica/complicações , Insuficiência Renal/congênito , Lesão Renal Aguda/diagnóstico por imagem , Consanguinidade , Diagnóstico Diferencial , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Humanos , Recém-Nascido , Rim/diagnóstico por imagem , Gravidez , Insuficiência Renal/diagnóstico por imagem , Insuficiência Renal/etiologia , Insuficiência Renal Crônica/diagnóstico por imagem
12.
Eur J Hum Genet ; 24(5): 652-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26306646

RESUMO

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.


Assuntos
Anormalidades Múltiplas/diagnóstico , Deficiência Intelectual/diagnóstico , Proteínas Nucleares/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade
14.
Orphanet J Rare Dis ; 9: 23, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24524299

RESUMO

BACKGROUND: Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1. METHODS: We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed. RESULTS: EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele. CONCLUSIONS: EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.


Assuntos
Complexo Multienzimático de Ribonucleases do Exossomo/genética , Atrofias Olivopontocerebelares/genética , Proteínas de Ligação a RNA/genética , Encéfalo/patologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Mutação
15.
J Assist Reprod Genet ; 30(9): 1133-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23934021

RESUMO

PURPOSE: To investigate the association of Progesterone Receptor (PR) gene variations and male infertility METHODS: DNA extraction, PCR and sequencing of PR gene, PROGINS insertion by PCR. Association of the variations with seminal parameters and outcomes of ICSI. RESULTS: Four known SNPs in the PR gene were identified in the study of which three (rs3740753, rs1042838, rs104283) were co-inherited and in complete linkage disequilibrium with the PROGINS Alu insertion. There were no differences in their frequencies between fertile and infertile males. The rs2020880 was found at a very low frequency only in the controls but not in the infertile subjects. The sperm counts, fertilization rate, embryo quality or pregnancy rates were not different in individuals with or without PROGINS allele. CONCLUSION: PR gene alterations are not associated with male infertility or ICSI outcome.


Assuntos
Estudos de Associação Genética , Infertilidade Masculina/genética , Receptores de Progesterona/genética , Injeções de Esperma Intracitoplásmicas , Alelos , Feminino , Frequência do Gene , Humanos , Mutação INDEL/genética , Desequilíbrio de Ligação , Masculino , Gravidez , Taxa de Gravidez
16.
Am J Med Genet A ; 161A(10): 2588-93, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23918704

RESUMO

Deficiency of carbohydrate sulfotransferase 3 (CHST3; also known as chondroitin-6-sulfotranferase) has been associated with a phenotype of severe chondrodysplasia and progressive spinal involvement. Recent reports indicate that affected individuals initially present with neonatal multiple joint dislocations. We describe a 14-year-old Somali patient and her 3-year-old maternal half-brother with novel homozygous CHST3 mutations. The proband presented at the age 5½ years with short stature and genua valga. Her clinical course was characterized by rapid progression of spinal deformities and large joint contractures. Her half-brother presented at birth with bilateral knee dislocation and talipes equinovarus. This report of a Somali family with CHST3-related chondrodysplasia illustrates the intrafamilial variability in phenotypic expression of this rare disorder. © 2013 Wiley Periodicals, Inc.


Assuntos
Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Fenótipo , Irmãos , Sulfotransferases/genética , Adolescente , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , Mutação , Somália
17.
Hum Mutat ; 34(3): 462-72, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23255504

RESUMO

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed "radial spoke defect." We sequenced CCDC39 and CCDC40 in 54 "radial spoke defect" families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice, and frameshift predicting early protein truncation, which suggests this defect is caused by "null" alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganization and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as "IDA and microtubular disorganisation defect," rather than "radial spoke defect."


Assuntos
Axonema/genética , Dineínas/genética , Síndrome de Kartagener/genética , Mutação , Proteínas/genética , Alelos , Axonema/patologia , Cílios/genética , Cílios/patologia , Proteínas do Citoesqueleto/genética , Exoma , Feminino , Imunofluorescência , Humanos , Masculino , Microscopia Eletrônica , Linhagem , Fenótipo
18.
Am J Med Genet A ; 158A(9): 2317-21, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22887843

RESUMO

Deletions of 17q12 are associated with renal cysts and maturity onset diabetes of the young, and have also been identified in women with reproductive tract anomalies due to Mullerian aplasia. Although initially identified in patients with normal cognitive ability, some patients with this recurrent microdeletion syndrome have learning problems. We identified a 17q12 microdeletion in three patients with renal cystic disease by array comparative genomic hybridization and the phenotypic spectrum of the 17q12 microdeletion syndrome is illustrated by the description of these patients. Of two patients who are old enough to be assessed, one has significant speech delay, autism spectrum disorder, and mild learning difficulty, while the other patient has only mild speech delay. This highlights the variability of cognitive involvement in this condition. The third patient presented with Alagille syndrome-like features in the neonatal period. All three patients had transient hypercalcemia in the neonatal period, a finding that has not previously been described in this condition. Moreover, two patients have mild or no dysmorphism, while one displays striking facial dysmorphism in addition to minor congenital anomalies. We suggest that while patients with 17q12 microdeletion syndrome can present with type 2 diabetes or renal cysts without any dysmorphic features, a subgroup may have dysmorphic features or present with neonatal cholestasis. Transient neonatal hypercalcemia may be a feature of this microdeletion syndrome.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17 , Pré-Escolar , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Fenótipo , Síndrome
19.
Pediatr Neurol ; 45(5): 347-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22000320

RESUMO

"Triple A" syndrome is a rare, autosomal recessive condition whose main clinical features are alacrima, achalasia, and adrenal failure. Most patients also develop some neurologic abnormalities. We describe an 11-year-old boy with triple A syndrome who presented with progressive axonal motor neuropathy. Molecular analysis revealed compound heterozygous mutations in the AAAS gene, confirming the clinical diagnosis. The clinical presentation of patients with triple A syndrome is variable. Our patient manifested neurologic problems during early childhood, before other features of this condition were apparent. We highlight the neurologic presentation of this multisystem disorder. In the presence of complex axonal neuropathy, other features of this condition should be sought.


Assuntos
Insuficiência Adrenal/complicações , Insuficiência Adrenal/diagnóstico , Acalasia Esofágica/complicações , Acalasia Esofágica/diagnóstico , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/diagnóstico , Criança , Humanos , Masculino , Exame Neurológico/métodos , Síndrome
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