RESUMO
We report a patient with a clinical and molecular diagnosis of LEOPARD syndrome (LS) associated with multiple granular cell tumors (MGCT). Bidirectional sequencing of exons 7, 12, and 13 of the PTPN11 gene revealed the T468M missense mutation in exon 12. This mutation has been previously reported in patients with LS. To our knowledge, this is the first report of MGCT associated with molecularly characterized LS and provides the first molecular evidence linking granular cell tumors (GCT) to the Ras/mitogen-activated protein (MAP) kinase pathway. We propose that MGCT can be associated with LS. Analysis of GCT from this case tested negatively for loss of heterozygosity (LOH) at the PTPN11 and NF1 loci and did not show deletions of the PTEN gene. The absence of LOH of PTPN11 supports published functional data that T468M is a dominant-negative mutation.
Assuntos
Tumor de Células Granulares/genética , Síndrome LEOPARD/genética , Mutação de Sentido Incorreto , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Adulto , Análise Mutacional de DNA , Feminino , Tumor de Células Granulares/etiologia , Humanos , Síndrome LEOPARD/complicações , Perda de HeterozigosidadeAssuntos
Testes Genéticos/normas , Garantia da Qualidade dos Cuidados de Saúde/normas , Canadá , Participação da Comunidade , Privacidade Genética/organização & administração , Privacidade Genética/normas , Humanos , Marketing de Serviços de Saúde/normas , Papel do Médico , Guias de Prática Clínica como Assunto , Saúde Pública/normas , Garantia da Qualidade dos Cuidados de Saúde/organização & administraçãoRESUMO
Sensorineural hearing loss (SNHL) is the most common inherited sensory disorder, reported in 1-3 of every 1,000 births. It has been estimated that 50% of all cases of prelingual SNHL are genetically determined. There is tremendous genetic heterogeneity, with multiple dominant and recessive loci. Mutations of the gap junction beta-2 gene (GJB2) emerge as a leading cause of autosomal recessive non-syndromic SNHL. Over 90 sequence alterations have been reported, the pathogenicity of some of them being unknown or unclear. The status of the V37I allele of connexin 26 (GJB2 amino acid product) with regards to its association with SNHL has been controversial. This study examines the pathogenicity of V37I by comparing the frequency of this allele in 40 patients with SNHL of Chinese and Caucasian descent with the frequency of the allele in 100 anonymized, ethnically matched controls. The V37I allele was identified in 43.75 and 11.5% of the patient and control alleles of Chinese ethnicity, respectively, but was not found in either Caucasian cohort. We also compiled the audiograms of 15 individuals with SNHL homozygous for the V37I allele, and showed that these individuals present with a mild to moderate SNHL. These results indicate that (1) the V37I allele is common in individuals of Chinese descent but rarely present in individuals of Caucasian decent; and (2) the V37I allele is pathogenic, but produces milder hearing loss compared to nonsense mutations of connexin 26 such as the 35delG mutation.