RESUMO
Metachondromatosis is a rare disorder of autosomal inheritance with incomplete penetrance, which is characterized by formation of osteochondroma and enchondroma, caused by loss of function of the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene. Diagnosis is made based on the distribution and orientation of lesions with history of regression of lesions with time and confirmed by genetic mutation of PTPN11 gene. We report a rare case of a 24-year-old male with Alport's syndrome with metachondromatosis due to missense variation in PTPN11 gene.
Assuntos
Neoplasias Ósseas/genética , Condromatose/genética , Colágeno Tipo IV/genética , Exostose Múltipla Hereditária/genética , Mutação , Nefrite Hereditária/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Sítios de Splice de RNA , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/enzimologia , Condromatose/diagnóstico , Condromatose/enzimologia , Análise Mutacional de DNA , Exostose Múltipla Hereditária/diagnóstico , Exostose Múltipla Hereditária/enzimologia , Predisposição Genética para Doença , Hemizigoto , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Nefrite Hereditária/diagnóstico , Fenótipo , Fatores de Risco , Adulto JovemRESUMO
We used exome sequencing of blood DNA in four unrelated patients to identify the genetic basis of metaphyseal chondromatosis with urinary excretion of D-2-hydroxy-glutaric acid (MC-HGA), a rare entity comprising severe chondrodysplasia, organic aciduria, and variable cerebral involvement. No evidence for recessive mutations was found; instead, two patients showed mutations in IDH1 predicting p.R132H and p.R132S as apparent somatic mosaicism. Sanger sequencing confirmed the presence of the mutation in blood DNA in one patient, and in blood and saliva (but not in fibroblast) DNA in the other patient. Mutations at codon 132 of IDH1 change the enzymatic specificity of the cytoplasmic isocitrate dehydrogenase enzyme. They result in increased D-2-hydroxy-glutarate production, α-ketoglutarate depletion, activation of HIF-1α (a key regulator of chondrocyte proliferation at the growth plate), and reduction of N-acetyl-aspartyl-glutamate level in glial cells. Thus, somatic mutations in IDH1 may explain all features of MC-HGA, including sporadic occurrence, metaphyseal disorganization, and chondromatosis, urinary excretion of D-2-hydroxy-glutaric acid, and reduced cerebral myelinization.