RESUMO
BACKGROUND: Geleophysic dysplasia (GD, OMIM 231050) is an autosomal recessive disorder characterised by short stature, small hands and feet, stiff joints, and thick skin. Patients often present with a progressive cardiac valvular disease which can lead to an early death. In a previous study including six GD families, we have mapped the disease gene on chromosome 9q34.2 and identified mutations in the A Disintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2). METHODS: Following this study, we have collected the samples of 30 additional GD families, including 33 patients and identified ADAMTSL2 mutations in 14/33 patients, comprising 13 novel mutations. The absence of mutation in 19 patients prompted us to compare the two groups of GD patients, namely group 1, patients with ADAMTSL2 mutations (n=20, also including the 6 patients from our previous study), and group 2, patients without ADAMTSL2 mutations (n=19). RESULTS: The main discriminating features were facial dysmorphism and tip-toe walking, which were almost constantly observed in group 1. No differences were found concerning heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngo-tracheal stenosis, deafness, and radiographic features. CONCLUSIONS: It is concluded that GD is a genetically heterogeneous condition. Ongoing studies will hopefully lead to the identification of another disease gene.
Assuntos
Nanismo/genética , Proteínas da Matriz Extracelular , Anormalidades do Olho/genética , Anormalidades da Pele/genética , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo , Criança , Pré-Escolar , Tecido Conjuntivo/anormalidades , Tecido Conjuntivo/patologia , Tecido Conjuntivo/fisiopatologia , Nanismo/etnologia , Nanismo/fisiopatologia , Europa (Continente)/epidemiologia , Proteínas da Matriz Extracelular/genética , Anormalidades do Olho/etnologia , Anormalidades do Olho/fisiopatologia , Feminino , Heterogeneidade Genética , Humanos , Corpos de Inclusão/genética , Lactente , Japão/epidemiologia , Deformidades Congênitas dos Membros , Masculino , Oriente Médio/epidemiologia , Mutação , LinhagemRESUMO
Choriocarcinoma is a highly malignant neoplasm resulting from the malignant transformation of proliferating trophoblastic cells and the molecular mechanisms leading to this transformation remain to be characterized. We report here the first case of a female germline TP53 mutation carrier who developed, as a first tumour, a lung choriocarcinoma, 6 months after a normal delivery. Molecular analyses established the gestational origin of the choriocarcinoma and showed, within the tumour, the presence of the germline mutant TP53 allele and loss of the wild-type allele. Resistance to methotrexate chemotherapy led to perform a surgical resection of the tumour. In agreement with the permissive role of TP53 mutations to oncogenic events, this report strongly suggests that TP53 mutations may promote malignant transformation of proliferating trophoblastic cells. Therefore, female TP53 mutation carriers may have an increased risk of developing gestational choriocarcinoma and might benefit from ß-hCG level monitoring after pregnancy.