Hirschsprung disease (HSCR) is a frequent neurocristopathy characterized by the absence of submucosal and myenteric plexuses in a variable length of the gastrointestinal tract. Pedigrees and segregation analyses suggested the involvement of one or several dominant genes with low penetrance in HSCR. Considering that RET and glial cell line-derived neurotrophic factor (GDNF) mutations have been reported in the disease, we regarded the other RET ligand, neurturin (NTN), as an attractive candidate gene, especially as it shares large homologies with GDNF. Here, we report on the finding of a heterozygous missense NTN mutation in a large non-consanguineous family including four children affected with a severe aganglionosis phenotype extending up to the small intestine. Interestingly, it appears that the NTN mutation reported here is not sufficient to cause HSCR, and this multiplex family also segregates a RET mutation. This cascade of independent and additive genetic events fits well with the multigenic pattern of inheritance expected in HSCR, and further support the role of RET ligands in development of the enteric nervous system.
Peutz -Jeghers syndrome (PJS, MIM175200) is an autosomal-dominant inherited disorder characterised by multiple gastrointestinal hamartomatous polyps, melanin spots of the oral mucosa and digits, and an increased risk for various neoplasms. The PJS results from germline alterations of the STK11/LKB1 tumour suppressor gene, located on 19p13.3, and encoding a serine/threonine kinase. The detection of STK11 germline mutations, in only 50 -70% of PJS families, has suggested a genetic heterogeneity of the disease. We report the case of a family with typical features of PJS, including gastrointestinal hamartomatous, breast cancers and melanin spots of the oral mucosa. Quantitative multiplex PCR of short fluorescent fragments (QMPSF) of the 19p13 region allowed us to identify an approximately 250 kb heterozygous deletion removing entirely the STK11 locus. This report, which constitutes the first description of a complete germline deletion of STK11, shows that the presence of such large genomic deletions should be considered in PJS families without detectable point mutations of STK11.
Two cases of pancreatoblastoma in children are reported here. Only biopsies were made at laparotomy as surgical resection by duodeno-pancreatectomy was not possible. In both children a dramatic response was observed with chemotherapy: doxorubicin plus cisplatin for one, cyclophosphamide, actinomycin D, bleomycin, vinblastine sulfate, and cisplatin for the other. After completion of the chemotherapy the first patient had a local resection; then he had radiotherapy. He is alive in first remission 40 months after the end of the treatment. In the second patient, regional recurrence occurred 8 months after chemotherapy was ended. A transient second remission was obtained with ifosfamide plus etoposide alternating with epirubicin plus vincristine. The patient died 36 months after the diagnosis. Therefore, these two cases suggest that chemotherapy may be proposed before any attempt at surgical excision. Nevertheless, early consolidation by radical resection or irradiation must be considered.
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