Abstract
Purpose
The RET proto-oncogene is involved in neural crest disorders. Activating germline mutations
in the RET proto-oncogene cause the development of familial medullary thyroid carcinoma (FMTC)
or medullary thyroid carcinoma (MTC) as a part of multiple endocrine neoplasia type
2 (MEN2) syndrome. Inactivating germline mutations in the RET proto-oncogene are detected in Hirschsprung's disease (HSCR). Only in a very small
number of families are these 2 diseases expressed together.
Methods
This study presents a novel Czech kindred with FMTC-HSCR phenotype. Two family members
(mother and daughter) were tested for RET germline mutations in exons 10, 11, 13, 14, 15, and 16.
Results
Direct fluorescent sequencing of genomic DNA revealed a heterozygous mutation in the
RET proto-oncogene in exon 10 at codon C609Y in both persons tested. This family was
reclassified, thanks to genetic screening from the apparently sporadic MTC-HSCR to
FMTC-HSCR.
Conclusion
The germline mutation was detected because of the systematic genetic screening of
the RET proto-oncogene, which is useful for genetic counseling of potential risk of HSCR
and MTC in other family members. This family could be added to the small worldwide
cohort of families with MEN2A/FMTC-HSCR.
Index words
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References
- Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis.J Med Genet. 2000; 37: 817-827
- Unilateral renal agenesis in a family with medullary thyroid carcinoma.N Engl J Med. 2000; 342: 1218-1219
- Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2a.Nature. 1993; 363: 458-460
- Mutations in the RET proto-oncogene are associated with MEN 2a and FMTC.Hum Mol Genet. 1993; 2: 851-856
- Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease.Nature. 1994; 367: 377-378
- Mutations of the RET proto-oncogene in Hirschsprung's disease.Nature. 1994; 367: 378-380
- Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung's disease.Hum Mol Genet. 1995; 4: 1381-1386
- Frequency of RET mutations in long- and short-segment Hirschsprung disease.Hum Mutat. 1997; 9: 243-249
- Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene.Hum Mol Genet. 1994; 3: 2163-2167
- Clinical presentations and RET protooncogene mutations in seven multiple endocrine neoplasia type 2 kindreds.Cancer. 1996; 78: 1996-2003
- Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung's disease.Surgery. 1995; 117: 386-391
- Mutational analysis of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease.J Pediatr Surg. 1999; 34: 1552-1554
- Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung's disease.Hum Mol Genet. 1995; 4: 1381-1386
- C618R mutation in exon 10 of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease.J Clin Endocrinol Metab. 1996; 81: 2731-2733
- Cys618 Arg mutation in the RET protooncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung's disease suggesting a role for imprinting.Hum Mutat. 1997; 10: 155-159
- Association of multiple endocrine neoplasia type 2 and Hirschsprung's disease.J Intern Med. 1998; 243: 515-520
- Oncological implications of RET gene mutations in Hirschsprung's disease.Gut. 1998; 43: 542-547
- Hirschsprung's disease in MEN2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation.Hum Mol Genet. 1998; 7: 129-134
- RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems.Hum Mutat. 2000; 15: 418-429
- RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease.Surgery. 2002; 131: 373-381
- Cys611Ser mutation in RET proto-oncogene in a kindred with medullary thyroid carcinoma and Hirschsprung's disease.Eur J Hum Genet. 2003; 11: 364-368
- Kasai's rectoplasty in the treatment of Hirschsprung's disease and other types of colorectal dysganglionosis in children. Analysis of 94 cases.Pediatr Surg Int. 1994; 9: 503-506
- The newly detected mutations in the RET proto-oncogene in exon 16 as a cause of sporadic medullary thyroid carcinoma.J Mol Med. 2003; 81: 819-823
- The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2.JAMA. 1996; 276: 1575-1579
- Molecular analysis of the RET and GDNF genes in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease.J Clin Endocrinol Metab. 1998; 83: 3361-3364
- A founding locus within the RET proto-oncogene may account for a large proportion of apparently sporadic Hirschsprung's disease and a subset of cases of sporadic medullary thyroid carcinoma.Am J Hum Genet. 2003; 72: 88-100
- Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung's disease.Clin Chem. 2004; 50: 93-100
- Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B.Science. 1995; 267: 381-383
- Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function?.Hum Mutat. 1999; 13: 331-336
- Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines.Oncogene. 1998; 17: 2851-2861
- Biological effects of the dual phenotypic Janus mutation of RET co-segregating with both multiple endocrine neoplasia type 2 and Hirschsprung's disease.Mol Endocrinol. 2004; 18: 1004-1017
- Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease.J Clin Invest. 1998; 101: 1415-1423
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© 2005 Elsevier Inc. Published by Elsevier Inc. All rights reserved.