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Hirschsprung’s disease and medullary thyroid carcinoma: 15-year experience with molecular genetic screening of the RET proto-oncogene

Pediatric Surgery International volume 28, pages 123–128 (2012)Cite this article

Abstract

Purpose

Inactivating germline mutations in the RET proto-oncogene are the major genetic cause of Hirschsprung’s disease (HD). In some cases, HD can be associated with medullary thyroid carcinoma (MTC) that is commonly caused by activating RET mutations.

Methods

The retrospective and prospective genetic analyses of 157 patients with HD operated on between December 1979 and June 2011 were carried out. DNA was isolated from peripheral leukocytes. HD patients and family members were tested for RET mutations by direct sequencing and single-strand conformation polymorphism methods.

Results

RET mutations were detected in 16 patients (10%). Association with MTC was found in two families, other eight families had a mutation with potentially high risk of MTC development and four novel mutations were detected. Total colonic aganglionosis was noted to have a high mutation detection rate (40%). Three patients underwent total thyroidectomy (two had clinical manifestation of MTC, one C-cell hyperplasia).

Conclusion

Results show the benefit of systematic RET mutation screening in HD patients in order to identify the risk of MTC in the preclinical stage of the disease. All patients should be tested for RET mutations at least in exon 10, and now additionally in exon 11 and 13, as well.

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Notes

  1. Previous experience with RET proto-oncogene screening in Czech patients with HD was published in articles of our work group [15, 16, 21].

Abbreviations

HD:

Hirschsprung’s disease

MTC:

Medullary thyroid carcinoma

RET :

Rearranged during transfection

TCA:

Total colonic aganglionosis

LCA:

Long segment colonic aganglionosis

RS:

Rectosigmoid form

NTSBA:

Nearly total small bowel aganglionosis

MEN:

Multiple endocrine neoplasia

CCH:

C-cell hyperplasia

PCR:

Polymerase chain reaction

SSCP:

Single-strand conformation polymorphism

TTE:

Total thyroidectomy

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Acknowledgments

The authors would like to thank all the subjects for their participation in this study. They also thank Dr. Lassuthova from Department of Child Neurology, University Hospital Motol, Prague for her assistance with in silico analyses of novel uncertain variants. This work was supported by grant projects GAUK 411611, IGA MH CR NR/9165-3 and GACR 301/06/P425.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Affiliations

  1. Department of Molecular Endocrinology, Institute of Endocrinology, Narodni trida 8, 11694, Prague 1, Czech Republic

    Eliska Vaclavikova, Sarka Dvorakova & Bela Bendlova

  2. Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 12840, Prague 2, Czech Republic

    Eliska Vaclavikova

  3. Department of Pediatric Surgery, 2nd Faculty of Medicine, Charles University and Hospital Motol, V Uvalu 84, 15006, Prague 5, Czech Republic

    Lucie Kavalcova, Richard Skaba & Blanka Rouskova

  4. Department of Pathology, 2nd Faculty of Medicine, Charles University and Hospital Motol, V Uvalu 84, 15006 , Prague 5, Czech Republic

    Pavla Macokova

Authors
  1. Eliska Vaclavikova
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  2. Lucie Kavalcova
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  3. Richard Skaba
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  4. Sarka Dvorakova
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  5. Pavla Macokova
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  6. Blanka Rouskova
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  7. Bela Bendlova
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Correspondence to Eliska Vaclavikova.

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Vaclavikova, E., Kavalcova, L., Skaba, R. et al. Hirschsprung’s disease and medullary thyroid carcinoma: 15-year experience with molecular genetic screening of the RET proto-oncogene. Pediatr Surg Int 28, 123–128 (2012). https://doi.org/10.1007/s00383-011-2993-2

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Keywords

  • Hirschsprung’s disease
  • RET proto-oncogene
  • Medullary thyroid carcinoma
  • Germline mutation
  • Genetics