Independent Case Report
An association of multiple endocrine neoplasia 2B, a RET mutation; constipation; and low substance P–nerve fiber density in colonic circular muscle

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Abstract

Background

Multiple endocrine neoplasia (MEN) 2B is a rare hereditary syndrome that results from an activating mutation of the RET proto-oncogene. The RET gene is involved in the development of the enteric nervous system. Patients with MEN 2B have enlarged enteric ganglia and may be affected by gastrointestinal dysmotility. A deficiency of the neurotransmitter substance P (SP) has been identified in both pediatric and adult patients with chronic constipation.

Methods

Three patients, in whom constipation was the presenting symptom and MEN 2B had been provisionally diagnosed, underwent genetic analysis. Seromuscular colonic biopsies were taken for immunofluorescence imaging in all 3 patients. A retrospective review of the patient notes was undertaken.

Results

All 3 patients had constipation refractory to conservative treatment. Genetic analyses in the 3 patients confirmed an identical RET mutation (Met918Thr). Immunofluorescence imaging in all 3 patients identified grossly enlarged myenteric plexus ganglia but surprisingly a low density of SP-labeled nerve fibers in the colonic circular muscle. Nitric oxide synthase and vasoactive intestinal peptide labeling were not reduced.

Conclusion

The results show an association between MEN 2B and its most common RET mutation, colonic dysmotility, and low density of SP in the colonic circular muscle. Larger numbers of patients need to be studied to investigate whether low SP is primarily associated with the constipation or RET mutation and if it is a common feature of MEN 2B.

Section snippets

Methods

A retrospective review of the patient notes of the 3 children was undertaken. All 3 children are regularly reviewed in clinic by JMH.

Patient 1

An 11-month-old female infant of nonconsanguineous parents presented with a history of constipation since birth. There was infrequent stooling while breast-feeding and stooling every 2 to 3 weeks while fed solids. Laxatives were commenced at the age of 7 months but were found to be decreasingly effective, resulting in the commencement of a regular enema plan. A rectal biopsy for acetylcholinesterase staining at 2 years of age revealed submucosal ganglia but no changes consistent with

Discussion

We have described 3 children with MEN 2B in whom constipation was a presenting feature. The diagnosis was initially made after the presenting symptoms of constipation and genetic analysis revealed the most common mutation, a missense mutation at codon 918 in the RET gene (Met918Thr) on chromosome 10 in all 3 children. Each child, despite diffuse enlarged ganglia that displayed SP immunoreactivity, demonstrated a low level of SP-labeled nerve fibers in the colonic circular muscle. It is

Acknowledgments

The authors thank Mrs P Farmer (Royal Children's Hospital, Melbourne, Victoria, Australia) for preparation of immunohistochemistry images, Dr CW Chow (Royal Children's Hospital, Melbourne, Victoria, Australia) for examination of the pathologic specimens, and Dr M Smith (Royal Melbourne Hospital, Melbourne, Victoria, Australia) for advice on mutational analyses. Mutational analyses were performed at The Royal North Shore Hospital, Sydney, and The Royal Melbourne Hospital, Melbourne, Australia.

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    Presented at the 52nd Annual Congress of British Association of Paediatric Surgeons, Dublin, Ireland, July 12-15, 2005.

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