Ann Dermatol.  2010 Nov;22(4):452-455. 10.5021/ad.2010.22.4.452.

Multiple Endocrine Neoplasia Type 2B: Early Diagnosis by Multiple Mucosal Neuroma and Its DNA Analysis

• Lee MJ
• Chung KH
• Park JS
• Chung H
• Jang HC
• Kim JW

• KMID: 2266186
• DOI: http://doi.org/10.5021/ad.2010.22.4.452

Abstract

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare disease caused by germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. It is characterized by medullary thyroid carcinoma, pheochromocytoma and mucosal neuroma developing in the tongue, lip, intestinal tract, palate etc. Among these neoplasias, mucosal neuroma generally develops from early childhood. Therefore, early detection and proper treatment can minimize the disease course. Here we describe a 9-year-old male who presented with multiple verrucous papules and nodules on his lips, tongue and gingiva that were there since birth. Histologic findings of his lips and tongue showed well-defined nerve bundles and DNA analysis revealed a M918T mutation at codon 918 of the RET oncogene. He was diagnosed early as having MEN 2B according to his genetic and phenotypic features.

Keyword

M918T; Medullary thyroid carcinoma; MEN 2B; Multiple mucosal neuroma

MeSH Terms

Child
Codon
DNA
Early Diagnosis
Germ-Line Mutation
Gingiva
Humans
Lip
Male
Multiple Endocrine Neoplasia
Multiple Endocrine Neoplasia Type 2b
Neuroma
Oncogenes
Palate
Parturition
Pheochromocytoma
Proto-Oncogenes
Rare Diseases
Thyroid Neoplasms
Tongue
Codon
DNA

Figure

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  Fig. 1 Well defined multiple papules and nodules on lips (A) and tongue (B).

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  Fig. 2 Tissue from lips: (A) Nerves of dermis were enlarged and hypercellular (H&E, ×20). (B) Fascicles of Schwann cells were arranged in interlacing patterns (H&E, ×200).

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  Fig. 3 Tissue from lips: (A) Immunohistochemical staining of the tumor body was positive for the S-100 protein (×40). (B) Immunohistochemical staining of the capsule was positive for EMA (×40).

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  Fig. 4 M918T mutation in the exon 16 of RET (arrows).

Reference

1. Raue F, Frank-Raue K. Multiple endocrine neoplasia type 2: 2007 update. Horm Res. 2007. 68:Suppl 5. 101–104.

2. Sanso GE, Domene HM, Garcia R, Pusiol E, de M, Roque M, et al. Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers. Cancer. 2002. 94:323–330.

3. Kouvaraki MA, Shapiro SE, Perrier ND, Cote GJ, Gagel RF, Hoff AO, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005. 15:531–544.

4. Lee CW, Oh CK, Jang HS, Kwon KS, Chung TA. A case of multiple endocrine neoplasia type 3 with multiple mucosal neuroma. Korean J Dermatol. 1999. 37:505–509.

5. Toledo SP, dos Santos MA, Toledo Rde A, Lourenço DM Jr. Impact of RET proto-oncogene analysis on the clinical management of multiple endocrine neoplasia type 2. Clinics (Sao Paulo). 2006. 61:59–70.

6. Camacho CP, Hoff AO, Lindsey SC, Signorini PS, Valente FO, Oliveira MN, et al. Early diagnosis of multiple endocrine neoplasia type 2B: a challenge for physicians. Arq Bras Endocrinol Metabol. 2008. 52:1393–1398.

7. Brauckhoff M, Machens A, Hess S, Lorenz K, Gimm O, Brauckhoff K, et al. Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: An exploratory analysis. Surgery. 2008. 144:1044–1050.

8. Lee YJ, Liu HC, Lee HC, Tzen CY, Huang CY, Yang TL. Picture of the month. Multiple endocrine neoplasia 2B syndrome. Arch Pediatr Adolesc Med. 2001. 155:845–846.

9. Smith VV, Eng C, Milla PJ. Intestinal ganglioneuromatosis and multiple endocrine neoplasia type 2B: implications for treatment. Gut. 1999. 45:143–146.

10. Cohen MS, Phay JE, Albinson C, DeBenedetti MK, Skinner MA, Lairmore TC, et al. Gastrointestinal manifestations of multiple endocrine neoplasia type 2. Ann Surg. 2002. 235:648–654.

11. Vasen HF, van der Feltz M, Raue F, Kruseman AN, Koppeschaar HP, Pieters G, et al. The natural course of multiple endocrine neoplasia type IIb. A study of 18 cases. Arch Intern Med. 1992. 152:1250–1252.

12. Cranston AN, Carniti C, Oakhill K, Radzio-Andzelm E, Stone EA, McCallion AS, et al. RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res. 2006. 66:10179–10187.

13. Miyauchi A, Futami H, Hai N, Yokozawa T, Kuma K, Aoki N, et al. Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res. 1999. 90:1–5.

14. Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PL, Mulligan LM, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab. 1997. 82:3902–3904.

15. Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene. 1997. 15:1213–1217.

16. Menko FH, van der Luijt RB, de Valk IA, Toorians AW, Sepers JM, van Diest PJ, et al. Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. J Clin Endocrinol Metab. 2002. 87:393–397.