THYROIDVolume 16, Number 6, 2006© Mary Ann Liebert, Inc.

Case History

Phenotypic Multiple Endocrine Neoplasia Type 2B, WithoutEndocrinopathy or RET Gene Mutation:

Implications for Management

Gill Spyer,1 Sian Ellard,2 Peter D. Turnpenny,3 Andrew T. Hattersley,1 and Bijay Vaidya1

The multiple endocrine neoplasia (MEN) type 2B is an autosomal dominant condition characterized by ag-gressive medullary C-cell tumors, pheochromocytoma, and a discrete physical appearance (marfanoid habitus,prominent corneal nerve fibers, thick lips, and mucosal and intestinal neuromas). A specific point mutation inthe RET proto-oncogene is present in 95% cases. Occasionally cases present with the characteristic physical ap-pearance of MEN 2B but no identifiable germline mutation or endocrinopathy, and it has been suggested thatthese patients may represent a discrete subgroup termed pure mucosal neuroma syndrome (MNS). We pres-ent a patient with MNS, who had a thyroidectomy at age 14.5 years with normal thyroid histology. Direct se-quencing of all 20 exons of the RET gene showed no mutation. This case supports the suggestion that pureMNS can exist in the absence of an identifiable RET gene mutation. We suggest that prophylactic thyroidec-tomy is unnecessary in these patients although they should still be screened for endocrinopathy on a regularbasis.

605

Introduction

MULTIPLE ENDOCRINE NEOPLASIA (MEN) type 2B, an auto-somal dominant condition, is typified by early devel-

opment of aggressive malignant medullary C-cell tumors ofthe thyroid (95%) and pheochromocytomas (50%) (1). In ad-dition, patients typically have a marfanoid habitus and otherskeletal anomalies, prominent corneal nerve fibers, thick lips,and multiple mucosal neuromas. A mutation within exon 16of the RET proto-oncogene on chromosome 10 is found in95% of patients (2). This mutation involves a single base pairtransition at codon 918 (ATG to ACG) resulting in replace-ment of methionone with threonine (M918T) (3–5). A highproportion of cases are new or sporadic mutations (1,5), andso there may not be a family history. A minority of MEN 2Bpatients without the M918T mutation has a RET gene muta-tion at codon 883 (A883F) on exon 15 (6). Rarely, MEN 2B isassociated with germline double mutations involving codon804 (V804M) in exon 14 and codon 806 (Y806C) in exon 14or codon 904 (S904C) in exon 15 (7,8).

It is recommended that prophylactic thyroidectomy is per-formed before age 5 years in RET gene mutation carriers withMEN 2A and before age 6 months in those with MEN 2B,

even in the absence of evidence for C-cell hyperplasia or ma-lignancy as the risk of developing an aggressive medullarythyroid carcinoma is high (9,10). The management of patientswho present with typical features of MEN 2B but who donot have evidence of endocrinopathy or germline mutationsis uncertain. There have been several reports of such patientsin the literature (2,11–16) and it has been suggested that theymay represent a distinct subgroup termed pure mucosal neu-roma syndrome (MNS) (11). We report a patient with MNS,who underwent prophylactic thyroidectomy, and discuss themanagement of such patients in the light of this and the othercases reported in the literature.

Case Report

A 13-year-old girl first presented to the ophthalmology de-partment with photophobia in 1987. She was noted to havestrikingly prominent corneal nerve fibers. She also had manyof the typical features of MEN 2B with thick lips, multiple bi-lateral mucosal neuromas, a marfanoid habitus (height, 166 cm;arm span, 167.5 cm), high arched palate, a “coast of Maine”café au lait patch on her back, and genu valgum (Figure1A–1C). Blood pressure was 120/65 mm Hg. Family history

Departments of 1Endocrinology, 2Molecular Genetics, and 3Clinical Genetics, Royal Devon & Exeter Hospital NHS Foundation Trust,Exeter, United Kingdom.

revealed two healthy female siblings and healthy parents, al-though her father suffers from diet-controlled type 2 diabetes.

Initial investigations showed normal 24-hour urinary cat-echolamines, serum calcium, serum parathyroid hormone,

and computed tomographic scan of the adrenal glands. Ba-sal and alcohol-stimulated calcitonin levels were also normal(�0.08 �g/L). She was followed up with six monthly repeaturinary catecholamine examinations, all of which were nor-mal, and yearly pentagastrin-stimulated calcitonin levels.Pentagastrin stimulation (0.5 �g/kg) 18 months after pre-sentation, when 14.5 years of age, gave equivocal results.Baseline calcitonin level was 0.09 mcg/l (normal, �0.08�g/L), rising to a peak of 0.14 �g/L at 2 minutes. A three-fold rise from baseline was considered to be indicative of C-cell hyperplasia (17).

Because of the uncertainty surrounding the natural history of patients presenting with this phenotype at a time when the gene was unknown, in association with a rise in basal calcitonin, a decision was made to proceedto prophylactic thyroidectomy. She made a good post-operative recovery although the procedure was com-plicated by permanent hypoparathyroidism. Histologic examination of the thyroid gland showed no evidence ofmedullary carcinoma or C-cell hyperplasia. Recently, di-rect sequencing of exons 1–20 of the RET gene showed nomutation in the coding region or splice sites of the exons,and specifically the RET mutations M918T and A883F wereexcluded.

The patient has been followed up annually for the last 18years and has remained well. Repeated urinary cate-cholamines have remained normal.

SPYER ET AL.606

FIG. 1. Clinical characteristics of the patient showing (A) mar-fanoid habitus with disproportionately long arms, (B) multiplebilateral mucosal neuromas of the tongue, and (C) thick lipstypical of those seen in multiple endocrine neoplasia (MEN) 2B.

TABLE 1. CHARACTERISTICS OF REPORTED PATIENTS WITH PHYSICAL APPEARANCES

OF MEN 2B BUT NO ASSOCIATED ENDOCRINOPATHY OR RET GENE MUTATION

Age at ThickenedStudy Case presentation corneal Marfanoid Family(reference)a number (yr) Site Unilateral/bilateral nerves habitat history Thyroidectomy

Dennehy 1 8 Tongue Bilateral Yes No Yes Noet al., 2 (sister 10 Tongue Bilateral Yes No Yes No1995 of 1)(14) 3 (mother 40 Tongue Bilateral Yes No Yes No

of 1 and 2)Pujol 1 7 Tongue, lower Bilateral No No No No

et al., lip1997(15)

Gordon 1 15 Tongue, buccal Unilateral Yes No No Noet al., mucosa, lips,1998 nose, palebral(11) fissures

2 12 Tongue Unilateral No No No No3 15 Tongue Unilateral Yes No No Yes4 4 Buccal mucosa Unilateral No No No No

Gomez 1 15 Tongue, lips Bilateral Yes No Yes Noet al., 2 (mother 39 Tongue, lips Bilateral Yes No Yes No1998 of 1)(13)

Truchot 1 53 Gingival Bilateral No No No Noet al., mucosa, face,2001 body(16)

This study 1 13 Tongue, lower Bilateral Yes Yes No Yeslip

aFurther examples are referred to by Mulligan et al. (12) and Eng et al. (2) but no specific details given.MEN, muliple endocrine neoplasia.

Mucosal neuromas

Discussion

We present a 13-year-old girl, followed up for 18 years,who presented with typical physical characteristics of MEN2B but no evidence of either C-cell hyperplasia or phaeochro-mocytoma. A prophylactic thyroidectomy was performedand histology was normal. Subsequent sequencing of exons1–20 of the RET gene was normal.

There are two familial and six sporadic cases reported inthe literature, who have phenotypic features of MEN 2B with-out a germline RET mutation (Table 1). None of these casesshowed evidence of C-cell hyperplasia (indicated by elevatedbasal and stimulated serum calcitonin levels) or pheochro-mocytoma (based on normal urinary catecholamines, vanil-lymandelic acid, and/or metanephrines). Gordon et al. (11)suggest they may represent a discrete subgroup and termedthis “pure mucocutaneous neuroma syndrome.” Our casesupports this description and represents the first reportedcase with bilateral disease in which thyroid histology wasavailable. The fact that thyroid histology at the age of 14 yearswas normal is significant and suggestive of a less aggressivedisease course compared to the typical MEN 2B phenotype.If this were a typical MEN 2B then one would expect at leastC-cell hyperplasia by this age (18).

This case and the others support the view that patientspresenting with the physical characteristics of MEN 2B donot require prophylactic thyroidectomy if they do not haveeither a mutation in the RET gene or biochemical evidenceof C-cell hyperplasia. It must be noted that Toogood et al.(19) describe a family who presented in early adulthood withMTC. When screened retrospectively two siblings werefound to have a physical appearance typical of MEN 2B butneither M918T nor other mutations on exons 2–20 of the RETgene. Both had abnormal calcitonin levels and one had ele-vated urinary catecholamine levels at presentation. It is notknown at what stage this family would have developed ev-idence of endocrinopathy prior to the development ofmedullary thyroid carcinoma (MTC) but it highlights thepoint that it is essential to follow up and screen regularly allpatients with suspected MEN 2B regardless of genotype. Itis unclear to date when this supervision can be relaxed. Thereis also uncertainty regarding genetic counseling and the out-come for the offspring of such individuals. To date there areonly two familial cases of MNS without MEN 2B (13,14).

In conclusion, the majority of subjects with MEN 2B willhave a distinct phenotype including characteristic en-docrinopathies and RET proto-oncogene mutations. How-ever, the existence of the physical appearance (MNS) can alsooccur in the absence of these associations. In these patientsprophylactic thyroidectomy is not mandatory.

Acknowledgments

We thank Martina Owens for her help in direct DNA se-quencing. This work was supported by The Research & De-velopment Directorate, Royal Devon & Exeter NHS Foun-dation Trust.

References

1. Eng C 1996 Seminars in medicine of the Beth Israel Hospi-tal, Boston. The RET proto-oncogene in multiple endocrineneoplasia type 2 and Hirschsprung’s disease. N Engl J Med335:943–951.

2. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, GagelRF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ,Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW,Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nor-denskjold M, Komminoth P, Hendy GN, Mulligan LM, et al.1996 The relationship between specific RET proto-oncogenemutations and disease phenotype in multiple endocrine neo-plasia type 2. International RET mutation consortium anal-ysis. JAMA 276:1575–1579.

3. Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stel-wagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK,Romeo G, et al. 1994 A mutation in the RET proto-oncogeneassociated with multiple endocrine neoplasia type 2B andsporadic medullary thyroid carcinoma. Nature 367:375–376.

4. Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Pon-der MA, Gardner E, Scheumann GF, Jackson CE, TunnacliffeA, et al. 1994 Point mutation within the tyrosine kinase do-main of the RET proto-oncogene in multiple endocrine neo-plasia type 2B and related sporadic tumours. Hum MolGenet 3:237–241.

5. Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jack-son CE, Wells SA, Jr., Goodfellow PJ, Donis-Keller H 1994Single missense mutation in the tyrosine kinase catalytic do-main of the RET protooncogene is associated with multipleendocrine neoplasia type 2B. Proc Natl Acad Sci USA91:1579–1583.

6. Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PL, Mul-ligan LM, Zajac JD, Robinson BG, Eng C 1997 Germline din-ucleotide mutation in codon 883 of the RET proto-oncogenein multiple endocrine neoplasia type 2B without codon 918mutation. J Clin Endocrinol Metab 82:3902–3904.

7. Miyauchi A, Futami H, Hai N, Yokozawa T, Kuma K, AokiN, Kosugi S, Sugano K, Yamaguchi K 1999 Two germlinemissense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple en-docrine neoplasia type 2B without codon 918 mutation. JpnJ Cancer Res 90:1–5.

8. Menko FH, van der Luijt RB, de Valk IA, Toorians AW,Sepers JM, van Diest PJ, Lips CJ 2002 Atypical MEN type 2Bassociated with two germline RET mutations on the sameallele not involving codon 918. J Clin Endocrinol Metab87:393–397.

9. Utiger RD 1994 Medullary thyroid carcinoma, genes, andthe prevention of cancer. N Engl J Med 331:870–871.

10. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-PeccozP, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, LibroiaA, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA,Raue F, Skogseid B, Tamburrano G, Thakker RV, ThompsonNW, Tomassetti P, Tonelli F, Wells SA, Jr., Marx SJ 2001Guidelines for diagnosis and therapy of MEN type 1 andtype 2. J Clin Endocrinol Metab 86:5658–5671.

11. Gordon C, Majzoub JA, Marsh DJ, Mulliken JB, Ponder BA,Robinson BG, Eng C 1998 Four cases of mucosal neuromasyndrome: multiple endocrine neoplasm 2B or not 2B? J ClinEndocrinol Metab 83:17–20.

12. Mulligan LM, Marsh DJ, Robinson BG, Schuffenecker I, Ze-denius J, Lips CJ, Gagel RF, Takai SI, Noll WW, Fink M, etal. 1995 Genotype-phenotype correlation in multiple endo-crine neoplasia type 2: Report of the International RET Mu-tation Consortium. J Intern Med 238:343–346.

13. Gomez JM, Biarnes J, Volpini V, Marti T 1998 Neuromas andprominent corneal nerves without MEN 2B. Ann Endocrinol(Paris) 59:492–494.

14. Dennehy PJ, Feldman GL, Kambouris M, O’Malley ER,Sanders CY, Jackson CE 1995 Relationship of familial promi-

MUCOSAL NEUROMA SYNDROME 607

nent corneal nerves and lesions of the tongue resemblingneuromas to multiple endocrine neoplasia type 2B. Am JOphthalmol 120:456–461.

15. Pujol RM, Matias-Guiu X, Miralles J, Colomer A, de Mora-gas JM 1997 Multiple idiopathic mucosal neuromas: a mi-nor form of multiple endocrine neoplasia type 2B or a newentity? J Am Acad Dermatol 37:349–352.

16. Truchot F, Grezard P, Wolf F, Balme B, Perrot H 2001 Mul-tiple idiopathic mucocutaneous neuromas: a new entity? BrJ Dermatol 145:826–829.

17. Lips CJ, Landsvater RM, Hoppener JW, Geerdink RA, Blijham G, van Veen JM, van Gils AP, de Wit MJ, ZewaldRA, Berends MJ, et al. 1994 Clinical screening as comparedwith DNA analysis in families with multiple endocrine neo-plasia type 2A. N Engl J Med 331:828–835.

18. Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, vanVroonhoven TJ, Roeher HD, Wahl RA, Lamesch P, Raue F,

Conte-Devolx B, Dralle H 2003 Early malignant progressionof hereditary medullary thyroid cancer. N Engl J Med349:1517–1525.

19. Toogood AA, Eng C, Smith DP, Ponder BA, Shalet SM 1995No mutation at codon 918 of the RET gene in a family withmultiple endocrine neoplasia type 2B. Clin Endocrinol (Oxf)43:759–762.

Address reprint requests to:Dr. Bijay Vaidya

Department of EndocrinologyRoyal Devon & Exeter Hospital

Barrack RoadExeter, EX2 5DW.

United Kingdom

E-mail: bijay.vaidya@pms.ac.uk

SPYER ET AL.608