Elsevier

Surgery

Volume 144, Issue 6, December 2008, Pages 1044-1051
Surgery

American Association of Endocrine Surgeon
Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: An exploratory analysis

https://doi.org/10.1016/j.surg.2008.08.028Get rights and content

Background

More than 90% of M918T carriers with multiple endocrine neoplasia type 2B (MEN 2B) harbor de novo mutations in the REarranged during Transfection (RET) protooncogene. DNA-based screening for RET germline mutations is rarely useful for early diagnosis, which thus is contingent on the clinical ascertainment of MEN 2B-specific symptoms as soon as they emerge. Little information exists about the presence of these symptoms in infancy.

Methods

Detailed information was gathered regarding the development of MEN 2B-associated symptoms from the parents of 25 M918T RET carriers and 50 age- and sex-matched controls with the use of a disease-specific questionnaire.

Results

Until the end of the study, at a median age of 16.2 (range, 0.5–34.9 years), all 25 M918T RET carriers had developed medullary thyroid cancer. By that time, 96%, 91%, 71%, 75%, and 28% of carriers displayed oral manifestations, ocular abnormalities, intestinal symptoms, musculoskeletal malformations, and pheochromocytoma, respectively. During the first year of life, fewer than 20% of carriers were found to express the typical MEN 2B phenotype, whereas 86% and 61% of these children, but none of the controls, were noted for their inability to cry tears and for constipation.

Conclusion

Because the classic MEN 2B phenotype is rare during the first year of life, more emphasis should be placed on the more subtle features of the syndrome. Additional studies are needed to validate the usefulness of the symptoms “inability to cry” and “constipation” for earlier diagnosis of MEN 2B.

Section snippets

MEN 2B patients and controls

A total of 29 patients with MEN 2B were operated on at the Medical High School Hannover (1989–1994) and the Martin Luther University Halle-Wittenberg (1994–2008), both in Germany. These 29 patients who all harbored the M918T RET germline missense mutation were prospectively recorded in a clinical MEN 2B register. Two of the 29 patients had inherited the mutation from their mothers, whereas the remaining 27 patients were the only affected family members. For the purpose of this study, the

Development of MTC

All 25 patients had developed MTC. Only 1 patient (4%) was operated on for MTC within the first year of life. All in all, MEN 2B was diagnosed at a median age of 14.0 years (range, 0.5–31.1) (ie, 3.1 years [range, 0–14] before the conduct of the study). At the time of initial neck surgery, MTCs extended beyond the thyroid capsule in 16 patients (64%), had spread to distant organs in 20 patients (80%), and involved cervical lymph nodes in 22 patients (88%).

Clinical outcome after initial neck surgery

By that time the study was conducted, 5

Discussion

Almost all MEN 2B-related symptoms develop in an age-dependent fashion, not just MTC and pheochromocytoma,15 but also oral, ocular, intestinal, and musculoskeletal stigmata.4 For early diagnosis of MEN 2B, only those clinical symptoms are useful that are present in early infancy and precede the development of metastatic MTC.

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