Ⅰ. INTRODUCTION
Multiple endocrine neoplasia type 2B (MEN2B) is a rare, autosomal dominant hamartoneoplastic syndrome occurring in 1 in 1,000,000 to 1 in 4,000,000.1-7) This syndrome is caused by a mutation in the RET proto-oncogene on chromosome 10 and a mutation in which substitution of methionine for threonine at codon 918 (M918T) is observed in 95% of the diseased patients.2-5) Patients with this disease are characterized by multiple mucosal neuromas on the tongue, lips, eyelid margins, and conjunctiva and features, such as marfanoid habitus, thick and protruding lips, open bite, and maxillary central diastema.8-11) It is reported that this syndrome causes 90%–100% of medullary thyroid carcinoma (MTC) and oral symptoms occur earlier than MTC. Thus, understanding the oral symptoms is very important for the early diagnosis of this syndrome.2-4)
In this report, we present a case of a 19-year-old male patient with MEN2B who visited a dental hospital for esthetic correction of multiple oral mucosal neuromas and diastema. This report aims to understand the oral characteristics of this syndrome and discuss the importance of early diagnosis.
Ⅱ. CASE REPORT
A 19-year-old male patient complaining of the maxillary central diastema and protuberant lips visited the Department of Oral and Maxillofacial Surgery, Kyungpook National University of Dental Hospital, to be esthetically corrected.
In oral examination, multiple round papules of 0.1–0.5 cm in size were observed on the tip and sides of the tongue and nodules of 0.5 cm × 0.8 cm in size were found on both sides of the buccal mucosa. Furthermore, round-shap-ed submucosal nodules were located on the upper and lower lip with a diameter of 0.8 cm. Central diastema was observed due to a thick 0.3 cm × 0.5 cm nodule between the maxillary central incisors. All lesions were asymptomatic (Fig. 1). The patient was tall and skinny and had a marfanoid appearance. In side views of the patient, the upper and lower lips were protruding and an anterior open bite was observed.
In the past, at the age of 3, the patient had a medical history of being hospitalized for abdominal pain, and the presence of nodules in the mucous membranes of the oral cavity including the tongue was recognized from infancy, but no further evaluation was done. At the age of 8, he visited a dermatologist and had an incisional biopsy. As a result, neuroma was diagnosed. At the age of 9, the patient visited a pediatric hospital for continuous physical fatigue, and after physical examination, thyroid cancer was diagnosed. Accordingly, he underwent thyroidectomy and was finally diagnosed with MEN2B syndrome through genetic testing.
The patient had a history of visiting our dental hospital at the age of 12 for orthodontic consultation but did not have any special treatments at that time. His orthodontic treatment for maxillary central diastema closure was delayed until the age of 19. After 6 months of orthodontic treatment, surgical excision was performed on the nodule in the interdental papilla between the maxillary central incisors and incisional biopsy was done on the nodule of the tongue. As a histopathological feature, multiple hyperplastic nerve bundles below the epithelial surface were observed being separated by marked thickening of the perineurium. Nerve bundles appeared to be oval or twisted and consisted of spindle- shaped cells with wavy nuclei. Both excised areas were diagnosed as neuroma (Fig. 2). Healing was favorable. After 1 month, the prominent submucosal mass of the upper lip was additionally excised, and it was also diagnosed as neuroma. Maxillary central diastema has been resolved through orthodontic treatment, and it has been maintained without recurrence so far. For a number of nodules distributed in the lower lip and tongue, a complete excision is planned under general anesthesia in the future for esthetic treatment.
Ⅲ. DISCUSSION
MEN is a rare genetic syndrome transmitted as an autosomal dominant condition characterized by multiple tumors or proliferation of neuroendocrine tissues.1-7) MEN2 syndrome includes MEN type 2A (MEN2A), MEN2B, and familial MTC (FMTC), of which only MEN2B shows the oral symptoms.1,5-7) It is characterized by a marfanoid habitus and multiple mucosal neuromas of the tongue, lips, eyelid margins, and conjunctiva, mucosal gastrointestinal neuromatosis, and no parathyroid disease.8,10-14) Additionally, type 2 subtype B (MEN2B) develops into aggressive MTC in 90% –100% of the cases, and pheochromocytoma may occur in 50%. Prophylactic thyroidectomy before the age of 1 is sometimes recommended because MTC is considered potentially curable if thyroidectomy is performed before the age of 4.3,4) Oral symptoms are very important signals for the early diagnosis of MEN2B because oral symptoms are known to appear before MTC or pheochromocytoma.2-4)
A previous study by Curtis J. Wray et al. reported that it takes an average of 2 years from the first recognition of discomfort or characteristics associated with MEN2B to being diagnosed with MEN2B syndrome.14) Mucosal neuroma is the most prominent symptom, and 27% of patients had a history of being diagnosed with a neuroma in the hospital for oral lesions before being diagnosed with MEN2B, but no one could relate this to a characteristic of MEN2B.14) In this patient, though oral symptoms were recognized from infancy, the evaluation was not done in proper time and the diagnosis of MEN2B was delayed because no one could assume neuroma as its characteristic.
Mark S Cohen et al. asserted that 93% of patients had gastrointestinal symptoms before being diagnosed with MEN2B.13-15) This patient also had a history of hospitalization for abdominal pain at the age of 2, but it was not correlated with other features of MEN2B, including intraoral neuroma. In MEN2B syndrome, multiple oral mucosal neuromas precede the endocrine tumors of the thyroid and adrenal glands. Therefore, dentists must understand the clinical characteristics of this syndrome.2-4) Particularly, it is important to diagnose MEN2B earlier by allowing DNA testing for endocrine evaluation and confirmation of RET mutation, with the possibility of MEN2B in mind when multiple neuromas appear in the oral cavity.16)
