Gastrointestinal Manifestations of Multiple Endocrine Neoplasia Type 2

Abstract

ObjectiveTo determine the clinical features, natural history, and role of surgery for gastrointestinal manifestations of the multiple endocrine neoplasia type 2 (MEN 2) syndromes. Summary Background DataThe MEN 2 syndromes are characterized by medullary thyroid carcinoma and other endocrinopathies. In addition, some patients with MEN 2A develop Hirschsprung's disease (HD), and all patients with MEN 2B have intestinal neuromas and megacolon that can cause significant gastrointestinal problems. MethodsFrom 83 families with MEN 2A, eight patients with HD were identified (MEN 2A-HD). These and all patients with MEN 2B followed at the authors' institution (n ϭ 53) were sent questionnaires to describe the onset and type of gastrointestinal symptoms and treatment they had before the diagnosis of MEN 2. Records of all patients responding were reviewed, including radiographic imaging, histology, surgical records, and genetic testing. ResultsThirty-six of the 61 patients (59%) responded (MEN 2A ϭ 8, MEN 2B ϭ 28) to the questionnaires. All patients with MEN 2A-HD were operated on for HD 2 to 63 years before being diagnosed with MEN 2. All patients responding were underweight as infants and had symptoms of abdominal pain, distention, and constipation. Eighty-eight percent had hematochezia, 63% had emesis, and 33% had intermittent diarrhea before surgery. All patients with MEN 2A-HD had rectal biopsies with a diverting colostomy as the initial surgical procedure. This was followed by a colostomy takedown and pullthrough procedure at a later interval. Ninety-three percent of patients with MEN 2B had gastrointestinal symptoms 1 to 24 years before the diagnosis of MEN 2. Symptoms included flatulence (86%), abdominal distention or being underweight as a child (64%), abdominal pain (54%), constipation or diarrhea (43%), difficulty swallowing (39%), and vomiting (14%). Seventy-one percent of patients with MEN-2B with gastrointestinal symptoms had radiographic imaging, 32% were admitted to the hospital, and 29% underwent surgery. ConclusionsPatients with MEN 2A-HD had a typical HD presentation and always required surgery. Patients with MEN 2B have significant gastrointestinal symptoms, but less than a third had surgical intervention. Understanding the clinical course and differences in these patients will improve clinical management.The multiple endocrine neoplasia (MEN) type 2 syndromes include MEN 2A, MEN 2B, and familial, non-MEN medullary thyroid carcinoma. These are autosomal dominant inherited syndromes that are caused by germline mutations in the RET protooncogene. The hallmark of these syndromes is the development of medullary thyroid carcinoma (MTC), which is multifocal and bilateral and usually occurs at a young age. MTC occurs in almost all patients with the MEN 2 syndromes. Other features are variably expressed. In MEN 2A, pheochromocytomas develop in approximately 42% of affected patients; they may also be multifocal and bilateral, and are associated with adrenal medullary hyperplasia. Hyperparathyroidism occurs in 25%...

A comprehensive review on MEN2B

“…Of note, increased secretion of catecholamines (such as would be seen in MEN2B-associated pheochromocytoma) can worsen constipation and rarely lead to toxic megacolon (Thosani et al 2015). MEN2B patients can also present with upper GI symptomatology and esophageal manifestations (Cohen et al 2002, Gibbons et al 2016. In a previously reported study of 28 MEN2B patients, 39% had difficulty swallowing and 14% had vomiting, suggesting a diagnosis of esophageal abnormalities.…”

“…Patients with MEN2B usually present with very early-onset MTC, a 50% lifetime risk of pheochromocytoma and universal extra-endocrine features, mainly bowel problems due to diffuse intestinal ganglioneuromatosis (constipation, feeding difficulties in infancy, megacolon) and alacrima, both of which can be the earliest presenting features, in addition to mucosal neuromas and a marfanoid body habitus (note that both may not be become clinically apparent until several years of age) (O'Riordain et al 1994, Cohen et al 2002, Brauckhoff et al 2008 (Table 1).…”

“…In a previously reported study of 28 MEN2B patients, 39% had difficulty swallowing and 14% had vomiting, suggesting a diagnosis of esophageal abnormalities. Medical management (dietary adjustments, laxatives, fiber supplements) of MEN2B patients can be difficult and some patients (about a third) will ultimately require hospital admission and/or surgery (Cohen et al 2002, Gibbons et al 2016. Finally, intestinal manifestations may also be predictive of MTC aggressiveness, as suggested by some authors showing that a worse MTC prognosis was associated with more severe gastrointestinal signs (Brauckhoff et al 2004).…”

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

“…Our patient also had multiple papules and nodules on his lips and tongue when he was born and the size and the number increased gradually as he got older without any irritation history. Chronic constipation caused by the intestinal ganglioneuromatosis and Marfanoid habitus are also early signs of MEN 2B like mucosal neuroma [9][10][11] . Our patient also had suffered from severe constipation.…”

Missed Diagnosis of Multiple Endocrine Neoplasia Type 2 B

“…Thickened corneal nerves can be appreciated on slit lamp examination. Intestinal gangliomatosis is found in nearly all patients [5]. The earliest presentation in a child could be constipation or intestinal obstruction secondary to the neuromas and manifest before extraintestinal endocrine manifestations.…”