Review

Multiple endocrine neoplasia type 2B (MEN2B) is a hereditary cancer syndrome induced by mutations in the RET receptor tyrosine kinase. It is defined clinically as consisting of medullary thyroid carcinoma (100%), bilateral pheochromocytoma (50%), and a complex clinical phenotype including mucosal ganglioneuromas, megacolon, thickened corneal nerves, and a marfanoid body habitus. Of the MEN2 syndromes, MEN2B is the most aggressive and has the earliest age of onset.

It is fascinating that distinct mutations in RET are responsible for MEN2A, MEN2B, familial medullary thyroid carcinoma, and Hirschsprung disease (congenital aganglionosis of the distal intestine). The vast majority of MEN2A patients carry a point mutation in one of six cysteine residues (codons 609, 611, 618, 620, 634). These mutations cause ligand-independent homodimerization through intermolecular disulfide bonds, producing constitutive activation of the RET kinase^1,2 and multiple downstream signals involved in cell cycle progression and accelerated proliferation.^3–6 The vast majority of MEN2B mutations occur at codon 918. This mutation alters signal transduction capabilities through the increased phosphorylation of another residue involved in the binding of several signaling molecules to the activated RET. Unlike MEN2A mutant RET, MEN2B mutant RET significantly suppresses apoptosis.⁶

RET is also the most important Hirschsprung susceptibility gene. RET mutations associated with Hirschsprung disease are generally hypomorphic or loss-of-function mutations. Interestingly, mutations of cysteine at codon 609, 611, 618, or 620 have also been identified in individuals with sporadic Hirschsprung disease and in families with both Hirschsprung disease and MEN2A or familial medullary thyroid carcinoma. These mutations appear to lead to uncontrolled proliferation of thyroid C cells and to apoptosis of enteric neuronal progenitors. The different effect of the mutation in the thyroid versus the enteric nervous system is thought to be related in sensitivity differences to the RET ligand GDNF. Mutations that render cells insensitive to GDNF are associated with Hirschsprung disease.^7–9

As illustrated by the case study of Qualia and colleagues,¹⁰ early diagnosis of MEN2B is essential because metastatic thyroid carcinoma has been found in very young children with the disorder. The earliest symptom of the syndrome is often severe constipation, suggesting that pediatric gastroenterologists have a key role in early recognition of the syndrome. Unfortunately, severe constipation in infants is a nonspecific symptom, and more specific physical findings associated with the syndrome, such as oral mucosal neuromas, may not be present in infants and young children. Brauckhoff and coworkers¹¹ analyzed the clinical manifestations and courses of 21 patients with MEN2B and medullary thyroid carcinoma. Of the 5 patients who were diagnosed between 1 and 6 years of age, all had severe constipation but 3 did not have lip manifestations at the time of diagnosis. As in the case presented by Qualia and colleagues, the lip and oral abnormalities became apparent with time: All 5 children developed bumpy lips, tongue neuromas, and buccal mucosal neuromas during the 4–5 years of follow-up.¹¹

Because approximately 50% of mutations are de novo, family history may not be helpful. In addition, there are no described diagnostic findings on the radiologic (barium enema) and manometric studies (anorectal manometry) commonly used to evaluate infants with severe constipation.

What of rectal suction biopsies, which are commonly performed on infants presenting with severe constipation? Can changes suggestive of MEN2B be identified in these specimens, allowing for very early recognition of the syndrome? Unfortunately, the answer is usually no, or, at least, not yet. As in the case described by Qualia and associates, rectal biopsies performed early to evaluate for Hirschsprung disease are often interpreted as normal. Interestingly, there are cases in the literature, in which a pathologist has recognized abnormalities suggestive of MEN2B on very early standard biopsies.^11–13 For example, King and associates reported a patient with an excessive numbers of neurons on a rectal mucosal biopsy at just 2 weeks of age. This finding, however, did not lead to the diagnosis of MEN2B. Fortunately, because of ongoing obstructive symptoms, this patient underwent a loop colostomy and colonic biopsies at 6 weeks of age. These biopsies revealed hyperplastic submucosal and myenteric plexus ganglia, which led to the diagnosis of MEN2B.¹² Hyperplasia in the submucosal plexus may be confused with intestinal neuronal dysplasia, a controversial entity also associated with severe constipation in infants and young children.¹⁴ Because it is critical to recognize MEN2B early, whenever the submucosal plexus is found to be increased on intestinal biopsies, diffuse intestinal ganglioneuromatosis should always be considered. The successful recognition of early abnormalities in several cases raises the hope that we can develop more sophisticated, standardized methods of examining the enteric nervous system to recognize intestinal MEN2B in infants.

Clinical recognition of a syndrome-related sign or symptom at the earliest possible stage gives the best chance for curative thyroid surgery. Sadly, Brauckhoff and colleagues reported that in their series of patients, the oldest patient who could be biochemically cured of thyroid disease was 14 years old. Children who were 12 years of age or younger at the time of diagnosis exhibited early severe constipation, preceding other signs and symptoms of the syndrome. Most importantly, these children also had a reduced long-term prognosis when not biochemically cured of thyroid disease. This suggests that additional pathologic processes may be active in a subgroup of MEN2B patients that manifests earlier, with more severe intestinal symptoms and more aggressive thyroid disease.¹¹

Despite growing, detailed understanding of MEN2B RET mutations and the resulting signaling abnormalities, this knowledge has yet to significantly impact the prognosis and management of the syndrome, once it is recognized. Less than 20% of individuals with MEN2B are surgically cured of their thyroid disease, and medical management of the intestinal disease is of limited efficacy. Very young patients with functional obstruction often require a colostomy with colonic resection. Megacolon with secondary diverticulosis is a common colonic finding in teenage and adult individuals with MEN2B. Emergency surgery for perforated diverticular disease in these older patients is described by several authors. Elective colectomy or appendicostomy with antegrade enemas can provide symptomatic relief.^12,15

Not surprisingly, there is considerable interest in developing chemotherapeutic agents that inhibit MEN2B mutant RET signaling. Several approaches are under investigation. Imatinib is a tyrosine kinase inhibitor that has successfully been used against gastrointestinal stromal tumors.^16,17 Imatinib shows inhibitory activity against MEN2A mutant RET and MEN2B mutant RET in medullary thyroid cancer-derived cell lines. Unfortunately, high concentrations were required to inhibit cellular proliferation.¹⁸ Also under investigation are agents that inhibit RET dimer formation¹⁹; agents that reduce autophosphorylation and, thereby, suppress RET (Continued on page 226) (Continued from page 212) growth-promoting signals²⁰; gene therapy that expresses a dominant negative RET mutant or introduces a ribozyme that specifically cuts mutant RET mRNA^21,22; and the targeting of RET with monoclonal antibodies.²³ Although the primary goal of these investigations is to improve the treatment of metastatic thyroid carcinoma, abnormal RET signaling also underlies the severe intestinal symptoms of individuals with MEN2B. They may, therefore, potentially lead to the development of agents to treat or, at least, slow the progression of the intestinal disease.