The MEN 2B subtype makes up about 5% of MEN 2 cases. The MEN 2B subtype was initially called mucosal neuroma syndrome or Wagenmann-Froboese syndrome. MEN 2B is characterized by the early development of an aggressive form of MTC in all patients.[68,69] Patients with MEN 2B who do not undergo thyroidectomy at an early age (approximately 1 year) are likely to develop metastatic MTC at an early age. Before intervention with early risk-reducing thyroidectomy, the average age at death in patients with MEN 2B was 21 years. Pheochromocytomas occur in about 50% of MEN 2B cases; about half are multiple and often bilateral. Clinically apparent parathyroid disease is very uncommon.[5,49,70]
Patients with MEN 2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. The lips become prominent over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination.
About 40% of patients have diffuse ganglioneuromatosis of the gastrointestinal tract. Associated symptoms include abdominal distension, megacolon, constipation, and diarrhea. About 75% of patients have a Marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.[66,67]
Genetically Related Disorder
Hirschsprung disease (HSCR)
HSCR (OMIM), a disorder of the enteric plexus of the colon that typically results in enlargement of the bowel and constipation or obstipation in neonates, is observed in a small number of individuals with MEN 2A, FMTC, or very rarely, MEN 2B. Up to 40% of familial cases of HSCR and 3% to 7% of sporadic cases are associated with germline mutations in the RET proto-oncogene and are designated HSCR1.[72,73] Some of these RET mutations are located in codons that lead to the development of MEN 2A or FMTC (i.e., codons 609, 618, and 620).[71,74]
In a study of 44 families, seven families (16%) had cosegregation of MEN 2A and HSCR1. The probability that individuals in a family with MEN 2A and an exon 10 Cys mutation would manifest HSCR1 was estimated to be 6% in one series. Furthermore, in a multicenter international RET mutation consortium study, 6 of a total of 62 kindreds carrying either the C618R or C620R mutation also had HSCR.
A novel analytic approach employing family-based association studies coupled with comparative and functional genomic analysis revealed that a common RET variant within a conserved enhancer-like sequence in intron 1 makes a 20-fold greater contribution to HSCR compared with all known RET mutations. This mutation has low penetrance and different genetic effects in males and females. Transmission to sons and daughters leads to a 5.7-fold and 2.1-fold increase in susceptibility, respectively. This finding is consistent with the greater incidence of HSCR in males. Demonstrating this strong relationship between a common noncoding mutation in RET and the risk of HSCR also accounts for previous failures to detect coding mutations in RET-linked families.