Level of evidence: 5
Mode of inheritance
All of the MEN 2 subtypes are inherited in an autosomal dominant manner. For the child of someone with MEN 2, the risk of inheriting the MEN 2 mutation is 50%. Some individuals with MEN 2, however, carry a de novo gene mutation; that is, they carry a new mutation that was not present in previous generations of their family and thus do not have an affected parent. The proportion of individuals with MEN 2 who have an affected parent varies by subtype.
MEN 2A: About 95% of affected individuals have an affected parent. It is appropriate to evaluate the parents of an individual with MEN 2A for manifestations of the disorder. In the 5% of cases that are not familial, either de novo gene mutations or incomplete penetrance of the mutant allele is possible.
FMTC: Multiple family members are affected; therefore, all affected individuals inherited the mutant gene from a parent.
MEN 2B: About 50% of affected individuals have de novo RET gene mutations, and 50% have inherited the mutation from a parent.[155,156] The majority of de novo mutations are paternal in origin, but cases of maternal origin have been reported.
Siblings of a proband: The risk to siblings depends on the genetic status of the parent, which can be clarified by pedigree analysis and/or DNA-based testing. In situations of apparent de novo gene mutations, germline mosaicism in an apparently unaffected parent must be considered, even though such an occurrence has not yet been reported.
The psychosocial impact of genetic testing for MEN 2 has not been extensively studied. Published studies have had limitations such as small sample size and heterogeneous populations; thus, the clinical relevance of these findings should be interpreted with caution. Identification as the carrier of a deleterious mutation may affect self-esteem, family relationships, and quality of life. In addition, misconceptions about genetic disease may result in familial blame and guilt.[158,159] Several review articles outline both the medical and psychological issues, especially those related to the testing of children.[160,161,162,163] The medical value of early screening and risk-reducing treatment are contrasted with the loss of decision-making autonomy for the individual. Lack of agreement between parents about the value and timing of genetic testing and surgery may spur the development of emotional problems within the family.
One study examined levels of psychological distress in the interval between submitting a blood sample and receiving genetic test results. Those individuals who experienced the highest level of distress were aged younger than 25 years, single, and had a history of responding to distressful situations with anxiety. Mutation-positive parents whose children received negative test results did not seem to be reassured, questioned the reliability of the DNA test, and were eager to continue screening of their noncarrier children.