Dear Sir, The useful application of RET mutation study in management of families with multiple endocrine neoplasia type 2 (MEN 2) was reviewed in a minisymposium series [ 1]. It is very useful in the identification of mutation carriers in families with the disease. However most patients with medullary thyroid carcinoma (MTC) present with a sporadic disease. Furthermore, it has been estimated that less than 5% of MTC patients without family history have a RET mutation. Eng et al. [ 2] studied 67 patients with apparently sporadic MTC and found only one germline mutation. Risk determination and genetic counselling are important in management of these patients and their family members. The important clinical judgement is to determine whether they have a familial disease. We describe here the way that we calculated the risk for familial disease and counselled the patients.
About 30% of all MTCs are hereditary, which may be a part of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma (FMTC) [ 3]. In FMTC, MTC is the only tumour phenotype. Although mutations are clustered in the five cysteine residues of exons 10 and 11 in almost all families of MEN 2A, mutations are less frequently found in FMTC families and a large difference in prevalence of RET mutations has been reported in the different series of FMTC families ( Table 1). On account of the very high prevalence (~95%) of RET mutations in MEN 2A [ 4], MEN 2A is virtually excluded in patients with no RET mutation.
However, these mutation-negative MTC patients may still have a small risk for FMTC. According to an early study, RET mutations in exon 10 or 11 were identified only in 66% FMTC [ 5]. Currently, there is no consensus on how to counsel these patients and their families [ 2] and only about 55% of the carriers of mutation will present with MTC by the age of 60 [ 6]. Elderly relatives appearing to be unaffected may be non-penetrant carriers of the disease. This problem was reported by Ponder et al. [ 6], who used age-related penetrance to calculate the conditional probability of having a familial form of MTC from the pedigree information. They reported that a family with unaffected 70-years-old parents and two additional healthy middle-age siblings would have a 13% chance of having the familial disease. We have studied six unrelated sporadic MTC patients and their family members by pentagastrin calcitonin test and mutation analysis of exons 10 and 11 of RET. All the calcitonin tests were negative and no RET mutation was found in these families. The calculation of conditional probability was employed in the counselling of these patients, in which the prevalence of RET mutation in FMTC is also incorporated. The figure of 79.5% was used for the percentage of RET mutations among FMTC families ( Table 1) [ 7–16]. The International RET Mutation Consortium [ 17] reported that 27 families showed a mutation in one of the five cysteine codons among a collection of 34 FMTC families, whilst another three families had a mutation in codon 768 of exon 13. Mutations in exon 10 and 11 accounted for 79.4% of FMTC families, which was similar to the figure derived from our analysis in Table 1.
The risk for FMTC is 3% in a family with clinically healthy parents and two other healthy siblings, and RET mutation is not found in the proband ( Table 2). Furthermore, if two healthy siblings have been screened by pentagastrin stimulation test and both are negative, the risk for FMTC will be further reduced to 1% ( Table 3). The estimated risk for FMTC in this family is around 1%, thus the prior risk for any child or sibling of the proband to carry an unidentified mutation will be 0.5%.
Family members were informed of this risk and they were allowed to decide whether to continue clinical follow up and provocative calcitonin tests. Although the role of calcitonin tests has been questioned in the diagnosis of families with MEN 2A, it may be useful in the calculation of risk for inherited disease among patients with sporadic disease. Therefore, a detailed family history together with provocative calcitonin test in first-degree relatives will contribute to the determination of possible risk for FMTC in these families.