FAMILIAL MEDULLARY-THYROID CANCER AND PROMINENT CORNEAL NERVES - CLINICAL AND GENETIC-ANALYSIS

A unique kindred manifesting medullary thyroid carcinoma and corneal n erve thickening without other aspects of the multiple endocrine neopla sia syndrome (MEN) was analyzed by linkage analysis using four highly polymorphic (CA)(n) repeat markers (sTCL-1, D10S141, ZNF22, and sJRH-1 ). Additionally, the RET protooncogene was examined for specific mutat ions by DNA sequence analyses in all affected family members. Screenin g of 11 family members spanning 4 generations revealed 7 subjects with corneal nerve thickening; of these subjects, 3 had abnormal pentagast rin-stimulated calcitonin studies, and these 3 subjects were each foun d to have C-cell hyperplasia or medullary thyroid carcinoma at surgery . Linkage analysis showed cosegregation of alleles (as defined by the above markers), with the presence of both corneal nerve thickening and medullary thyroid carcinoma/C-cell hyperplasia (maximum LOD score, 2. 69; consistent with, but not proving Linkage). DNA sequence analysis s howed that none of the affected individuals had mutations in either ex on 10 or 11, or in exon 16 of the RET protooncogene, regions where mut ations have been described for MEN type 2A (MEN-2A) and MEN-SB familie s, respectively. Thus, compared to the defined syndromes of MEN-2A and MEN-2B, this kindred appears to represent a true clinical overlap syn drome whose genetic basis may be distinct fi om these two syndromes.