Familial medullary thyroid cancer and prominent corneal nerves: clinical and genetic analysis.
A unique kindred manifesting medullary thyroid carcinoma and corneal nerve thickening without other aspects of the multiple endocrine neoplasia 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 mutations by DNA sequence analyses in all affected family members. Screening of 11 family members spanning 4 generations revealed 7 subjects with corneal nerve thickening; of these subjects, 3 had abnormal pentagastrin-stimulated calcitonin studies, and these 3 subjects were each found 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 showed that none of the affected individuals had mutations in either exon 10 or 11, or in exon 16 of the RET protooncogene, regions where mutations have been described for MEN type 2A (MEN-2A) and MEN-2B families, respectively. Thus, compared to the defined syndromes of MEN-2A and MEN-2B, this kindred appears to represent a true clinical overlap syndrome whose genetic basis may be distinct from these two syndromes.
Kane
L A
LA
Division of Endocrinology, Metabolism, and Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905.
Tsai
M S
MS
Gharib
H
H
Khosla
S
S
Robertson
D M
DM
Schaid
D J
DJ
Honchel
R
R
Thibodeau
S N
SN
D000368:Aged; D001483:Base Sequence; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000473:pathology; D003315:Cornea / Q000294:innervation*; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D006801:Humans; D008297:Male; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D018814:Multiple Endocrine Neoplasia Type 2b / Q000235:genetics; D009420:Nervous System / Q000473:pathology; D010375:Pedigree; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
D005819:Genetic Markers; D015335:Molecular Probes