The RET proto-oncogene (REarranged during Transfection; RET) plays an important 
role in the causation of many thyroid tumours. Germline RET proto-oncogene 
missense mutations have been clearly linked to medullary thyroid carcinoma (MTC) 
and the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2A, 
MEN2B).
METHODS: We investigated a cohort of MEN2-related patients referred to Tygerberg 
Hospital, W Cape (2003-2009). The study cohort was divided into three groups 
based on pathology (viz. MEN/MTC, phaeochromocytoma, and a miscellaneous group 
of MEN pathologies). Families with identified high-risk factors were recalled. 
Serum calcitonin levels were monitored where indicated. DNA was extracted from 
whole blood by standard techniques and polymerase chain reaction (PCR) products 
screened for RET gene variations by heteroduplex single-strand duplication 
techniques (heteroduplex single-strand conformation polymorphism analysis) being 
validated with automated sequencing techniques showing conformational variants 
in acrylamide gel.
RESULTS: We screened 40 persons, male/female ratio 1:1.5. Three ethnic groups 
were represented (white (12), black (11) and mixed race (17)). Nine were index 
MTC cases, 5 phaeochromocytoma, 3 Hirschsprung's disease-MEN associations and 2 
miscellaneous (1 neuroblastoma, 1 intestinal neuronal dysplasia), while 1 fell 
into the MEN2B category. The remaining 19 were unaffected relatives screened for 
carrier status, among whom afamilial recurrence was observed in 7. On genetic 
testing, an RET point mutation at the high-risk 634 cysteine allele was 
identified in 11 cases. A further cysteine radical mutation at the 620 position 
was related to MEN2 in 3 families plus 1 other family referred from elsewhere. 
Other less-recognised gene variations were detected throughout the RET gene in 
70% of cases and included the 691 position on codon 11 (11 cases); the 432 
position (4 cases, 1 homozygous) intronic mutations on exon 4 (1 case); and an 
IVS19-37G/C and a D1017N variation in exon 19 in 2 MEN families. Fifteen MTC 
patients have had thyroidectomies, of which 2 were prophylactic (C-cell 
hyperplasia; early occult MTC). A further 3 are awaiting prophylactic surgery.
CONCLUSION: RET gene mutation carries a risk of MEN2 and MTC in all ethnic 
groups in South Africa. Prophylactic surgery may prevent MTC, so genetic 
screening is important to identify and treat high-risk patients.