[Show abstract][Hide abstract] ABSTRACT: Hyperparathyroidism-jaw tumour (HPT-JT) syndrome is a rare autosomal dominant cause of benign and malignant parathyroid tumours, ossifying jaw tumours, various cystic and neoplastic renal abnormalities and benign and malignant uterine tumours. Disease-causing mutations have been localised in the tumour suppressor gene CDC73. There is limited information available on the mutations, and resulting phenotypes and long-term follow-up data are especially scarce.
We analysed the clinical data from 16 patients (including three families) carrying mutations in the CDC73 gene. We describe five new mutations/gene variants, the corresponding phenotypes of these carriers and the long-term follow-up.
The 16 patients were evaluated at an endocrine outpatient clinic and at a surgical department. DNA samples were obtained for sequence analysis of the CDC73 gene.
Clinical features of HPT-JT syndrome were detected in 13 of the 15 carriers with germline CDC73 mutations. The major features were benign (n=7; 47%) or cancerous (n=3; 20%) HPT-JT was present in eight cases (53%). Most patients had severe hypercalcaemia, and median serum calcium levels were 3.36 mmol/l. A patient with non-secretory parathyroid carcinoma was included. HPT was diagnosed at a median age of 28.5 years. Mutational analysis of the CDC73 gene identified eight sequence changes, three of them have been reported previously, whereas five are novel: c.1346delG, c.88_94delTTCTCCT, the non-coding variants, c.307+5G>T and c.424-5T>C and c.*12C>A of unknown significance.
This study significantly increases the information available on the mutations and phenotypes of HPT-JT syndrome.
European Journal of Endocrinology 06/2011; 165(3):477-83. DOI:10.1530/EJE-11-0003 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For rare and novel RET mutations associated with hereditary medullary thyroid carcinoma (MTC), clinical and functional studies are needed to classify the RET mutation into one of the three clinical risk groups.
We analyzed proliferative properties and clinical implications associated with the RET protooncogene transmembrane domain mutation S649L.
The transforming potential and mitogenic properties of S649L mutation were investigated clinically and by evaluating kinase activity, cell proliferation, and colony formation.
Fifteen individuals from five kindreds were identified as carriers of a RET protooncogene mutation in exon 11 codon 649 (TCG(Ser)-->TTG(Leu)). In two out of five index patients, a second RET mutation (C634W or V804L) was detected.
Eight gene carriers were operated on. Histology revealed MTC and C-cell hyperplasia in three index and three screening patients respectively. In all other gene carriers (aged 41-64 years), calcitonin levels were in the normal range, and pentagastrin-stimulated calcitonin levels were <100 pg/ml. Therefore, thyroidectomy had not yet been performed. In one index patient carrying the S649L mutation, hyperparathyroidism was confirmed histologically. RET S649L-expressing NIH3T3 cells exhibited a clear increase of phosphotyrosine and proliferation rate when compared with parental NIH3T3 cells but a significantly lower kinase activity and cell growth rate when compared with RET C634R-expressing cells. When compared with RET C634R, the S649L mutant showed moderate transforming potential with small-sized colonies.
Our clinical and in vitro findings indicate that the transmembrane RET S649L mutation is associated with late-onset non-aggressive disease. Recommendations for prophylactic thyroidectomy should be individualized depending on stimulated calcitonin levels.
European Journal of Endocrinology 07/2008; 158(6):811-6. DOI:10.1530/EJE-07-0817 · 4.07 Impact Factor