Clinical testing for mutations in the MEN1 gene in Sweden: a report on 200 unrelated cases.

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is a tumor syndrome of the parathyroid, endocrine pancreas, and anterior pituitary caused by mutations in the MEN1 gene on 11q13. OBJECTIVE: The goal of this study was to determine the MEN1 mutation spectrum and detection rate among Swedish patients and identify which patient categories should be tested for MEN1 mutations. DESIGN/SETTING/PATIENTS: DNA sequences and referral forms from patients referred to the Department of Clinical Genetics at Karolinska University Hospital, Sweden, for clinical MEN1 mutation screening were analyzed. The mutation status of 371 patients (including 200 probands) was ascertained, and the multiplex ligation-dependent probe amplification (MLPA) assay was evaluated for the detection of large deletions. MAIN OUTCOME MEASURE: The main outcome measure was MEN1 genotypes. RESULTS: Forty-eight of 200 index cases (24%) shared 40 different mutations (18 novel). A total of 69% of all mutations resulted in a truncated protein. Two large deletions were detected by MLPA. A total of 94% of all MEN1 families had a mutation in the coding region of the MEN1 gene. A total of 6% of sporadic cases had MEN1 mutations. There was no correlation between severe disease and mutation type or location. CONCLUSIONS: A total of 4% of all mutations were large deletions, and MLPA is now included in our standard MEN1 mutation screening. Individuals with at least one typical endocrine tumour and at least one of the following: 1) a first-degree relative with a major endocrine tumor; 2) an age of onset less than 30 yr; and/or 3) multiple pancreatic tumors/parathyroid hyperplasia were most likely to harbor a mutation; thus these patients should be screened for MEN1 mutations.

An androgen receptor gene mutation (E653K) in a family with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency as well as in partial androgen insensitivity.

An androgen receptor (AR) variant (E653K) was found in two unrelated Swedish families. One family had two girls affected with congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency. The girls, who showed mild virilization in relation to their CYP21 genotype, had inherited the AR gene mutation from their father, who showed no symptoms of androgen insensitivity. The other family had a boy with partial androgen insensitivity and ambiguous genitalia, and he had inherited the AR gene mutation from his mother. The mutant receptor showed a transactivating capacity in the same range as the normal receptor at high concentrations of ligand (1 and 10 nM dihydrotestosterone), but absent or reduced transactivation at low levels (0.01 and 0.1 nM). The receptor variant was not found among 250 additional unselected Swedish men. Sequencing of the AR gene in five unrelated CAH girls with the I172N mutation in CYP21 and minimal virilization did not reveal any additional deviations from the normal reference sequence. In addition, there was no difference in lengths of the polymorphic CAG repeat in the AR gene between CAH girls with the I172N mutation who showed minimal and severe virilization, and we found no evidence of skewed X-inactivation. We conclude that AR gene mutations or polymorphisms are not a common factor influencing the degree of hyperandrogenic symptoms displayed by CAH girls, and that the AR E653K mutation is compatible with normal genital development, although it can cause genital malformations in susceptible individuals.