Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene.
BACKGROUND
Familial isolated primary hyperparathyroidism (FIHP) is an autosomal dominant disorder that can represent an early stage of either the multiple endocrine neoplasia type 1 (MEN1) or hyperparathyroidism-jaw tumor (HPT-JT) syndromes; alternatively, the condition can be caused by an allelic variant of MEN1 or HRPT2 (hyperparathyroidism 2 gene), or caused by a distinct entity involving another locus. We have explored these possibilities in a patient with primary hyperparathyroidism, whose mother had a history of renal calculi and primary hyperparathyroidism.


METHODS
Serum biochemistry and radiological investigations for primary hyperparathyroidism, MEN1 and HPT-JT, and genetic testing for MEN1 and HRPT2 mutations were undertaken.


METHODS
FIHP with primary hyperparathyroidism as the sole endocrinopathy due to a previously unreported heterozygous missense germline MEN1 mutation, Tyr351Asn. In addition, another unreported heterozygous missense germline MEN1 mutation, Trp220Leu, was identified in an unrelated male patient with FIHP, whose mother and sister also had primary hyperparathyroidism. DNA from a parathyroid tumor from the sister revealed a loss of heterozygosity in which the mutant allele was retained. This is consistent with Knudson's 'two-hit' model of hereditary cancer and a tumor suppressor role for MEN1 in FIHP.


RESULTS
The patient underwent parathyroidectomy and has remained normocalcemic over a follow-up period of 6 years. The other four patients have remained normocalcemic for a follow-up period of 4-15 years following parathyroidectomy. None has developed abnormalities of the MEN1 syndrome, providing further support that FIHP is a distinct genetic variant of the MEN1 syndrome.
Hannan
Fadil M
FM
Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Oxford, UK.
Nesbit
M Andrew
MA
Christie
Paul T
PT
Fratter
Carl
C
Dudley
Nicholas E
NE
Sadler
Greg P
GP
Thakker
Rajesh V
RV
D000328:Adult; D000483:Alleles; D005260:Female; D006801:Humans; D006961:Hyperparathyroidism / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation / Q000235:genetics*; D016105:Parathyroidectomy; D011518:Proto-Oncogene Proteins / Q000235:genetics*
C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins