Multiple endocrine neoplasia type 1 (MEN-1) mutation analysis in patients with primary hyperparathyroidism under the age of 40 years

Radu Mihai; Gregory Sadler; Lisa Walker; Rajesh Thakker

Background: Primary hyperparathyroidism (PHPT) is commonly diagnosed after the fifth decade of life. Current guidelines suggest that young patients with apparently sporadic PHPT should be screened as potential index cases for the multiple endocrine neoplasia type 1 (MEN-1) syndrome.

Aim: To determine the prevalence of mutations in the MEN1 gene in young patients presenting with apparently sporadic PHPT before the age of 40 years.

Method: A prospective database maintained in our Unit was used to identify patients who underwent parathyroidectomy before their 40th birthday. An invitation letter was sent asking them to consider genetic screening. MEN1 mutation analysis was performed using leukocyte DNA.

Results: Between January 2000 and October 2009, 581 patients of median age 62 years (range 15–90 years) were operated for PHPT. Only 57 patients were under the age of 40 years (range 15–40 years, median 34 years). The proportion of men was much higher in the young group (43%) compared with those aged 40–60 years (31%) or 60–80 years (22%).

Ten young patients were known to have familial PHPT due to MEN1 (n=7), MEN2 (n=1) or hyperparathyroidism–jaw tumour (HPT–JT) syndrome (n=2). One patient had a radical excision of local recurrence of parathyroid cancer. Forty-six patients had preoperative neck imaging and underwent scan-directed minimally invasive parathyroidectomy (n=29) or bilateral neck exploration (n=17) and were found to have single adenomas (n=44) or multigland disease (n=2). All 46 patients were cured after undergoing 49 operations.

All young patients were prospectively invited for genetic tests and 17 of them agreed to proceed (Table).

	Genetic screening (n=17) mean±S.D. (median)	Not screened (n=29) mean±S.D. (median)	Patients 40–90 years (n=516) mean±S.D. (median)
Sex	6M:11F	11M:18F	132M:384F
Age	28±11 (32) years	34±5 years (35 years)	65±12 (65) years
Severity of hypercalcaemia	2.94±0.2 (2.90) mmol/l	2.99±0.3 (2.93) mmol/l	2.90±0.3 (2.90)
Weight of adenomas removed	884±600 (746) mg	1533±1000 (1340) mg	1715±3700 (900) mg
Length of follow-up	37±32 (33) months	25±19 (22) months	25±64 (16) months

One mutation in the MEN1 gene was identified in a 27 years old woman with double adenomas (c1045c>T, pGln349X). The overall prevalence of MEN1 gene mutation in patients under the age of 40 years was 14% (8/57 patients) but only 5% in apparently sporadic tumours (1/18 patients). A further eight patients were operated for MEN1-related PHPT at and age over 40 years (range 42–70 years).

Conclusion: These data indicate that ~15% of patients under the age of 40 years with PHPT may have MEN1 mutations.

Endocrine Abstracts

OC4.1