LARGE KINDRED WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN1): FOUNDER EFFECT, TUMOR PREVALENCE, AND BONE MINERAL DENSITY PROFILES

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Delmar M. Lourenço-Jr, Rodrigo A. Toledo, Flavia L. Coutinho, Maria G. Cavalcanti, Joya E.M. Correia-Deur, Fabio L.M. Montenegro, Sheila A.C Siqueira, Leontina Margarido, Marcel CC Machado, Sergio P.A. Toledo
Unidade de Endocrinologia Genetica, LlM-25, Endocrinologia, Hospital das Clinicas do Faculdade de Medicina do Un ivers ida de de Sao Paulo, Brazil.
Background: MEN1 is characterized by hyperparathyroidism (HPT) and pituitary (PIT) and entero-pancreatic (PET) tumors. Five very large families affected by MEN1 (> 25 cases) have been described and in all ofthem, a founder effect has been reported (1 ).In addition, the prevalence of classic MEN1-related tumors in very large families may differ from that found in typical MEN1 series that usually include small families (2). Furthermore, bone mineral density (BMD) in HPT/MEN1 cases has not been fully studied (3). Aims: To document the phenotype of an extended Brazilian MEN1 genealogy resulting from a founding MEN 1 mutation, in which we emphasize, a) the prevalence of classic MEN1-related tumors in 28 affected cases and b) the study of BMD in 20 HPT /MEN1 cases.

Methods: Clinical/biochemical/image studies were used to characterize the MEN1 tumors. Haplotype analysis was employed to study the founder effect. BMD was measured by bone densitometry (DEXA).

Results: Seventy six MEN 1-related tu mors were diagnosed within the 28 fully examined affected cases. The tumor prevalence was: HPT (93%); PET (68.2%), and PIT (52%). High frequencies of non-functioning tumors were documented: pancreatic (54.5%), pituitary (1704%), and adrenocortical (45.5%) tumors. The prevalence of prolactinoma (29.6%) was similar to that described in the prolactinomavariant Burin (32%). Co-occurrence of functioning/nonfunctioning pancreatic tumors was present in 60% of MEN1 cases with PET. Prevalence of PIT was higher (P<0.05) than in nine series involving 873 MEN1 cases. Furthermore, BMD analysis revealed osteoporosis (T, -2.87 ± 0.32) in the compact bone (1/3 distal radius) of HPT/MEN1 patients. Bone mineral loss in the lumbar spine (T, -1.95 ± 0.39) and femoral neck (T, -1048 ± 0.27) was present.

Conclusions: We described the sixth very large MEN1 family reported to-date. High frequencies of functioning and non-functioning MEN1-related tumors were found. These data confirmed previous findings suggesting that the prevalence of MEN1-related tumors in large families may differ from MEN1 series. Furthermore, early and severe bone demineralization was documented in all three bone sites studied, indicating that the bone mineral profiles in HPT/ MEN1 may in differ somewhat from classical patterns described in sporadic primary HPT.

References:

1. Vierimaa 0, et al. Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype phenotype correlation. European Journal of Endocrinology 2007 157285-294.
2. Hao W, et al. Multiple endocrine neoplasia type 1 variant with frequent prolactinoma and rare gastrinoma. Journal of Clinical Endocrinology and Metabolism, 2004 89 3776-3784.
3. Bilezikian JP, et al. Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. Journal of Internal Medicine 2005 257 6-17.

Support: RAT. is recipient of Coordena<;ao de Aperfei<;oamento de Pessoal de Nfvel Superior (CAPES) PhD fellowship. D.M.L is recipient of Funda<;ao Faculdade de Medicina (FFM) pas-doctoral fellowship.