IJUP08 - Universidade do Porto

Primary Hyperparathyroidism: the unknown world of sporadic
cases and their genetic alterations
Alvelos M. 1,3, Barbosa E.2 and Soares P.3,4
1Faculty of Science, University of Porto, Portugal.
2 Biomedical Institute Abel Salazar, University of Porto, Portugal.
3Institute of Molecular Pathology and Immunology of University of Porto, Portugal.
4 Department of Pathology, Medical Faculty, University of Porto, Portugal.
Hypercalcemia is a condition characterized by elevated calcium levels in the blood. It is a
common under diagnosed metabolic abnormality and a health problem that affects, in
Portugal, about 10.000 individuals. Approximately 90% of the cases are due to primary
hyperparathyroidism (PHPT). The majority of PHPT cases are sporadic and related with
parathyroid adenoma (80-85%), hyperplasia (15-20%) or carcinoma (1%). About 10% of
the PHPT cases are hereditary forms that include MEN 1 gene mutations (Multiple
Endocrine Neoplasia type 1) and RET gene mutations (Multiple Endocrine Neoplasia type
2). Recently, it was described a germ-line mutation in the CDKN1B gene in a MEN1
mutation-negative patient with parathyroid and pituitary tumors. The molecular
mechanisms underlying the pathogenesis of sporadic PHPT are incompletely understood
although alterations in MEN1, HRPT2 and CDKN1B genes have already been reported. In
the present work, we aim to perform the genetic characterization of apparently sporadic
PHPT cases. [1,3]
Constitutional DNA samples were obtained from thirty apparently sporadic PHPT patients.
Germ-line mutations in RET, MEN1 and CDKN1B genes were searched by PCR/SSCP
and direct DNA sequencing. Detection of somatic alterations involving Cyclin D1
expression was performed by immunohistochemistry.[2]
Only polymorphic alterations were detected in RET and CDKN1B genes. These results
confirm that none of the cases in our series corresponds to hereditary forms of MEN2 or
MEN4. In one case a MEN1 germ-line mutation was detected, showing that this patient
harbors, in fact, a familial form of MEN1 instead a sporadic form of PHPT. The Cyclin D1
immunohistochemistry study revealed that four of the 29 (14%) cases analyzed had nuclear
staining in 20-35% of the tumor cells, raising the possibility of Cyclin D1 mutation in
sporadic PHPT.
In conclusion, these results showed that all, except one case, of our series probably
corresponds to true sporadic forms of PHPT. Moreover, it was observed an overexpression
of Cyclin D1 in 14% of the studied cases. Further studies are in course in order to fully
characterize the molecular alterations underlying PHPT.
References:
[1] Miedlich, S., Krohn, K. and Paschke, R. (2003), Update on genetic and clinical aspects of
primary hyperparathyroidism, Clinical Endocrinology, 59, 539-554.
[2] Hsi, E.D., Zukerberg, L.R., Yang, W., and Arnold, A. (1996), Cyclin D1/PRAD1 expression in
parathyroid adenomas: an immunohistochemical study, Journal of Clinical Endocrinology and
Metabolism, 81(5), 1736-1739.
[3] Pellegata, N. S.,Martinez, L.Q., Siggelkow, H.,Samson, E., Blink, K., Höfler, H., Fend, F.,
Graw,
J. and Atkinson, M. J. (2006),Germ-line mutations in p27 kip1 cause multiple endocrine neoplasia
syndrome in rats and humans, PNAS, 103(42), 15558-15563.
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