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Diagnosis of Parathyroid Tumors in Familial Isolated Hyperparathyroidism with HRPT2 Mutation: Implications for Cancer Surveillance

Units of Endocrinology (A.S., C.B., M.L.M.), Genetics (V.G., L.A.M., L.D.), Surgery (N.B.), and Pathology (M.B.), Hospital "Casa Sollievo della Sofferenza" Instituto di Ricovero e Cura a Carattere Scientifico, 71013 San Giovanni Rotondo (FG), Italy; Department of Clinical Science (S.M.), University of Rome "La Sapienza", 00185 Rome, Italy; and Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics (D.E.C.C.), University of Toronto, Toronto, Ontario, Canada M5S 1A1

Address all correspondence and requests for reprints to: Alfredo Scillitani, Unit of Endocrinology, "Casa Sollievo della Sofferenza" Hospital Instituto di Ricovero e Cura a Carattere Scientifico, 71013 San Giovanni Rotondo (FG), Italy. E-mail: alscill{at}tin.it.

Context: Mutations of the HRPT2 gene have recently been implicated in the development of parathyroid carcinoma.

Objective: The objective of this study was early diagnosis of parathyroid tumor in a family with germline HRPT2 mutation.

Patients, Methods, and Results: In a 40-yr-old male previously treated for parathyroid atypical adenoma, we screened the 17 translated HRPT2 exons and their exon-intron boundaries and found a germline frameshift mutation in exon 7 (685delAGAG) predicting a premature stop codon at nucleotides 767–769. Nine family members (age, 33.9 ± 19.8 yr, mean ± SD) also carry the mutation, but eight have had normal serum calcium. Biochemical and ultrasonographic evaluation uncovered a 27-yr-old hypercalcemic carrier niece with an atypical parathyroid adenoma, and a 43-yr-old normocalcemic carrier sister was found by ultrasonography to have an extrathyroidal nodule, which proved to be parathyroid carcinoma. The index case, 12 yr after surgery, was normocalcemic, but ultrasonography revealed an extrathyroidal nodule in the contralateral hemithyroid tissue that proved to be atypical adenoma.

Conclusions: Our report confirms that germline mutations of HRPT2 gene may be associated with multiple parathyroid neoplasms. Our experience suggests that longitudinal surveillance by serum biochemistry alone may not be 100% sensitive, and addition of routine neck ultrasonography is a readily accepted adjunct that may facilitate earlier disease detection in some families.

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