Endocrine Abstracts (2006) 11 P157

Small intragenic somatic mutation associated with a germline mutation of HRPT2 gene in a patient with sporadic primary hyperparathyroidism

E Pardi, F Cetani, E Ambrogini, S Borsari, M Lemmi, A Pinchera & C Marcocci

Department of Endocrinology, University of Pisa, Pisa, Italy.

We describe a 39-yr-old man with recurrent sporadic primary hyperparathyroidism (PHPT). In 1987, at the age of 21 yr, a severe form of PHPT was diagnosed [serum calcium 17.3 mg/dl; C-PTH 3.17 ng/ml (<0.88 ng/ml), cortical thinning and erosion] and a right parathyroid adenoma was removed. Three years later recurrence of PHPT was diagnosed but no treatment was initially advised. In 1993 the patient underwent cervical exploration and a right parathyroid adenoma was excised. Serum calcium and PTH remained normal for up to 1997 when a further recurrence of PHPT was documented and the patient was referred to our Department. The patient was in good health. Serum calcium and PTH were moderately elevated (10.6 mg/dl and 72 pg/ml, respectively). There was no evidence of MEN1-associated neoplasia. No kidney lesions or jaw tumor were detected. PTx was advised but the patient was lost to follow-up until 2004 when he was submitted to surgery with removal of the superior and inferior left parathyroid glands. Histological examination showed chief cells hyperplasia. After a transient hypocalcemia serum calcium and PTH remained normal up to September 2005. Serum calcium and PTH were normal in 13 family members. Studies of MEN1 and HRPT2 genes were undertaken. Matched samples of DNA from patient’s blood and abnormal parathyroid tissue were used. Loss of heterozygosity at 11q13 and HRPT2 genes, using microsatellite polymorphisms PYGM and DS11S449 and intragenic polymorphisms of intron 10 and 14, respectively, was negative. Coding regions and splice junctions of MEN1 and HRPT2 genes were sequenced for mutations. Sequence analysis of HRPT2 gene revealed a somatic stop codon mutation in exon 2 (Y54X) and a germline missense mutation in exon 3 (R91P). The germline R91P mutation was absent in the 13 families members. No mutation of MEN1 gene was found. In conclusion, we describe a patient with recurrent PHPT with a biallelic inactivation of HRPT2 gene due to a germline mutation as ‘first hit’ and a small intragenic somatic mutation as ‘second hit’, consistent with the Knudson ‘two hits’ hypothesis.

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