Correspondence

PTH Mutation with Primary Hyperparathyroidism and Undetectable Intact PTH

N Engl J Med 2008; 359:1184-1186September 11, 2008

Article

To the Editor:

We describe a case of hypercalcemia associated with the secretion of an abnormally truncated parathyroid hormone (PTH) from a parathyroid adenoma. A 59-year-old postmenopausal woman presenting with back pain had an elevated serum calcium level, at 11.8 mg per deciliter (normal range, 8.8 to 10.2), and an intact serum PTH level that was consistently below the limit of detection on two different assays: less than 3 pg per milliliter on Immulite assay (Bio-Mediq DPC) and less than 4 pg per milliliter on Liaison N-tact assay (DiaSorin). Neither PTH-related protein nor paraprotein was detected in serum. Other findings, including markers of bone turnover and histomorphometric analysis of a biopsy specimen from transiliac bone, are presented in Table 1 in the Supplementary Appendix, available with the full text of this letter at www.nejm.org.

Computed tomography (CT) of the neck and chest showed a soft-tissue mass inferior to the right thyroid lobe (Fig. 1 in the Supplementary Appendix). A sestamibi scan showed intense uptake in this region (Fig. 2 in the Supplementary Appendix). On surgical exploration of the neck, three normal parathyroid glands were identified, and a right inferior parathyroid adenoma weighing 4.98 g was excised. The calcium levels normalized within 24 hours after surgery (Figure 1AFigure 1Levels of Calcium and Intact Parathyroid Hormone (PTH), Immunohistochemical Analysis, and Sequencing of the PTH Gene.). Histopathological analysis confirmed the features of a typical parathyroid adenoma, except that immunohistochemical analysis for PTH was negative; in contrast, an adjacent rim of suppressed non-neoplastic parathyroid stained strongly for PTH (Figure 1B).

Surprisingly, microarray analysis showed up-regulated PTH expression in the tumor (Table 2 in the Supplementary Appendix). We therefore sequenced the coding exons of the PTH gene from tumor DNA and found a missense mutation of CGA to TGA at codon 83 (R83X), which predicts a premature truncation after the 52nd amino acid in the secreted PTH peptide (Figure 1C). The wild-type sequence at this position was not observed in tumor DNA. However, sequencing of DNA from peripheral-blood leukocytes showed a heterozygous pattern, which suggested that the wild-type PTH allele had been deleted in the tumor (Fig. 3 in the Supplementary Appendix). Loss-of-heterozygosity studies confirmed the deletion of microsatellite markers that flank the PTH locus on chromosome 11p in a manner that is not unusual in parathyroid tumors.1 We confirmed that an N-terminal PTH fragment was produced by tumor cells cultured ex vivo (Table 3 in the Supplementary Appendix).

This case provides evidence that an endogenously produced N-terminal PTH fragment can be biologically active.2 This PTH mutation has previously been studied in vitro and shown to impair translocation across the endoplasmic reticulum, cleavage of pro-PTH, and secretion of PTH.3 Nevertheless, the truncated PTH in this case produced hypercalcemia and the skeletal manifestations of typical hyperparathyroidism,4 as evidenced by coupled increases in formation and resorption on histomorphometric analysis of bone. These observations show that hypercalcemia can arise from a parathyroid adenoma, even in the absence of detectable serum PTH, and can have implications for the tissue-specific biologic actions of PTH and, more broadly, for the pathophysiological basis of primary hyperparathyroidism.

Amy Y.M. Au, Ph.D.
Kerrie McDonald, Ph.D.
Kolling Institute of Medical Research, Sydney, NSW 2065, Australia

Anthony Gill, F.R.C.P.A.
Mark Sywak, F.R.A.C.S.
Royal North Shore Hospital, Sydney, NSW 2065, Australia

Terrence Diamond, F.R.A.C.P.
University of New South Wales, Sydney, NSW 2217, Australia

Arthur D. Conigrave, M.D., Ph.D.
Roderick J. Clifton-Bligh, Ph.D.
University of Sydney, Sydney, NSW 2006, Australia
jclifton@med.usyd.edu.au

Supported by the Department of Endocrinology, Royal North Shore Hospital, Sydney.

Dr. Clifton-Bligh reports receiving lecture fees (directed to research funds) from Servier, Sanofi-Aventis, and GlaxoSmithKline. No other potential conflict of interest relevant to this letter was reported.

Presented in part at the 17th Annual Scientific Meeting of the Australian and New Zealand Bone and Mineral Society, Queenstown, New Zealand, September 9–12, 2007.

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Citing Articles (3)

Citing Articles

1. 1

   Murat Bastepe, Harald Jüppner, Rajesh V. Thakker. 2012. Parathyroid Disorders. , 557-588.
   CrossRef

2. 2

   Hirotaka Komaba, Takatoshi Kakuta, Masafumi Fukagawa. (2011) Diseases of the parathyroid gland in chronic kidney disease. Clinical and Experimental Nephrology 15:6, 797-809
   CrossRef

3. 3

   M. Mannstadt, E. Holick, W. Zhao, H. Juppner. (2011) Mutational analysis of GCMB, a parathyroid-specific transcription factor, in parathyroid adenoma of primary hyperparathyroidism. Journal of Endocrinology 210:2, 165-171
   CrossRef