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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.

	Abstract

Top Abstract Introduction Initial case presentation Subjects and Methods Results Discussion References

 
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.

	Introduction

Top Abstract Introduction Initial case presentation Subjects and Methods Results Discussion References

 
THE AUTOSOMAL DOMINANT syndrome of hyperparathyroidism with jaw tumors (HPT-JT) may be attributable to mutations in the HRPT2 gene located on chromosome 1q25 (1). Little is known about the function of the gene product, parafibromin, but it appears to act as a tumor suppressor. Recent studies suggest parafibromin is an accessory factor for RNA polymerase II and part of the PAF1 complex that plays a key role in transcription and heterochromatin modeling (2, 3, 4, 5). In a study of 21 sporadic parathyroid carcinomas in 15 patients, truncating mutations were identified in 10 patients, and three were found to be germline (6). Subsequently, truncating mutations were reported in tumors from four patients (7). Simonds et al. (8) recently identified a germline frameshift mutation in a proband with metastatic parathyroid carcinoma coming from a family previously classified as having familial isolated hyperparathyroidism. Cetani et al. (9) identified two germline mutations of seven apparently sporadic parathyroid carcinomas. In studies of apparently sporadic carcinomas with germline mutations (6, 9), jaw tumors were not reported. Other authors reported significant associations of parathyroid tumors with renal anomalies, including tumors and cystic disease, and evidence for a higher incidence of uterine tumors (10, 11). Thus, there is considerable variability in penetrance and expressivity of truncating HRPT2 mutations, making it difficult to develop comprehensive but efficient guidelines for carrier surveillance.

However, primary hyperparathyroidism (PHPT) is the most prevalent trait, occurring in 80% of adult carriers at a mean age of 32 yr, but subjects younger than 10 yr of age have been reported (12). More importantly, PHPT is associated with parathyroid carcinoma in 15% of cases. For early identification of PHPT and carcinoma in carriers of germline HRPT2 mutations, suggestions have focused on biochemical monitoring including serum calcium, or calcium plus PTH (6, 11). We describe our experience with longitudinal surveillance of a family bearing a germline mutation of the HRPT2 gene. The subsequent discovery of a parathyroid carcinoma in a normocalcemic carrier and the reoccurrence of atypical adenoma in the normocalcemic index case suggest that adding neck ultrasonography to the surveillance protocol may have a role in early detection of potentially serious parathyroid neoplasms in such families.

	Initial case presentation

Top Abstract Introduction Initial case presentation Subjects and Methods Results Discussion References

 
The index case first came to our attention at 29 yr of age, suffering from a hypertensive crisis and acute heart failure. He was noted to have nephrocalcinosis with chronic renal failure, and a serum calcium of 10.2 mg/dl (reference interval, 8.2–10.4 mg/dl). The family history was negative for parathyroid disease, but renal stones were reported in siblings and more distant paternal relatives. After 6 months, repeat serum calcium was 11.5 mg/dl, creatinine was 2.1 mg/dl, phosphate was 2.45 mg/dl, and intact PTH was 160 pg/ml (reference interval, <55 pg/ml). Ultrasonography of the neck showed a 15-mm nodule behind the left lobe of the thyroid, and parathyroid scintigraphy with ^99mTc-SestaMIBI showed uptake at the base of the left thyroid lobe. The patient underwent left hemithyroidectomy and excision of a 1.5-cm hard parathyroid nodule. Microscopy revealed oxyphil cells arranged in a trabecular or nesting pattern and nonoxyphil cells of the usual type with nondescript diffuse architecture and fibrous banding. Mitotic figures (three per 50 high-power fields) and capsular invasion were observed, without evidence for metastatic spread warranting a diagnosis of atypical parathyroid adenoma. Moreover, another normal parathyroid gland was identified and biopsied. Two weeks postoperatively, serum calcium decreased to 8.32 mg/dl and PTH decreased to 42 pg/ml. Thereafter, annual screenings with serum calcium and PTH were unremarkable.

	Subjects and Methods

Top Abstract Introduction Initial case presentation Subjects and Methods Results Discussion References

 
Molecular studies

Peripheral blood was obtained from the index case as part of a research survey to identify germline HRPT2 mutations in all patients with parathyroid tumors, as approved by the local ethics committee of the Ospedale Casa Sollievo della Sofferenza in San Giovanni Rotondo (FG), Italy, and according to the Helsinki Declaration II. Extracted DNA was amplified in 18 segments to allow mutation screening of the 17 translated HRPT2 exons and their exon-intron boundaries. PCR amplifications were carried out in a 25-µl reaction volume containing 2.5 µl 10x PCR buffer (Applied Biosystems, Foster City, CA), 0.125 nM dNTPs, 20 pmol of each primer, 0.2 U AmpliTaq Gold DNA polymerase (Applied Biosystems), and 100 ng DNA. Ten microliters of each PCR product was denatured and loaded on the Transgenomic Wave dHPLC (Transgenomic Inc., Omaha, NE). The primers used for PCR amplification are given in Table 1. Samples with an abnormal denaturing HPLC elution profile were purified with GFX PCR DNA and Gel Band Purification Kit (Amersham Biosciences, Little Chalfont Buckinghamshire, UK) and eluted in 20 µl H₂O, according to the manufacturer’s instructions, then sequenced using the corresponding forward or reverse PCR primer. Sequencing reactions were carried out in a 10-µl volume containing 1.5 µl purified PCR product, 1 µl Big Dye Terminator v1.1 (ABI PRISM), and 3.5 pmol of primer and loaded on a ABI 3100 (Applied Biosystems).

Fasting serum total calcium, albumin, and creatinine were measured by a multichannel autoanalyzer. Serum ionized calcium was measured by an ion-selective electrode (AVL LIST GmbH Medizintechnik, Graz, Austria). Intact PTH was determined in the index case 12 yr ago by an immunoradiometric assay (Allegro Intact PTH RIA; Nichols Institute Diagnostics, San Juan Capistrano, CA) and for all other samples by a chemiluminescence immunoassay (Nichols Advantage; Nichols Institute Diagnostics).

Ultrasonography was performed using color Doppler scanner (Toshiba SSA340A, Tokyo, Japan) equipped with multifrequency probes. An investigator skilled in neck ultrasonography used a frequency of 7.5 MHz for identifying thyroid and parathyroid tissue. Planar and SPECT parathyroid ^99mTc-SestaMIBI scan was performed after the iv injection of 740 MBq of the radiotracer using a two-head camera (Marconi Axis, Cleveland, OH).

	Results

Top Abstract Introduction Initial case presentation Subjects and Methods Results Discussion References

 
Molecular diagnosis

The denaturing HPLC profile for amplicon 7, comprising 217 bases of exon 7, showed multiple peaks and was clearly different from that for 20 controls and 143 subjects with PHPT. Direct sequencing with forward and reverse primers revealed a four-base deletion at codon 229. This heterozygous n.685delAGAG frameshift mutation predicts a premature stop codon at nucleotides 767–769 and truncation after 25 amino acids, predicting a protein of 254 amino acids. It has not been reported previously in either germline or somatic DNA (1, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16).

First-degree relatives were then examined and genomic DNA was extracted, with informed consent, after approval by the local ethics committee. The mother of the index case, two brothers, two sisters, and one daughter were found by direct sequencing to carry the 685delAGAG mutation. In a second screening to identify carriers among more distant relatives, mutations were also identified in two nieces and one of their offspring (Fig. 1).

View larger version (21K): [in this window] [in a new window]   FIG. 1. Family pedigree. All members of the family have been screened for the HRPT2 685delAGAG mutation; those with a plus sign above the symbols are carriers. Year of birth is given below the symbols. None of the carriers studied had jaw or renal tumors (Table 2). For the index case (arrow), normal serum calcium and PTH levels referred to data obtained before the second surgery (at age 41).

In a review of the family history, it was apparent that the 69-year old mother of index case was clinically unaffected, despite her carrier status. However, there was a strong paternal family history for renal stones, and historically, sporadic survey of serum calcium among first-degree relatives had been negative. With identification of the HRPT2 mutation, more extensive monitoring was initiated. Jaw pantomograms and renal ultrasonograms were performed in carriers, but were uniformly negative for tumors or cysts, although a number of carriers and noncarriers showed renal stones (Table 2). Transabdominal ultrasonography was performed in five women, and echogenic structures suggestive of uterine leiomyomata were found in two. Serum calcium concentrations in first-degree relatives of the index case were normal, although the serum PTH was modestly elevated in three of six. Ultrasonography of the neck with attention to the thyroid gland and surrounding structures was performed and was positive in two of these relatives, initiating a diagnostic work-up.

View larger version (114K): [in this window] [in a new window]   FIG. 2. Ultrasonography of the neck in patient II-8 shows an extrathyroidal 10-mm diameter nodule below the left thyroid lobe (white arrow) consistent with a parathyroid mass.

Among the more distant relatives of the index case, a 27-yr-old carrier niece (III:3) was found to have an increased serum calcium (11.8 mg/dl), ionized calcium (1.54 mmol/liter), and serum PTH (106 pg/ml). Neck ultrasonography showed a spindle nodule in the posterior aspect of right thyroid lobe, which was also positive on SestaMIBI scan. Aspirate fluid contained high PTH (>1000 pg/ml) and low thyroglobulin (0.5 ng/ml) concentrations. Excision en bloc of the thyroid lobe with nodule, isthmus, and lymph nodes surrounding the laryngeal recurrent nerve revealed a 2-cm atypical parathyroid adenoma with capsular invasion. Two months postoperatively, serum calcium and PTH were 8.72 mg/dl and 55 pg/ml, respectively.

As part of a second annual screening of all affected individuals and asymptomatic carriers, the index case (now age 41) underwent repeat neck ultrasonography, and an extrathyroidal nodule below the remaining right lobe was noted. Serum calcium (9 mg/dl), blood ionized calcium (1.25 mmol/liter), and PTH (61 pg/ml) were in the normal range. Aspirate fluid from ultrasonographically guided fine-needle aspiration showed a high PTH (>1000 pg/ml) and low thyroglobulin (0.2 ng/ml) and consistent with a parathyroid origin. The patient underwent excision en bloc of the thyroid lobe with the nodule and the lymph nodes surrounding the laryngeal recurrent nerve. Histologically, neoplastic parathyroid tissue was found throughout the 1.2-cm encapsulated nodule. Capsular invasion was apparent, but without invasion of surrounding tissues, suggesting the diagnosis of a second primary atypical parathyroid adenoma. Another parathyroid gland was also identified at surgery and excised, but was histopathologically normal.

	Discussion

Top Abstract Introduction Initial case presentation Subjects and Methods Results Discussion References

 
Detailed clinical study of families carrying germline mutations of the HRPT2 gene are essential for a better understanding of the resultant phenotype. First identified causative in many cases of the HPT-JT syndrome (1), such mutations have subsequently been observed in families with familial isolated hyperparathyroidism (7, 8, 9, 13). Most authorities agree that the frequency of parathyroid carcinoma in classic HPT-JT is about 15%, but the number of families contributing to this analysis is not large, and ascertainment bias may be a significant confounder. Identification of the gene has led to an expansion of the phenotype and recognition of greater pleiotropy than previously recognized. A variety of renal anomalies are found in a subset of HRPT2 mutation carriers (7, 10, 14) and uterine tumors may be more frequent (11). Whether predisposition to other less common tumors may be present is still open to question.

In this family, we report a phenotype restricted to parathyroid neoplasms. Although the penetrance is clearly reduced, as evidenced by the unaffected status of the carrier mother of the proband, the predisposition to carcinoma or atypical adenoma, the latter potentially malignant, rather than adenoma, is high. Such a variable penetrance underscores the importance of appropriate surveillance.

The usefulness of a genetic test for predisposition is directly related to the effectiveness of screening, early detection, and preventive interventions. In this regard, the suggested protocol outlined by Bradley et al. (11) represents an important first step. They recommend serum calcium and PTH as the primary biochemical screening modalities for hyperparathyroidism. In our kindred, surveillance limited to biochemical testing would have missed one individual who proved to have a parathyroid tumor detected by neck ultrasonography and treated by early surgery. Of the 10 mutation-positive family members (Table 2), four (I:2, II:5, II:8, III:3) had modestly elevated serum PTH levels, but the normal serum calcium in three of them and the low 25-OH vitamin D levels in all four made interpretation equivocal. In I:2, vitamin D supplementation normalized PTH without any significant change in calcium (Table 2), but other family members with low 25-OH vitamin D have not been similarly treated and the extent to which hypovitaminosis D, which is relatively common in Southern Italy (17), contributes to elevated serum PTH in these family members cannot be determined. Thus, when performing biochemical screening in this setting, an elevated PTH level should be taken as a possible indicator of PHPT unless it can be proven to be due to vitamin D deficiency.

In general, a normal serum calcium is unusual in parathyroid carcinoma (18), but it is possible that normocalcemia is more typical of early parathyroid carcinoma associated with germline HRPT2 mutations. In any event, additional surveillance measures, particularly neck ultrasonography may improve sensitivity and lead to early detection of tumors. Assay of PTH in aspirate fluid, if available from extrathyroidal nodules detected by imaging, may suggest the parathyroid origin of the lesion, but the experience we acquired following this family suggests that the presence of an extrathyroidal nodule in HRPT2 mutation carriers is a strong indication for surgery, thus avoiding any risk of seeding associated with biopsy (19). Which surgical approach is best for carriers with suspected parathyroid tumors has not been established (20). In our index case, the appearance of a second parathyroid neoplasm 12 yr after the first had been completely resected indicates that more aggressive surgical intervention with ipsilateral hemithyroidectomy and total parathyroidectomy may be warranted in some. On the other hand, the ability to detect the tumor at an early stage may mean that close surveillance is sufficient, given the clinical burden and costs that lifelong replacement therapy with calcium and vitamin D (or, in the future, recombinant human PTH) can represent. Experience with a single family cannot define which surgical approach is indicated in others, but our observations can contribute to the development of better guidelines.

In this context, one other observation in our family bears mentioning. We saw no evidence for abnormal reproductive history in any of our female carriers, and only two minor uterine lesions (presumably leiomyomata) were found on transabdominal ultrasound. Like the jaw tumors, it may be that mutation-specific expression is important, but more likely other factors are responsible for interfamilial differences in syndrome expression.

In conclusion, our findings confirm suggestions that parafibromin is an important tumor suppressor of parathyroid gland tissue and that mutations in the HRPT2 gene may be associated with substantial propensity to high grade neoplasms of the parathyroid. Our experience with this particular kindred suggests that there may be occurrence of parathyroid tumor without a hypercalcemic harbinger. PTH levels may provide added sensitivity in screening, but even so, longitudinal surveillance by serum biochemistry may not always be enough, as was the case in the recurrence among patients 2–9. Adding neck ultrasonography to periodic screening with serum calcium and PTH assays may occasionally lead to even earlier disease detection, although the actual clinical benefit added by ultrasonography remains uncertain and should be examined in other kindreds. Certainly, optimal prospective surveillance leading to early removal of malignant or potentially malignant parathyroid nodules is an important therapeutic and preventative goal in HRPT2 mutation carriers.

	Acknowledgments

 
We thank the patients and their family for their participation. We acknowledge Ornella Morelli for her technical assistance.

	Footnotes

 
This work was supported by Ministero della Salute of Italy (Ricerca Corrente 2003, to A.S.) and by a fellowship from Associazione Italiana per la Ricerca sul Cancro (to V.G.).

First Published Online May 23, 2006

¹ V.G. and A.S. contributed equally to the study.

Abbreviations: HPT-JT, Hyperparathyroidism with jaw tumors; PHPT, primary hyperparathyroidism.

Received June 1, 2005.

Accepted May 11, 2006.

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Top Abstract Introduction Initial case presentation Subjects and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Guarnieri, V. Articles by Cole, D. E. C. Search for Related Content PubMed PubMed Citation Articles by Guarnieri, V. Articles by Cole, D. E. C. Pubmed/NCBI databases OMIM Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Related Collections Calcium and Bone Metabolism