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Familial Isolated Hyperparathyroidism Is Rarely Caused by Germline Mutation in HRPT2, the Gene for the Hyperparathyroidism-Jaw Tumor Syndrome

Metabolic Diseases Branch (W.F.S., S.K.A., S.J.M.), National Institute of Diabetes and Digestive and Kidney Diseases, and Cancer Genetics Branch (C.M.R., J.D.C.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; and Departments of Medicine, Physiology, and Human Genetics (G.N.H.), McGill University, and Calcium Research Laboratory, Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada

Address all correspondence and requests for reprints to: Dr. William F. Simonds, Building 10, Room 8C-101, 10 Center Drive, MSC 1752, Bethesda, Maryland 20892-1752. E-mail: wfs{at}helix.nih.gov.

	Abstract

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Familial isolated hyperparathyroidism (FIHP) can result occasionally from the incomplete expression of a syndromic form of familial hyperparathyroidism (HPT), specifically multiple endocrine neoplasia type 1 (MEN1), familial hypocalciuric hypercalcemia, or the hyperparathyroidism-jaw tumor syndrome (HPT-JT). The cause of FIHP has not been identified in the majority of families. We investigated 32 families with FIHP to determine the frequency of occult mutation in HRPT2, the gene causing HPT-JT. All families had negative clinical testing for MEN1, hypocalciuric hypercalcemia, and HPT-JT and negative mutational screening of MEN1 and CASR, the gene for the calcium-sensing receptor. Thus, an extended effort was made to exclude each of the principal syndromic causes of FIHP. The families were characterized by young probands (42 ± 3 yr) and occasionally unusual parathyroid histology, including four families with one case of parathyroid cancer. We had speculated that there was a high frequency of occult mutation in HRPT2 among such carefully screened kindreds. This hypothesis became testable with the recent identification of that gene. Among the 32 FIHP families, only a single one was found to have a mutation in HRPT2 (679insAG); this mutation predicts premature truncation of its gene product, parafibromin, and thus its presumed inactivation. Even accounting for families with one of the three occult syndromes and false negative biochemical or DNA testing, these results indicate that an unexpectedly large fraction of FIHP has currently unrecognized causes.

	Introduction

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FAMILIAL ISOLATED HYPERPARATHYROIDISM [FIHP; HRPT1, Mendelian Inheritance in Man (MIM) 145000¹] has an estimated frequency of approximately 1% among all primary hyperparathyroidism (HPT) (1). FIHP can result from the incomplete expression of a syndromic form of familial HPT or from other entities. Syndromes with familial HPT and potentially FIHP include multiple endocrine neoplasia (MEN) type 1 (MIM 131100) (2, 3), MEN type 2A (MEN2A) (MIM 171400) (4, 5, 6), familial hypocalciuric hypercalcemia (FHH) (MIM 145980, 145981, 600740) also known as familial benign hypercalcemia (7, 8), and the hyperparathyroidism-jaw tumor syndrome (HPT-JT; HRPT2, MIM 145001) (9). MEN2A does not figure prominently in the differential diagnosis of FIHP because its more highly penetrant features of medullary thyroid cancer and pheochromocytoma usually place it into the syndromic category (4, 5, 6). Understanding how many and how often as-yet-unrecognized clinical entities, including mutant genotypes, may also present as FIHP could clarify FIHP and have important implications for understanding the causes of sporadic HPT.

Thirty-six kindreds with a provisional diagnosis of FIHP were recently studied with tests designed to recognize occult expressions of the syndromic forms of FIHP (1). Three kindreds among the 36 proved to have HPT-JT, five families had likely inactivating mutation in the calcium-sensing receptor gene (CASR), and none had MEN1 syndrome or detectable MEN1 gene mutation. The remaining 28 among the 36 study kindreds had apparently nonsyndromic FIHP. One major diagnostic uncertainty within the nonsyndromic FIHP subgroup was the possible failure to recognize families with occult HPT-JT. This uncertainty was due in large part to the lack of a specific gene mutational test and exacerbated by small family sizes that precluded genetic linkage testing.

HPT-JT is an autosomal dominant syndrome with high but incomplete penetrance (9). The major features are primary hyperparathyroidism (90%) including 15% of all affected by HPT-JT with parathyroid cancer, jaw tumors (30%), bilateral renal cysts (10%), and less commonly solid renal tumors (1, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27). Nearly 10% of adult cases appear to be silent carriers (1, 14). The trait in a few large kindreds with FIHP but without evident jaw tumors links to the HRPT2 locus at 1q25-q31 (12, 15, 28), and one such 1q-linked FIHP family was found to have occult HPT-JT based on a nonsense mutation in the HRPT2 gene (29).

HRPT2, the gene on the long arm of chromosome 1 (27) responsible for HPT-JT, was recently identified (29). With the ability to screen for HRPT2 germline mutations, the prevalence of incomplete forms of HPT-JT among kindreds with the FIHP phenotype can be addressed directly. We present here an evaluation of occult HRPT2 gene mutation among 32 well-characterized nonsyndromic FIHP kindreds.

	Subjects and Methods

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Subjects

The provisional diagnosis of FIHP was made in a family if there was biochemical evidence of primary HPT in the proband, biochemical diagnosis of HPT in one or more first-degree relatives, histopathologically verified abnormal parathyroid tissue in at least one member with HPT, and no evidence by history for disease outside the parathyroids that would enable diagnosis of a syndromic variant of HPT (1). Details of 28 families with negative biochemical, imaging, and gene mutational (MEN1, CASR) screening for the presence of occult MEN1, FHH, and HPT-JT, and thus given a diagnosis of nonsyndromic FIHP, were described (1). Those 28 families plus four more recently accrued kindreds meeting the same criteria are included in the present study.

Probands, and whenever possible other affected members, were evaluated through the Metabolic Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the Clinical Center of the National Institutes of Health (NIH) between 1971 and 2003. All testing was performed with informed consent under protocols approved by the NIDDK Institutional Review Board. Clinical aspects of kindreds 24,700, 28,200, and 30,300 have been reported previously in part (30, 31, 32).

Laboratory data

Testing at NIH was through the Clinical Chemistry Service of the Department of Laboratory Medicine and through the Diagnostic Radiology Department of the NIH Clinical Center. Relative hypocalciuria was diagnosed in a hypercalcemic patient if the ratio of the renal clearance of calcium to the renal clearance of creatinine was less than 0.01 (7). Screening for jaw tumors used orthopantographic x-rays and/or computed tomography scan of the mandible and maxilla. Evaluation of the kidneys used standard ultrasound or computed tomography scan. A subset of patients had undergone repeated parathyroidectomy. When multiple preoperative blood and urine chemistry examinations were available for a patient from this subset, the earliest preoperative data were used. When the earliest preoperative data were not available for such a patient, data from the initial NIH evaluation were used. For the evaluation of patients not seen in the Clinical Center, appropriate tests were recommended, and reports of available outside laboratory or imaging tests were obtained with written consent.

Germline mutation analysis of the MEN1, CASR, and HRPT2 genes

Leukocyte DNA for analysis was extracted from anticoagulated whole blood. Analysis for mutations in the exons and intron-exon junctions of the MEN1 gene (33) and the CASR gene (34) was as described (1). Mutational analysis of the HRPT2 gene using primers corresponding to the intronic sequence flanking exons to amplify each of the 17 coding exons by PCR was performed as described (29).

Statistical analysis

Statistical analysis used GraphPad InStat software version 3.0a for Macintosh (GraphPad Software, San Diego, CA). For comparison of continuous variables between two patient subgroups, the unpaired t test was used. Multiple means analysis, comparing a continuous variable among three or more patient groups, used one-way ANOVA. Post-ANOVA comparison between two of the three patient groups used the Tukey-Kramer multiple comparisons test. Variation was expressed as the SEM.

	Results

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Clinical characteristics of 32 kindreds with nonsyndromic FIHP

Thirty-two families with nonsyndromic FIHP were studied (Table 1). Of 84 known affected individuals, 83 (99%) were evaluated, 50% at the NIH Clinical Center. The 32 probands had 125 living first-degree relatives over age 18 yr; 81 (65%) were screened by serum calcium determination and sometimes additional tests. The median number of affected individuals per kindred was two (mean, 2.6; range, 2–8). The gender ratio of the affected members was 1.7:1 female: male, a female predominance not significantly different from that among sporadic cases of HPT (2.7:1) (35).

Benign or malignant tumors not known to be related to HPT-JT in affected members from two or more of 32 nonsyndromic FIHP kindreds include breast cancer (eight cases among five kindreds), lipoma (six cases in four kindreds), colorectal cancer (four cases among three kindreds), papillary thyroid cancer (three cases in three kindreds), renal angiomyolipoma (two cases in two kindreds), and malignant dermal melanoma (two cases in two kindreds) (Table 1and Ref. 1). None of the breast cancers segregated with ovarian cancer or had other clinical features suggestive of hereditary breast cancer (40).

Testing for occult HRPT2 germline mutation among nonsyndromic FIHP kindreds

A germline DNA sample from an index case representing each of the 32 nonsyndromic FIHP kindreds was sequenced for mutations across the 17 exons of HRPT2 encompassing the entire coding region of the 531-amino acid protein parafibromin (29) (Table 1). Among the 32 families, a single kindred was found to have a frameshift mutation, a 2-bp insertion in exon 7 of HRPT2 (679insAG) that predicted addition of 27 amino acid residues of unrelated sequence in the altered reading frame with truncation after codon 229 of parafibromin (kindred 35,900; Table 1). The frameshift mutation tracked with the HPT phenotype in this kindred (Fig. 1). Both the absence of the same mutation in 150 normal individuals and segregation of the 2-bp insertion with the trait in this FIHP kindred give additional support to the conclusion that the HRPT2 mutation causes the HPT (29). Lastly, this is supported by the observation that the mutation predicted parafibromin inactivation, like other HRPT2 mutations in HPT-JT. Indeed, the identical frameshift mutation in exon 7 (679insAG) has been found in two families with typical expressions of HPT-JT (29), although no genealogical connection has so far been established among the three geographically dispersed families. A haplotype analysis could definitively establish whether the FIHP family shares ancestry with the two HPT-JT families harboring the identical 679insAG HRPT2 exon 7 mutation (29), although this has not yet been performed.

View larger version (22K): [in this window] [in a new window]   FIG. 1. Pedigree of kindred 35,900 with nonsyndromic isolated hyperparathyroidism and HRPT2 gene mutation. Square symbols indicate males, and round symbols indicate females. A diagonal slash mark through the symbol means deceased. The arrow indicates the proband. Filled quadrants indicate a diagnosis or history of the trait indicated in the inset legend. None of the affected members had a known history of jaw tumors; panographic jaw x-rays were obtained only for the proband. The proband also had normal renal imaging; renal imaging was not available for the other affected members (Table 1). Blank symbols represent family members not evaluated for this study. The sign below the symbol indicates the presence (asterisk) or absence (pound sign) of a 2-bp frameshift mutation (679insAG) in exon 7 of HRPT2 on germline DNA sequencing; a black dot below the symbol indicates normal serum calcium at the most recent examination in an individual never known to have hypercalcemia.

The FIHP kindred with HRPT2 mutation has four known affected members with HPT, including two with a lipoma and the proband with parathyroid cancer (Table 1, Fig. 1). Panographic x-ray examination of the mandible of the proband showed a "ground-glass" appearance, a nonspecific finding reflecting bone disease caused by the patient’s severe primary HPT (41) (Table 1). Jaw and renal imaging studies were available only for the proband. The proband had parathyroid cancer with extensive cervical metastases. The other three affected kindred members had a single parathyroid adenoma removed at surgery with subsequent postoperative normocalcemia (duration from 3 to 29 yr), a pattern often seen in HPT-JT (1, 9). A benign parathyroid tumor in one of the four affected cases was cystic (Fig. 1), a tumor property sometimes associated with the HPT-JT syndrome (9, 19).

	Discussion

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There have been very few reports of kindreds with FIHP, perhaps because of a bias that most such families have occult MEN1 (1). The available series from other institutions that investigated for occult syndromic causes of FIHP are all smaller than eight kindreds, and the families in all other series, including a study by Huang et al. (42) of 14 families, were characterized in much less detail than the 32 kindreds in the current report (15, 43, 44, 45, 46, 47, 48, 49, 50).

Seeking HRPT2 mutation and proving its rarity among FIHP kindreds

We speculated that a major cause of FIHP was HRPT2 mutation (1). The recent identification of the gene for HPT-JT offers an important new tool to magnify the investigation of FIHP (29). Unexpectedly, the present analysis suggests that nonsyndromic germline mutation of HRPT2 is an uncommon cause of FIHP. Although unsupported by our findings, our speculation had been based on the following: 1) the known incomplete penetrance of the gnathic and renal expressions of HPT-JT that may be clinically silent (1, 9, 14); 2) the presence of features sometimes associated with HPT-JT such as parathyroid carcinoma (four cases in four families), cystic parathyroid tumors (four cases in two families), renal cysts (one case), and jaw tumor (one case) among affected members in the 32 FIHP study kindreds (Table 1); 3) the prior demonstration of 1q25-q31-linkage and/or HRPT2 mutation in several FIHP families (15, 28, 51); and 4) the lack of reported linkage of HPT to any gene locus other than MEN1, HRPT2, and those related to FHH [CASR, HHC2 (52), and HHC3 (53)] among large families with apparently isolated hyperparathyroidism³(see below).

Known genotypes presenting as FIHP

All previously reported kindreds with FIHP and a subsequently identified occult syndrome have had their trait linked to or have had finding of germline mutation in one of the following: either the MEN1 gene locus at 11q13 (38, 45, 46, 48, 54, 55, 56, 57, 58, 59, 60, 61, 62), the CASR gene locus at 3q21-q24 (1, 63), other loci at 19p (52) and 19q (53) rarely implicated in FHH, or the HRPT2 gene locus at 1q25-q31 (15, 28, 29, 51). The small family size or the unavailability of living affected members made genetic linkage analysis impossible in each of the 32 FIHP families in the present study.⁴

In our total series of 40 FIHP kindreds [36 families (1) plus four added in the present study], we diagnosed four with HPT-JT (10%), three on clinical grounds, and one occult case by HRPT2 mutation. Thus, this diagnosis is about as frequent as CASR mutation [five families (1) among 40, 12.5%] and more frequent than MEN1 (none among 40). It is likely that one or several kindreds among the 31 remaining HRPT2 mutation-negative families in our study have FIHP on the basis of a still unrecognized HRPT2 gene mutation. This is so because current HRPT2 gene sequencing fails to identify a mutation in approximately half of index cases from kindreds with full expression of HPT-JT and with proven genetic linkage to 1q25-q31 (29). The possibility of a second gene for HPT-JT in this locus seems unlikely. These presumably unidentified mutations may be in the HRPT2 promoter or other regulatory regions that have yet to be defined. The so-far-unidentified mutations may also represent large deletions or complex rearrangements in HRPT2 that cannot be readily identified using standard sequencing techniques, and analysis of genomic DNA in lymphoblasts from affected HRPT2 mutation-negative patients by Southern blotting and other techniques is in progress to address this possibility. Furthermore, not every affected member in the 31 mutation-negative families underwent renal and jaw imaging studies to uncover occult clinical expressions of HPT-JT. Indeed, in 11 of the 31 HRPT2 mutation-negative kindreds, no affected member had jaw imaging. The presence of features often associated with HPT-JT distributed among five of 31 FIHP kindreds without identified HRPT2 mutation also suggests unrecognized germline HRPT2 mutation (see above, Table 1).

There are likely other causes for FIHP among the remaining 31 kindreds besides unrecognized HRPT2 mutation. Few among the remaining 31 families may have occult MEN1 or CASR mutation because the false negative rate for either of these gene mutational tests is approximately 30% (2, 64, 65). Linkage study to exclude these loci and others less commonly associated with FIHP (52, 53) was not possible because of the small size of each kindred (4). Assuming two to five kindreds each with unrecognized germline mutation in MEN1, CASR, or HRPT2, then some 16–25 kindreds (50–80%) would remain without a syndromic diagnosis. This is an unexpected deduction that has not been anticipated in recent reviews (49, 50).

Speculations about unrecognized causes of FIHP

What types of unknown etiologies might account for FIHP among the remaining families? The small size of nonsyndromic FIHP kindreds in this study is consistent with the paucity of large nonsyndromic FIHP kindreds in literature reports (See Footnote 3³) and suggests that highly penetrant monogenic causes are unlikely to be frequent. A possible exception to this generalization would be a highly penetrant gene that also causes decreased fertility or diminished fetal viability. We did not recognize fertility or fetal viability problems among HPT carriers, although we did not evaluate this in detail. Mutation of single genes of low penetrance are also possible as are polygenic etiologies in which the small FIHP kindred size would reflect the improbability of more than one close relative inheriting the required set of causative mutations or polymorphisms. It is worth noting that any of these hypothesized genetic etiologies might also contribute to a portion of so-called sporadic primary HPT. Nongenetic etiologies for FIHP might include autoimmune processes (66), environmental factors (e.g. exposure to excessive cervical or mediastinal radiation) shared among several family members, or fortuitous clustering of sporadic primary HPT among close relatives.

We conclude that nonsyndromic FIHP is only rarely caused by occult germline mutation in HRPT2 but instead results from genetic and/or nongenetic processes that remain to be identified. Understanding these processes could have important implications for the management of familial HPT, sporadic HPT, and other neoplastic states.

	Acknowledgments

 
We thank the many patients and relatives who participated in this study. We thank Craig Cochran and the NIH Clinical Center 8 West nursing staff for expert patient care. We also thank our colleagues Drs. Lee Weinstein and Monica Skarulis as well as the past and present fellows of the NIDDK, National Institute of Child Health and Human Development Interinstitute Endocrine Training Program.

	Footnotes

 
This work was supported in part by grants (to G.N.H.) from the Canadian Institutes of Health Research (MT-9315) and The Kidney Foundation of Canada.

Abbreviations: CaSR, Calcium-sensing receptor; CASR, CaSR gene; FHH, familial hypocalciuric hypercalcemia; FIHP, familial isolated hyperparathyroidism; HPT, hyperparathyroidism; HPT-JT, hyperparathyroidism-jaw tumor syndrome; HRPT2, the gene for HPT-JT; MEN1, multiple endocrine neoplasia type 1; MEN1, gene for MEN1; MEN2A, multiple endocrine neoplasia type 2A; MIM, Mendelian Inheritance in Man.

¹ The six-digit number is the entry number for the disorder in Mendelian Inheritance in Man (MIM) (67 ). The continuously updated online version (Online Mendelian Inheritance in Man) is accessible from the National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD, through the World Wide Web (http://www. ncbi. nlm.nih.gov/omim/).

² The difference in the means of proband age of onset between HPT-JT and FIHP groups did not reach statistical significance with a q value of 2.9 in the Tukey-Kramer multiple comparisons test (q values greater than 3.9 are associated with P < 0.05).

³ A kindred with nonsyndromic familial isolated hyperparathyroidism has been reported with five affected members that lack mutations in the coding regions of MEN1, CASR, and RET and with exclusion of linkage to MEN1, CASR, and HRPT2 (68 ). The trait was not studied at other FHH loci (52 53 ).

⁴ Kindred 28,200 has eight known affected members in three generations (Table 1) (1 31 ); however, leukocyte DNA is available from only three surviving affected individuals precluding linkage analysis.

Received April 17, 2003.

Accepted September 15, 2003.

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