Dissecting the Genetics of Hyperparathyroidism—New Clues from an Old Friend

Catharina Larsson

Endocrine Tumor Unit Center for Molecular Medicine CMM Karolinska Hospital Karolinska Institutet S-171 76 Stockholm, Sweden

Address correspondence and requests for reprints to: Catharina Larsson, Endocrine Tumor Unit, Center for Molecular Medicine CMM, Karolinska Hospital L8:01, Karolinska Institutet, S-171 76 Stockholm, Sweden.


    Introduction
 Top
 Introduction
 References
 
The parathyroid gland was "born" in the University of Uppsala (Uppsala, Sweden) when the medical student Ivar Sandström presented the first detailed description of this gland in 1880. Following extensive dissections in several species, including man, he reported not only the number and anatomical position, but also the histology of the newly detected organs (1). He further showed that the microscopical appearance was different from that of the thyroid, and he correctly predicted that the glands have an endocrine function and that pathologists would find tumors in them. One hundred years later, the teams of endocrine surgeons, endocrinologists, and pathologists at the Academic Hospital still keep a place for the University of Uppsala on the map of major centers for clinical and fundamental research on the parathyroid gland. Among their most highly recognized contributions to this field are the demonstration in 1984 of supernumerary parathyroid glands in a significant proportion of the population, as well as the establishment of a coupling between polymorphisms in the vitamin D receptor gene and the increased risk of primary hyperparathyroidism (HPT) in 1995. In this issue of The Journal of Clinical Endocrinology & Metabolism, Carling et al. (2) report a unique pedigree affected by an atypical hypercalcemic disorder, the elucidation of which will inevitably lead to improved understanding of the pathogenesis of HPT.

Familial hypercalcemia has been shown to constitute a broad group of heritable disorders characterized by either primary HPT or by hypercalcemia due to impaired cellular response to extracellular calcium fluctuations (Table 1Go). Familial isolated HPT (FIHP) (HRPT1, OMIM 145000) is a rare disorder in the adult. It is typically inherited as an autosomal dominant trait with reduced penetrance. In the classical case, FIHP is characterized by hypercalcemia, elevated PTH levels, and uni- or multiglandular parathyroid tumors. The diagnosis involves the exclusion of other familial disorders characterized by primary HPT, mainly multiple endocrine neoplasia type 1 (MEN 1) and the HPT-jaw tumor syndrome (HPT-JT or HRPT2). The familial syndrome MEN 1 (OMIM 131100) is transmitted as an autosomal dominant trait with an equal sex distribution and close to full penetrance. Hyperparathyroidism occurs in over 90% of cases and is invariably associated with multiglandular disease. In addition, patients develop tumors of the endocrine pancreas, the anterior pituitary, and the adrenal cortex, as well as lipomas and carcinoids. The MEN1 tumor suppressor gene was cloned from 11q13 by positional cloning (3, 4). Its product menin has been found to bind specifically to JunD, whereas disruption of this binding activity by MEN1 mutations leads to inhibition of JunD-activated transcription (5). HPT-JT (OMIM 145001) is a recently identified syndrome characterized by solitary parathyroid adenomas/carcinomas, fibro-osseous JTs, and occasionally renal lesions, namely Wilms’ tumors, polycystic kidney disease, and renal hamartomas (6). This syndrome is inherited in an autosomal dominant manner with an overall very high penetrance, although a reduced penetrance of primary HPT is evident in female gene carriers. Clinically, the HPT in HPT-JT syndrome is characterized by solitary parathyroid adenoma, but some patients may have more than one adenoma. In contrast to MEN 1-related HPT, which consists invariably of benign multiglandular parathyroid hyperplasia but never malignant transformation, the HPT-JT is associated with an increased risk of carcinoma. The HRPT2 locus has been assigned to a limited interval within chromosomal region 1q21-q32, but the gene remains to be cloned. Familial hypercalcemic hypercalciuria (FHH; OMIM 145980, 14598, and 600740) is an autosomal dominant syndrome of life-long nonprogressive hypercalcemia that is present already from birth. The heterozygous form of FHH is further characterized by relatively low urinary calcium excretion, inappropriate PTH levels, and hypercalcemia that is not responsive to parathyroid surgery. In the homozygous form, neonatal severe HPT with hypercalcemia and increased parathyroid glands is seen. The generally poor result of parathyroidectomy in curing the hypercalcemia is one of the features of FHH that lead to its recognition as a separate clinical entity. The vast majority of patients who have undergone parathyroidectomy have remained hypercalcemic. This circumstance is one of the main reasons why a definite diagnosis of FHH should be made to avoid unnecessary neck exploration. The FHH syndrome is genetically heterogenous, resulting from mutations in genes in at least three distinct locations (3q13, 19p, and 19q). In the affected families assigned to the 3q locus, the phenotype results from inactivating mutations in the gene encoding the parathyroid cell surface calcium receptor (CaR) that mediates the suppression of PTH secretion by extracellular calcium (7). It was later demonstrated that activating mutations in this receptor gene also give rise to familial hypocalcemic hypercalciuria (8).


View this table:
[in this window]
[in a new window]
 
Table 1. Familial disorders predisposing to hypercalcemia as a major feature

 
The family presented by Carling et al. (2) shows an autosomal dominant inheritance of a unique disorder characterized by early onset of hypercalcemia combined with hypercalciuria, and inappropriate PTH levels. In agreement with a diagnosis of FIHP, MEN 1 and HPT-JT were excluded clinically and genetically, and the hypercalcemia was, in most cases, responsive to parathyroidectomy at which modest hyperplasia or adenomas were revealed in all of the operated patients. On the other hand, an inactivating mutation of the calcium-sensing receptor gene CaR was identified as the predisposing genetic defect, which would by itself support the diagnosis of FHH. Thus, the hypercalcemic disorder in this intriguing family has features of both FIHP and of FHH but cannot be readily classified as either of the two and is, hence, described as familial hypercalcemia and hypercalciuria (Table 1Go).

The identification of an inactivating CaR mutation as pathogenetic in primary HPT suggests that this gene could also be responsible for disease in FIHP families in which the predisposing genetic defect remains to be shown. To date, more than 100 FIHP pedigrees have been reported. In analyzing this group of disease, mainly two histopathological entities are found. One is characterized by multiglandular disease or hyperplasia, and the other is characterized by solitary parathyroid adenoma occasionally associated with parathyroid carcinomas. So far, three large FIHP families have been shown to be linked to the HRPT2 locus in chromosome 1q21-q32, therefore, suggesting that they represent a variant of the HPT-JT syndrome (9). The parathyroid tumors in these families were typically solitary adenomas with a cystic component, showing somatic loss of the wild-type 1q alleles and a reduced penetrance in women. Yet another subset of FIHP families has been shown to be a variant of MEN 1 by the demonstration of novel missense mutations in the MEN1 gene in two large families, where the affected members developed multiglandular disease, with similar penetrance in women and men, and in the tumors somatic loss of the wild type 11q13 alleles were regularly seen (10). A few smaller kindreds with familial HPT have also been reported to be associated with MEN1 mutations. However, in the majority of such pedigrees, no MEN1 mutations have been identified, making the CaR gene an excellent candidate in these cases.

It is now established that mutations in some genes for inherited syndromes can give rise to similar but distinct clinical variants. For example, specific mutations of the RET proto-oncogene are associated with each of the three variants of MEN type 2 (MEN 2), i.e. MEN 2A, MEN 2B, and familial medullary carcinoma of the thyroid, as well as Hirschsprungs disease. Similarly constitutional MEN1 mutations may predispose to full-blown MEN 1 or to FIHP (10). Clinically, the HPT in MEN1-related FIHP seems to run a rather mild course, although pathologically the multiglandular parathyroid disease found is consistent with that seen in MEN 1. The two FIHP families occurring as MEN 1 variants demonstrated missense mutations in close vicinity, which may lead to speculations about a genotype-phenotype correlation. Two separate regions of menin have been shown to separately bind JunD, and at the C-terminus two nuclear localization signals have been identified (5). The two reported FIHP-associated MEN1 mutations fall outside all these regions, suggesting a functional basis for this milder variant of MEN 1 (10). The first FHH gene identified presents a similar picture of one gene-many syndromes. Constitutional mutations of this calcium receptor CaR in 3q are associated with a whole spectrum of phenotypes affecting calcium homeostasis, some of which can give rise to adenomas in their homozygous form (1, 7, 8). The identification of a novel inactivating CaR mutation in the present family with hypercalcemia and hypercalciuria adds yet another syndrome to the list of CaR-associated phenotypes (Ref. 2 ; Table 1Go). The particular mutation in this family gave rise to hypercalcemia in the presence of hypercalciuria, suggesting that it lead to a less pronounced inactivation of the CaR in renal cells (2). Thus, unlike most cases of FHH, the renal cells would still be able to respond to hypercalcemia by an increased urinary calcium excretion. In agreement with this hypothesis, the expression of the mutant receptor in human embryonic kidney cells only resulted in a moderate shift in the dose response (2).

In general, parathyroid tumors can be described as having a benign phenotype, but nevertheless most of the recognized mechanisms for tumor development are operative in the tumorigenesis. Two main types of pathological growth of parathyroid cells have been postulated (1). Calculations based on estimations of the frequency of mitoses and the date of tumor initiation indicate that most of the parathyroid adenomas have ceased to proliferate at the time of surgery. This could be explained by a change in set-point for PTH secretion, which would have given the cell a growth advantage because of continuous stimulation by the relative hypocalcemia. This clone of cells will have continued to grow until the secretion of PTH is so high that it raises serum calcium to a level that matches the new set-point, and then the growth will be slowed down. Changes in CaR have been proposed to be responsible for the increase in set-point of PTH secretion seen in primary HPT, but it has been difficult to establish the role of CaR in the tumorigenesis of sporadic parathyroid tumors. A tumor-specific down regulation of CaR expression has been demonstrated in the majority of tumors in primary HPT. Because the down-regulation could not be related to somatic loss or mutations of CaR, this has been interpreted as a secondary phenomenon. The second type of parathyroid growth is postulated to be the result of a mutation in, for instance, a cell cycle gene. The tumors are then expected to grow exponentially in a similar way as tumors in other tissues. Possible genetic events contributing to this type of growth would include somatic deletions and amplifications of specific chromosomal regions harboring putative tumor suppressor genes and oncogenes. The PTH-cyclinD1/PRAD1 rearrangement was the first oncogenic event that was fully characterized in parathyroid tumorigenesis (11). Although this inversion has been shown only in a subset of tumors, overexpression of cyclinD1/PRAD1 is a more common phenomenon, which is seen in approximately one fifth of the cases. Subsequently, the contribution of the MEN1 tumor suppressor gene to parathyroid tumor development has been clarified. The MEN1 gene is somatically lost in one fourth of sporadic parathyroid tumors, and in the majority of these an inactivating MEN1 mutation can also be identified (12).

It has also been proposed that the asymptotic and exponential types of pathological parathyroid growth can occur sequentially instead of being alternative events. In this case, the alterations of the set-point control would give a limited proliferation, which in turn should facilitate for mutations to occur in cell cycle genes. This hypothetical model has not yet been confirmed in parathyroid tumorigenesis. However, it could well explain the spectra of pathological parathyroid glands reported in the family by Carling et al. (2), where hyperplasia was seen in most cases and adenomas occurred in two of the oldest patients. The genetic profile of these particular tumors is, thus, expected to shed further light on the tumor development, not only in this family, but also in HPT, in general.

Received January 24, 2000.

Accepted January 24, 2000.


    References
 Top
 Introduction
 References
 

  1. Bilezikian JP, Marcus R, Levine MA. The parathyroids, basic, and clinical concepts: Eds. Raven Press; 1–841.
  2. Carling T, Szabo E, Bai M, et al. 2000 Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab. 85: 2042–2047.
  3. Larsson C, Skogseid B, Öberg K, et al. 1988 Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature. 332:85–87.[CrossRef][Medline]
  4. Chandrasekharappa SC, Guru SC, Manickam P, et al. 1997 Positional cloning of the gene for multiple endocrine neoplasia-type I. Science. 276:404–407.[Abstract/Free Full Text]
  5. Agarwal SK, Guru SC, Heppner C, et al. 1999 Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell. 96:143–152.[Medline]
  6. Szabo J, Heath B, Hill VM, et al. 1995 Hereditary hyperparathyroidism-jaw-tumor syndrome: the endocrine-tumor gene HRPT2 maps to chromosome 1q21–q31. Am J Hum Genet. 56:944–950.[Medline]
  7. Pollak MR, Brown EM, Chou YH, et al. 1993 Mutations in the human Ca(2+) sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 75:1297–1303.[Medline]
  8. Pearce SH, Williamson C, Kifor O, et al. 1996 A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med. 335:1115–1122.[Abstract/Free Full Text]
  9. Teh BT, Farnebo F, Twigg S, et al. 1998 Familial isolated hyperparathyroidism maps to the hyperparathyroidism-jaw tumor locus in 1q21–q32 in a subset of families. J Clin Endocrinol Metab. 83:2114–2120.[Abstract/Free Full Text]
  10. Kassem M, Kruse TA, Wong F-K, et al. 2000 Familial isolated hyperparathyroidism—a variant of MEN1. J Clin Endocrinol Metab. 85:165–167.[Abstract/Free Full Text]
  11. Motokura T, Bloom T, Kim HG, et al. 1991 A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 350:512–515.[CrossRef][Medline]
  12. Heppner C, Kester MB, Agarwal SK, et al. 1997 Somatic mutations of the MEN1 gene in parathyroid tumors. Nat Genet. 16:375–378.[Medline]