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.
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Introduction |
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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 1). 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).
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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 1). 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.
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References |
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