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Original Studies |
Department of Molecular Medicine (B.T.T., F.F., F.K.W., C.L.), Department of Pathology (A.H., L.G.), Department of Surgery (K.S., L-O.F.), Karolinska Hospital, Stockholm, S-17176 Sweden; Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, 2065 Australia; Department of Clinical Genetics (S.K.), Oulu University Hospital, Oulu, 90220 Finland; Department of Internal Medicine (E.K-H.), Seinäjoki Central Hospital, Seinäjoki, 60220 Finland; Department of Surgery (J.N.), Huddinge Hospital, S-14186 Sweden
Address correspondence and requests for reprints to: Bin Tean Teh M.D., Ph.D., Department of Molecular Medicine, Endocrine Tumor Unit, CMM L8:01, Karolinska Hospital, S-171 76 Stockholm, Sweden; E-mail: Bin.Teh{at}cmm.ki.se
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The frustration in managing FIHP mainly concerns genetic counselling and screening for other tumors associated with MEN1 and HPT-JT, which obviously entails expensive multimodal investigations on the patients as well as related family members. This problem can be alleviated if the genetics of this condition are elucidated. To date, only two FIHP families that are large enough for linkage analysis have been studied genetically. One family with a case of parathyroid carcinoma was previously excluded from MEN1 (16). However, subsequent studies confirmed that it is a classic HPT-JT family showing linkage to 1q21-q32, the HRPT2 region (Wassif W, Farnebo F, Teh BT, et al., submitted). Genetic analysis of the other FIHP family produced positive linkage results in the MEN1 region indicating that it is a variant of MEN1, but yet to be proven by mutation analysis (18). Obviously, more genetic studies of FIHP families are needed to dissect out its genetic basis. Here we describe our clinical, histopathological, and genetic findings of three previously unreported families.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Family 1 is of Caucasian origin residing in Australia (Fig. 1
). The proband (IV-7) is a male who at
age 22 was found to have hypercalcemia (corrected total serum calcium
3.24 mmol/L; normal range 2.20–2.60) during hospitalization for
treatment of incidental head injury. Further investigations confirmed
primary hyperparathyroidism with a 10-fold elevation of PTH when
corrected total serum calcium was 2.90 mmol/L and 24-h urinary calcium
16.9 mmol (normal range 1.25–7.5). In hindsight, he had been
symptomatic of hypercalcemia for at least 2 yr with symptoms including
polyuria and polydipsia. The hyperparathyroidism was treated with
parathyroidectomy, where one enlarged gland was found, weighing
approximately 4 g. Family history revealed that the proband’s
paternal grandmother (II-1) had had a parathyroid gland, also weighing
about 4 g, removed at age 58, after recognition of primary
hyperparathyroidism that presented with multiple renal calculi. Three
grand aunts (II-3, II-4, and II-5) were clinically unaffected, but the
son (III-8) of II-4 was found to have primary hyperparathyroidism. The
father (III-6) had parathyroidectomy at age 25, also for renal calculi
due to hyperparathyroidism. A further parathyroidectomy was performed
at age 42, after recurrence of hypercalcemia. The gland removed at the
second operation weighed 1.5 g. A paternal aunt (III-5) was found
to have borderline elevated ionized serum calcium and upper limit of
normal parathyroid hormone. The other 2 aunts (III-1) and (III-3), now
aged in their 40’s, have normal range total serum calcium levels, most
recently 2.28 mmol/L and 2.47 mmol/L. A year after the proband’s
parathyroidectomy, a male cousin (IV-1) was found to have hypercalcemia
(3.02 mmol/L) at age 20 during investigation for incidental head
injury. Subsequent investigations confirmed primary
hyperparathyroidism, and at parathyroidectomy a single enlarged gland
weighing 0.41 g was removed. Orthopentography of the jaw, renal
ultrasound, and biochemical screening for MEN1 were performed on all
members of the family. No case of jaw or renal tumors, and no evidence
of MEN1 was found.
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Family 2 is also of Caucasian origin residing in Sweden (Fig. 1
). The proband (III-1) initially presented in 1964 at age 31 with
renal calculi, nephrocalcinosis, and primary HPT, with a preoperative
serum calcium 3.4 mmol/L (reference range 2.20–2.60 mmol/L). X-ray
examinations of the skull and jaws were normal. Two abnormal
parathyroid glands with a total weight of 4.4 g were removed, and
the patient has remained normocalcemic during 31 yr of follow-up. An
orthopentogram of the mandible and maxilla performed in 1996 did not
reveal any signs of fibrous osteoma or cysts. Her nephew (IV-2) was
found to have asymptomatic primary HPT in 1991 at the age of 27, and
two abnormal parathyroids were removed (total weight 1.2 g).
Primary HPT was diagnosed in 1994 at age 28 in patient IV-4 following a
period of extreme fatigue. Preoperative serum calcium was 3.0 mmol/L,
and one pathological gland (1.2 g) was removed. No recurrence has been
seen in patients IV-2 and IV-4 after 6 and 3 yr of follow-up,
respectively. Individual III-8 is asymptomatic but was recently found
to have an elevated serum-PTH, which was repeated on several occasions.
Serum creatinine, prolactin, gastrin, and pancreatic polypeptide were
normal at follow-up in all these patients, and no case of jaw tumor or
renal tumor were found on orthopentography or renal ultrasound. No
family member had a history of jaw tumors. In addition individuals
III-2, III-4, III-5, III-7, III-10, IV-1, and V-1 were all
normocalcemic and had normal PTH levels.
Family 3
Family 3 is an unreported Finnish family with four affected
siblings (Fig. 1). All of them had parathyroidectomy between the ages
of 31 and 38 yr. One of them (II-5) was operated at the age of 31 with
a diagnosis of parathyroid carcinoma. He was reoperated 4 yr later
because of recurrence that showed invasive growth to the neck muscle.
Multiple cysts were noted in his kidneys. His sister (II-3) had two
parathyroid adenomas removed at the age of 37. Multiple renal cysts
were detected in both of her kidneys. The other two siblings each had a
single parathyroid adenoma removed at the ages of 36 and 37,
respectively. In both cases, there is no evidence of recurrence after 5
and 7 yr of follow-up. Both parents and the remaining healthy child
(II-1) were screened repeatedly, but no evidence of hyperparathyroidism
was found, and radiological investigation also failed to detect any jaw
or renal lesions.
Linkage analysis
Informed consent was obtained from all participating members. Peripheral blood samples were obtained from 41 members of 3 families, and high molecular weight DNA was isolated according to standard protocols. In one case (II-2 in Family 2) where a blood sample could not be obtained, DNA was extracted from normal paraffin-embedded tissues as previously described (19). Three microsatellite markers, cen-D11S1883-PYGM-MEN1-D11S913-tel, located close to and flanking the MEN1 gene at 11q13 were used (20). The HRPT2 locus has been mapped to a region between 26cM region between markers D1S215 and D1S249 in 1q21-q32 region (12, 15, Wassif et al. submitted), and 20 microsatellite markers from this region were used: cen-D1S218, D1S215, D1S222, D1S238, D1S428, D1S461, D1S422, D1S492, D1S412, D1S413, D1S477, D1S306, D1S510, D1S456, D1S249, D1S504, D1S471, D1S245, D1S491 and D1S425-tel (21). Genotyping was performed as previously described (22). Two-point analysis was performed using the FASTLINK (version 2.3P) linkage program and multipoint analysis using the GENEHUNTER program (23, 24). Using a conservative approach, all unaffected cases were considered as unknown except 2 who were over 80 yr old. These 2 individuals (II-3 and II-5) were labelled as unaffected after repeated negative screening. Conventional cut-off levels were used, i.e. lod score of more than 3.0 signified linkage to a given marker, and that of less than -2 excluded linkage.
Loss-of-heterozygosity (LOH) studies
Tissue blocks from the following patients were studied: II-1, III-6, IV-1, and IV-7 in Family 1; IV-2 and IV-4 in Family 2; II-4 and II-5 in Family 3. DNA was extracted from microdissected 5 µm sections of fixed, paraffin-imbedded, parathyroid tumors by standard methods. Paired somatic and tumor DNA samples were analyzed for LOH using D1S218, D1S222, D1S422, D1S412, D1S413, D1S477, D1S510, D1S491, and D1S249 at 1q21-q32, and PYGM and D11S913 at 11q13.
Histochemical stainings
For routine histopathological examination, sections were stained with hematoxylin and eosin, and by the van Gieson method, the latter in particular for visualizing collagenous connective tissue. To differentiate between blood vessels and cysts in the sections, antibodies against Factor VIII related protein (Dakopatts, Glostrup, Denmark) and CD34 (Immunotech, Marseille, France) were used (25, 26). Deparaffinized sections were incubated with primary antiserum overnight and stained according to the Avidin-Biotin-peroxidase Complex method, following the manufacturers instructions (Vectastain, Vector Laboratories, Burlingame, Ca). Diaminobenzidine was used as chromogen, and counterstaining was made with Mayer’s hematoxylin.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The pedigrees of the 3 families analysed are shown in Fig. 1.
Genetic linkage analysis was performed in a total of 42 individuals,
including 13 affected members, 6 spouses, 22 presently unaffected
family members, and 1 deceased individual (II-2 Family 2 in Fig. 1)
whose disease state was unknown. Linkage to MEN1 was
excluded on the basis of haplotype analysis and significantly negative
lod scores (< -2) in all families (data not shown). We thus focused
on the other candidate region, i.e. the HRPT2
locus in chromosome 1q21-q32. Families 1 and 2 were considered as a
homogenous group as they shared the same clinical phenotypes without
evidence of jaw or renal lesions and thus were analyzed together.
Cystic kidney disease and parathyroid carcinoma were found in Family 3,
which was therefore considered as affected by the classic HPT-JT
syndrome. In this family (Fig. 1), although both parents were
clinically normal, the disease haplotypes were thought to be
transmitted from the father (I-1) based on two factors: first, all 4
affected cases shared the same haplotypes from the father, and second,
in the parathyroid carcinoma, loss of the maternal alleles were
found.
In Families 1 and 2, the two-point lod scores for seven of the
chromosome 1 markers are detailed in Table 1. All markers except D1S218 and D1S491
gave positive lod scores, which varied depending on the informativeness
of the markers in the kindreds. Five markers gave the total lod scores
of more than 2 and two of them more than 3. Markers D1S222 and D1S249
gave the maximum lod scores of 3.10 and 3.39 respectively at
recombination fraction of 
= 0.00. This was further confirmed by
multipoint linkage analysis, which gave the lod scores of over 3 in 13
markers from markers D1S222 to D1S504. These results confirmed that the
disease in these two kindreds are linked to the 1q21-q32 region.
Haplotypes were constructed (data not shown), and meiotic
recombinations were detected in affected individuals in both families.
Centromeric recombination was detected between D1S218 and D1S222 in
affected members III-5 and IV-7 in Family 1, and between D1S215 and
D1S222 in the affected members III-1 and IV-2 in Family 2. A telomeric
cross-over was identified in affected individual III-5 in Family 1,
between D1S491 and D1S425. The disease region, flanked by D1S215 and
D1S425, spans approximately 37 cm, which overlaps with the
HRPT2 region between D1S215 and D1S249 (15).
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Four abnormal glands from Family 1, two from Family 2, and four
from Family 3 were reexamined. One or two enlarged glands had been
identified and removed from each of the cases, while at least one
normal-sized gland had been identified and left in situ. The
enlarged glands were one carcinoma and nine adenomas that consisted of
one oxyphil/oncocytic type (II-1 Fig. 2)
and eight chief cell type (Fig. 3). The
parathyroid carcinoma from II-5 in Family 3 consists mainly of solidly
arranged cells with large nuclei and nucleoli (Fig. 4). Mitoses are frequently seen with foci
of coagulation-type necrosis and fibrosis (27). All tumors except one
contained cysts of varying size, and some of the cysts were lined by
parenchymal cells (Fig. 3). Immunohistochemical staining for factor
VIII and CD34 showed numerous vessels and not the cysts. These
stainings results thus verified that the small thin-walled cysts did
not represent dilated capillaries. Except in the parathyroid carcinoma,
no signs of infiltrative growth was seen in any of the tumors.
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Loss of heterozygosity was sought in parathyroid tumors from four
patients from Family 1, two from Family 2, and two from Family 3. In
Family 1, the tumor from III-6 did not amplify with any of the markers,
but the other three tumors, one oxyphil tumor and two chief cell
tumors, showed LOH in the 1q21-q32 region. In all three cases the
losses invariably involved the loss of the wild-type allele derived
from the unaffected parent (Fig. 5, Table 2). The two tumors from Family 2 remained
heterozygous for markers at 1q21-q32. In Family 3, unfortunately, one
chief cell adenoma did not amplify despite several attempts by
different methods, but the parathyroid carcinoma showed LOH of the
maternal alleles (Table 2).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The finding of cystic kidney disease in two siblings in the third family further confirms our previous findings (15) that it is part of HPT-JT, and it should be investigated in all 1q-linked FIHP families. Its association with HPT-JT, together with that of Wilm’s tumor and renal nephroblastoma (12, 15) suggests that HRPT2 might play an important role in the organogenesis of kidney (29). It will be worthwhile to test the 1q markers in those polycystic kidney disease families that are not linked to PKD1 (chromosome 16p) or PKD2 (chromosome 4p).
Clinically, there is a reduced penentrance of HPT, especially in the
females, which is consistent with our previous findings in HPT-JT
families linked to the same locus (15). In the two FIHP families, there
are three female obligate gene carriers who have not shown any
biochemical signs of primary HPT despite careful screening (Families 1
and 2, Figure 1). The father in Family 3 cannot be confirmed as an
obligate carrier as no affected individuals besides his children are
known. He can be a mosaic or new mutant. This reduced penetrance is in
contrast with MEN1, in which primary HPT occurs in over 95% of cases.
This observation has clinical implications: in dealing with small
families with familial HPT whereby both parents of a proband appear to
be normal, the extended family of the parents, especially the maternal
side, should be investigated carefully.
Histopathologically, we demonstrate a spectrum of parathyroid pathology in 1q-linked primary HPT. The parathyroid neoplasia seen in FIHP may represent one or more adenomas. Unlike MEN1, in which patients invariably develop multiglandular or hyperplastic disease and subsequent recurrence if less than total or three and a half parathyroidectomies are performed (30), the majority of patients with 1q-linked primary HPT are cured after the removal of single adenoma. Another distinction of 1q-linked primary HPT is its associated risk of carcinoma in these patients (3, 4, 5, 6), which has not been reported in MEN1. This is exemplified in the third family, in which a case of parathyroid carcinoma was found.
Besides the parathyroid carcinoma, the rest of the tumors classified as adenomas showed no sign of malignancy, although our previous studies have indicated that parathyroid tumors from 1q-linked families have increased expression of Ki-67, a marker for cell proliferation (31). These results suggest that the 1q-linked tumors might have transforming potential. The occurrence of cysts may be over-represented in these families as all tumors studied except one have either cystic formations or microcysts. The significance of these cystic structures is not known and needs to be further explored. In addition, we found two types of benign parathyroid tumors in the same family: chief cell and oxyphil/oncocytic cell types. The latter has not been reported in 1q-linked families. Case II-1 in Family 1 fulfills all the criteria of an oxyphil cell tumor (32): the gland weighing 4 g consisting entirely of oxyphil cells, with normal biopsy of other glands, and the patient remaining normocalcemic for the last 17 yr. The other three affected family members all have chief cell tumors. Oxyphil/oncocytic parathyroid cells have been considered to be aged, degenerate, nonfunctioning forms of the parathyroid chief cell (2). Interestingly, this particular oxyphil tumor was detected in the oldest affected member when she was 58 yr of age, compared with the other three chief cell tumors, which occur at the ages of 20, 22, and 25 yr, respectively. What might be relevant is the fact that oxyphil parathyroid adenomas are usually nonfunctional. This might explain our clinical observation of reduced penetrance of HPT in the 1q-linked families because in these cases, oxyphil tumors might have occurred but were not detected due to their nonfunctional nature.
One important finding of the present studies is our demonstration of loss of the wild-type allele in four tumors involving the whole spectrum of the parathyroid pathology: chief cell tumor, oxyphil/oncocytic tumor, and carcinoma. These findings suggest that HRPT2 is involved in the tumorigenesis of all three pathological entities and this phenomenon, which implicates the HRPT2 gene as a tumor suppressor gene, has not been reported previously in 1q-related parathyroid tumors. The absence of LOH in previous studies, eight tumors from reference 12, and one tumor from reference 15 did not exclude the possibility that microdeletions could still exist in these tumors but were beyond the detection of the markers used. In the studies of the eight tumors (12) for example, the only three heterozygous markers the authors reported (D1S191, D1S196, D1S212) are located outside the refined HRPT2 region. Furthermore, inactivating mechanisms other than LOH (such as methylation) might play a role in these tumors (33).
In conclusion, FIHP is a genetically heterogenous disease, and a subset is genetically linked to HRPT2, most likely representing a variant of HPT-JT. In encountering families with FIHP, it is thus important to first establish whether they are genetically linked to HRPT2 or MEN1. Once this is confirmed, appropriate clinical screening should be carried out for other associated tumors, although some of these families might only have FIHP without ever expressing any other tumors. Finally, studies of additional families will enhance our understanding of the clinical expression and natural history of the disease besides contributing to the positional cloning of the gene involved.
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Footnotes |
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Received December 31, 1997.
Revised March 4, 1998.
Accepted March 11, 1998.
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, 
) indicate members affected with hyperparathyroidism;
open symbols (
, 
), unaffected; hatched
symbols (
), unaffected family members who are obligate gene
carriers; family members with an unknown status are marked with a
question mark. #, polycystic kidney disease; *, parathyroid
carcinoma.
