Familial isolated hyperparathyroidism

Introduction

Familial isolated hyperparathyroidism (FIHP; HRPT1) is a diag­nostic subgroup of familial hyperparathyroidism (HPT) that can be non-syndromic or can result from the incomplete expression of a syndromic form of familial HPT (Fig. 1). Syndromic forms of familial HPT that can present as FIHP include multiple en­docrine neoplasia type 1 (MEN1), familial hypocalciuric hypercalcemia (FHH) (also known as familial benign hypercal­cemia), and the hyperparathyroidism-jaw tumor syn­drome (HPT-JT; HRPT2). Multiple endocrine neoplasia type 2A (MEN2A), unlike MEN1, is not typically a consider­ation in the differential diagnosis of FIHP, because of the high­er penetrance of medullary thyroid carcinoma and pheochro- mocytoma than of HPT in MEN2A families. It is unknown how many as yet unrecognized genotypes may also present as FIHP.

MEN1 is an autosomal dominant disorder characterized by en­docrine and non-endocrine tumors, most prominently involving the parathyroids, enteropancreatic endocrine system, and pitu­itary. Because HPT is the earliest and most frequent en- docrinopathy in MEN1, some kindreds with apparent FIHP rep­resent early and/or occult expressions of MEN1. The gene re­sponsible for MEN1 has been cloned, leading to gene mu­tational analytical methods applicable to MEN1, FIHP, and oth­er conditions.

Figure 1 - The relationship as a Venn diagram

Figure 1 – The relationship as a Venn diagram among familial forms of hyperparathyroidism that may present as familial isolated hyperparathyroidism (FIHP) [modified and updated from reference]. The dashed circle represents the set of patients presenting with the provisional diag¬nosis of FIHP. Contained entirely within this dashed circle is a subset of families who have subsequently been thoroughly evaluated for, but lack findings diagnostic of, MEN1, FHH and HPT-JT (FIHP (non-syndromic); in a solid circle). Subsets of patients with incomplete expression of MEN1, FHH and HPT-JT (the total set of patients in each syndrome rep¬resented by a solid circle) can also present with the FIHP phenotype. The distinction between the FIHP category and the syndromic categories arbitrarily depends on the sensitivity of diagnostic tests used to detect the syndrome. MEN2A is a familial form of hyperparathyroidism seldom if ever presenting as FIHP. Within each circle representing a defined syndrome are included the genetic locus (or loci in the case of FHH) of the syndromic trait and the responsible gene product. An asterisk next to the genetic locus indicates that the gene and gene product are unknown for the form of familial hyperparathyroidism mapping to this site. The relationship among the patient groups is intended to be qualitative, and the area of each circle and the area of overlap between circles are not intended to be proportional to their encountered or predicted values.

FHH is an autosomal dominant trait usually causing mild HPT with relative hypocalciuria; hypercalcemia in FHH is highly penetrant at all ages, even in the perinatal period. FHH cas­es almost always remain hypercalcemic following partial or subtotal parathyroidectomy (PTX). Mild hypermagnesemia is sometimes seen in FHH but is unusual in other forms of primary HPT. Most cases of FHH result from a loss-of-function mutation in the gene for the calcium-sensing receptor (CaSR) on the long arm of chromosome 3. However two undis­covered genes have been implicated in rare kindreds with FHH; 1 gene at chromosome 19p and 1 gene at 19q. HPT-JT syndrome is an autosomal dominant disorder with high but incomplete penetrance of HPT. It may present with parathyroid adenoma, parathyroid carcinoma, and/or fibro-os- seous jaw tumors. Renal cysts and solid renal tumors have also been associated with HPT-JT. Cystic parathyroid tumors have been associated with HPT-JT. HRPT2, the gene for HPT-JT, has been identified on the long arm of chromosome 1. FIHP with or without parathy­roid carcinoma but lacking evident jaw tumors can result from occult germline HRPT2 mutation as can apparently sporadic parathyroid cancer. Uterine tumors have been suggested to be part of the HPT-JT phenotype, even though demonstration of somatic HRPT2 mutation or loss of heterozygosity (LOH) at 1q25-q31 in DNA from such uterine tu­mors is still lacking. This contrasts with the level of evidence for MEN1-associated uterine leiomyomata, in which most tumors have demonstrable LOH at the MEN1 gene locus. This mini-review will survey the clinical and molecular genetic studies of FIHP kindreds reported since 1997 when the identifi­cation of the MEN1 gene allowed for the first time sensi­tive evaluation of such families for occult germline mutation of a gene predisposing to a familial form of HPT. Screening for occult germline mutation of the CASR gene and the HRPT2 gene after its identification in 2002 added to the power of such analyses. Particular emphasis will be given to the analysis of 40 kindreds from our own institution with a provisional diagnosis of FIHP and described in detail in two previ­ous reports(Table I).
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Table I – Clinical characteristics and gene mutational screening results in 40 kindreds with a provisional diagnosis of familial isolated hyperparathyroidism, modified from previous reports. The kindreds are grouped according to their final diagnostic classification as HPT-JT, CASR-mutation-positive, or non-syndromic FIHP.

Kindred

Proband

Index case testing results

Notes

I.D.

Number affected (a)

Age at diagnosis of HPT

Sex

Gene mutational screening (b)

No.

Tot.

M

F

(Years)

(M/F)

MEN1

CASR

HRPT2

Hyperparathyroidism-Jaw Tumor Syndrome Group

417

5

3

2

27

F

N

N

exon 7 679insAG

2862

7

2

5

48

M

N

N

N

c

27,000

2

1

1

10

F

N

N

exon 1 34delAACATCC

d

35,900

4

3

1

34

M

N

N

exon 7 679insAG

e

Calcium-Sensing Receptor Mutation-Positive Group

1214

2

2

0

26

M

N

exon 4 V268del-11X273

N

5780

11

7

4

53

F

N

exon 7 R886P

N

10,147

3

1

2

30

F

N

exon 4 R220W

N

23,300

3

2

1

21

M

N

exon 3 L159P

N

28,300

2

1

1

53

M

N

exon 4 E250K

N

Familial Isolated Hyperparathyroidism Group

13

2

0

2

53

F

N

N

N

225

2

0

2

43

F

N

N

N

410

2

1

1

53

F

N

N

N

4318

3

0

3

50

F

N

N

N

5977

4

1

3

41

F

N

N

N

Kindred

Proband

Index case testing results

Notes

I.D.

Number affected (a)

Age at diagnosis of HPT

Sex

Gene mutational screening (b)

No.

Tot.

M

F

(Years)

(M/F)

MEN1

CASR HRPT2

6324

2

1

1

61

F

N

N

N

6325

3

2

1

45

N

N

N

6326

2

0

2

61

F

N

N

N

6335

2

1

1

39

F

N

N

N

7751

3

0

3

19

F

N

N

N

8715

4

0

4

49

F

N

N

N

9462

2

2

0

37

N

N

N

10,021

2

0

2

74

F

N

N

N

10,157

2

1

1

40

F

N

N

N

21,300

3

1

2

34

F

N

N

N

24,200

2

0

2

44

F

N

N

N

24,700

3

2

1

43

N

N

N

f

25,200

2

1

1

51

N

N

N

26,500

3

1

2

30

F

N

N

N

27,300

3

0

3

29

F

N

N

N

28,200

8

5

3

14

F

N

N

N

g

28,400

2

1

1

43

N

N

N

28,500

2

1

1

52

F

N

N

N

28,600

2

0

2

12

F

N

N

N

28,700

2

1

1

20

F

N

N

N

28,800

2

1

1

54

F

N

N

N

28,900

3

2

1

28

M

N

N

N

30,300

2

0

2

8

F

N

N

N

33,100

2

1

1

73

M

N

N

N

33,800

2

1

1

66

M

N

N

N

35,100

2

1

1

51

M

N

N

N