Tests of affected individuals from provisionally diagnosed FIHP kindreds to identify occult MEN1 include blood testing of hor­mone levels, imaging studies and gene mutational analysis. Clinical studies of FIHP kindreds often utilize biochemical tests and/or pituitary or pancreatic imaging to explore for incomplete expressions of MEN1. Prior diagnosis of gastrinoma or pro- lactinoma in the proband or any known affected relative in an FIHP family was an exclusion criterion in the studies reviewed here. Molecular genetic analysis of germline DNA for loss-of- function mutation in the MEN1 gene is the most sensi­tive test for occult MEN1 in FIHP kindreds.

Taken together, series examining 2 or more FIHP kindreds since the identification of MEN1 in 1997 have found occult MEN1 mutation in nearly 20% of families (Table II). Our own studies found no cases of occult MEN1 among 40 FIHP kin­dreds (Table I), and no family initially characterized as FIHP at study entry was subsequently reclassified as MEN1 and excluded. The typically small size of FIHP kindreds in our studies precluded 11q13 linkage analysis as a test for undiag- nosed MEN1 mutation.

The identification of MEN1 as the etiology for FIHP in none of the kindreds in our series may relate partly to the high average age (39 years) at diagnosis among the FIHP probands. The penetrance of all neoplasms in familial tumor syndromes must increase with age, and by age 40 at least 1 non-parathy­roid endocrine tumor is expressed in the majority of MEN1 pa­tients.

Table II – Syndromic causes of hyperparathyroidism identified among series of kindreds with a provisional diagnosis of FIHP studied by ge­ne mutational and clinical testing since 1997. Only studies that analy­zed two or more FIHP kindreds are included. The three genes that account for most cases of syndromic familial HPT are shown (MEN1, CASR, and HRPT2 (HPT-JT), see text) with the number of positive and total kindreds tested in parentheses below each gene. In the MEN1 gene testing column, 20 out of 107 FIHP kindreds tested posi­tive since 1997 (19%), but only 8 of 76 kindreds (10%) tested positi­ve in the more recent studies since 2002 that included testing for all three syndromic HPT genes.

FIHP series

Year

MEN1 (+/total)

CASR (+/total)

HPT-JT (+/total)

Ref

Notes

1

1 997

0/5

(33)

a

2

1 998

0/4

(38)

3

2000

1/5

(63)

4

2000

2/2

(67)

5

2002

2/7

(68)

6

2002

2/4

(42)

7

2002

1/2

(69)

8

2003

4/7

(70)

9, 10

2002, 2004

0/40

5/40

4/40

(8, 11)

b

11

2004

5/22

4/22

0/22

(34)

12

2004

0/7

0/7

2/7

(27)

13

2004

1/3

(26)

14

2006

3/7

0/7

0/7

(35)

Totals

(%)

20/1 07 (19%)

9/76 (12%)

7/79 (9%)

Some 31 different kindreds with a provisional diagnosis of FIHP have been reported in the literature to have germline mu­tations of the MEN1 gene (Table III). The types and distribu­tions of MEN1 mutations in these 31 FIHP kindreds are similar to those in typical MEN1 families. One mutation was recur­rent in 2 apparently unrelated FIHP families, a D418H mis- sense mutation in exon 9. It has been previously ob­served that a significant excess of germline missense/in-frame mutations was present among FIHP kindreds with MEN1 gene mutation compared to mutation-carrying MEN1 families. As more such FIHP families are reported, this significant differ­ence in germline missense/in-frame mutation frequency be­tween FIHP and MEN1 groups has persisted (FIHP, 47%; MEN1, 28%; p < 0.05) (Table III). This suggests that MEN1 gene mutations that encode truncated, frame-shifted, or null protein products are more penetrant in non-parathyroid tis­sues resulting in more frequent pituitary and enteropancreatic tumors and a clinical picture recognizable as MEN1. Interest­ingly several MEN1 mutations identical to those reported in FIHP kindreds (Table III) have been found in families with full phenotypic expression of MEN1 including 359del4, E363del, and R527X. Long term follow up of some kindreds with germline mutation of MEN1 and initially charac­terized as FIHP revealed the development of pituitary and/or enteropancreatic tumors typical of MEN1 that were not evident at the initial evaluation. Since HPT is usually the earliest and most penetrant feature of MEN1, evaluation of only younger MEN1 mutation carriers at the time of kindred ascer­tainment may lead to a provisional diagnosis of FIHP.
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Table III – Kindreds with familial isolated hyperparathyroidism and germline MEN1 gene mutation from the literature.

Kindred

Affected

MEN1 Germline Mutation

Ref

No.

No.

Sex

Exon/ Intron

Base

Consequence

(M/F)

(IVS) (a)

(b)

(c)

1

4

4/0

2

359

359del4

(64)

2

2

2

365

365ins19

(34)

3

3

2

369

369ins18

(63)

4

3

0/3

2

444

V112L

(68)

5

2

0/2

3

568

D153V

(70)

6

4

3/1

3

639

639del4

(70)

7

3

2/1

3

661

V184E

(71)

8

3

700

T197I

(34)

9

8

3/5

3

764

abnl splicing

(72)

10

7

3/4

4

873

E255K

(58)

11

14

6/8

4

889

Q260P

(57)

12

3

2/1

IVS4

894-9

abnl splicing

(35)

13

4

4/0

5

910

L267P

(73)

14

3

1/2

IVS5

934+1

abnl splicing

(35)

15

7

5/2

6

940

P277H

(42)

16

3

1/2

7

1124

G305D

(74)

17

2

2/0

7

1157

1157del4

(70)

18

2

8

1167

1167del3

(34)

19

3

1/2

8

1169

Y353X

(75)

20

6

3/3

8

1197

E363del

(36)

21

3

2/1

8

1206

E366X

(67)

22

4

2/2

9

1341

A411P

(70)

23

4

4/0

9

1350

L414del

(65, 76)

24

9

1362

D418H

(34)

25

2

1/1

9

1362

D418H

(35)

26

11

3/8

IVS9

1460+1

abnl splicing

(77)

27

5

2/3

10

1483

1483del4

(67)

28

10

1656

1656ins1

(34)

29

8

4/4

10

1658

1658del1

(68)

30

3

2/1

10

1689

R527X

(42)

31

5

1/4

10

1785

1785del1

(69)