Familial hyperparathyroidism

Biomed & Pharmacother 2000 ; 54 Suppl 1 : 21-4 © 2000 t~ditionsscientifiqueset m6dicalesElsevier SAS. All rights reserved

Mini review

Familial hyperparathyroidism H. Takami ~, S. Shirahama 2, Y. Ikeda 1, Y. Sasaki ~, N. Wada, M. Niimi 1, K. Kameyama3 i First Department of Surgery, Teikyo University School of Medicine, Tokyo 173-8605; 2 Center for Molecular Biology and Cytogenetics, SRL Inc., Tokyo 191-0002; 3 Division of Diagnostic Pathology, Keio University Hospital, Tokyo 160-8582, Japan

Summary - Familial hyperparathyroidism(HPT) is a hereditary disease in which HPT is transmittedin an autosomaldominant fashion. It includes a variety of diseases: multiple endocrine neoplasia (MEN) type 1 and type 2, and familial isolated hyperparathyroidism(FIHPT). We screened for MEN 1 mutations by direct nucleotide sequencingof all protein-codingregions and identifiedthe germline mutations of the MEN 1 gene in two families with familial HPT. Patients with FIHPT have multiple abnormal parathyroid glands and are prone to both recurrent and persistent HPT. They frequently present with profound hypercalcemia, in contrast to patients with MEN-associated HPT or sporadic HPT. We recommend subtotal or total parathyroidectomy plus autotransplantationin patients with MEN-associated HPT and patients with FIHPT. Because parathyroidremains or supernumeraryglands are often present in the thymus or perithymictissue, we advocate routine bilateral dissectionof the central zone with bilateral cervical thymectomy.© 2000 t~ditionsscientifiqueset mrdicales Elsevier SAS familial hyperparathyroidism / familial isolated hyperparathyroidism / multiple endocrine neoplasia

INTRODUCTION Familial hyperparathyroidism(HPT) is a rare inherited disorder that was first reported by Goldman and Smyth [1] in 1936. It is characterized by hypercalcemia, inappropriately high parathyroid hormone (PTH) levels, and isolated parahyroid tumors. Most cases of familial HPT occur in association with multiple endocrine neoplasia (MEN). Primary HPT can be classified into three categories: 1) sporadic HPT; 2) familial HPT with multiple endocrine neoplasia type 1 (MEN 1) and type 2 (MEN 2); 3) non-MEN familial HPT (NMFH) or familial isolated HPT (FIHPT); and 4) familial HPT with jaw-tumor [2]. FIHPT is uncommon and is confused with benign familial hypocalciuric hypercalcemia with HPT and neonatal severe primary HPT. The former is an autosomal d o m i n a n t syndrome marked by lifelong serum calcium elevation and relative hypocalciuria [3]. In the latter disease, infants may be born with severe hypercalcemic HPT, with both life-threatening hypercal-

cemia and severe bone disease, and the patients have a specific chromosomal defect on chromosome 3. The gene responsible for MEN 1 was isolated in 1997 [4], making it possible to directly determine whether FIHPT is a variant of MEN or not. We attemped to identify germline mutations of the M E N 1 gene in two families with familial HPT. We also reviewed our experience at Teikyo University Hospital, Tokyo, and the literature. GENETIC STUDY

Subjects Two Japanese families that include five and three patients each with familial HPT were studied. Neither of the families had MEN-like endocrinopathies. The pedigrees of the families are shown infigure 1, and the clinical features of the affected families are summarized in table I. Direct D N A s e q u e n c i n g

Correspondenceand reprints: HiroshiTakarni,M.D., First Department of Surgery, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku,Tokyo 173-8605, Japan.

Genomic DNA was extracted from peripheral leukocytes or tissues with a DNA extraction kit. Four sets of nucleotide sequences representing the ten exons of the

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H. Takami et al.

Table I. Genetic analysis of affected subject.

Subject

Age at initial diagnosis~gender

Family S 1 10) 2 3 4P 5 6 7 Family M Iv 2 3 4 5 6

Pathology (No. of glands removed)

LOH (1 lq13) (codon 418 or 541)

Mutation

68 yo/F

hyperplasia (4)

noninformative*

1483de 14 (exon

49 yo/M 47 yo/M 35 yo/F 28 yo/M 26 yo/F 21 yo/M

hyperplasia ( l ) hyperplasia (2) hyperplasia (1) hyperplasia (1)

noninformative* + (codon 418)

1483de14 1483de 14

+ (codon 418) noninformative*

1483de14 1483de14

78 yo/F 59 yo/M 58 yo/M 47 yo/M 55 yo/M 22 yo/M

hyperplasia (5) hyperplasia (1) hyperplasia (5) -

noninformative*

Q366X (exon 8)

noninformative* + codon 418)

Q366X (exon 8) Q366X (exon 8)

p: proband; * homozygous at codon 418(GCA or GAT) and 541 (GCA or ACA).

Family S

BigDye Terminator Cycle Sequencing Ready Reaction Kit.

Mutations of the M E N 1 gene

d--k' Family M

Figure 1. Pedigrees of the familial HPT patients. Upper panel: Family S; lower panel: Family M. The arrows point to the probands. The filled symbols indicate affected family members.

M E N 1 coding region were amplified from the genomic DNA of familial HPT patients with the Expand T M Fidelity PCR System [5]. The PCR products were purified and directly sequenced by using the ABI PRISM

Two different heterozygous germline mutations of the M E N 1 gene were detected in the two families with familial HPT. The mutations were a frameshift mutation, 1483de14, in family S and nonsense mutation, Q366X, in family M (figure 2). The frameshift and nonsense mutations predict protein truncation with loss of function and potential instability of the mRNA. To determine whether allelic loss is present on 1 lq13 in tumor tissues, allelic loss for two synonymous polymorphisms were assesed at codon 418, GAC or GAT, and at codon 541, GCA or ACA, in DNA samples of tumor tissue and leukocytes. The allelic losses were confirmed at codon 418 in the members of family S, and at codon 541 in family M (table L figure 3). HPT is usually expressed at an early age (85% by age 35) and has a high penetrance (95%) in MEN 1 [6]. HPT usually antedates other manifestations of M E N 1. The differential diagnosis between FIHPT and MEN 1 is being made by DNA genetic analysis. We confirmed two novel germline heterozygous mutations of M E N 1 in two Japanese families with familial HPT. We also detected loss of heterozygosity (LOH) at 1 l q13, with polymorphisms at codon 418 or 541 of M E N 1 in patients with familial HPT. These familial HPT patients with M E N 1 mutations are thought to be in an early stage of MEN 1 or a variant type of MEN 1.

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Familial hyperparathyroidism

codon 457 GO

GO

AT

458

459

T Q AS

AS

co
T T C T T T G A A e

QG

TA

G

TA

GO

m

GO

AG

GOAT

T G AGIC

CG

T T CT

T T ~AAG

IC CG A G A G

T W

~le

Figure 2. Direct sequence analysis of M E N 1 in familial HPT. A) Sequencing pattern of exon 10 in the proband in family S. The germline mutation is an alteration of GTGAGC to GC (1483de14) at codons 458 to 459. B) Sequencing pattern of exon 8 in the proband in family M. Germline mutation is a nonsense mutation of GAA to TAA (G366X) at codon 366.

C L I N I C A L STUDY

codon 418 C

T

A C

G

A ~T G

G C

A T

C

T

1 C

T

A C

G

A ~.? G

G C

A T

C T

T

Figure 3. Direct sequence analysis at codon 418 of M E N 1 of the proband in family S. The sequencing data of DNA samples from leukocytes and tumor tissue are shown in the upper and lower panel. The arrows point to the position of the C or T nucleotide substitutions. The height of the T peak in the tumor is lower than in the blood and the height of the C peak is higher.

Clinical manifestations

The clinical data on the seven patients with familial HPT from two families operated on at Teikyo University Hospital and 67 FIHPT patients reported in the literature are summarized in table H. FIHPT occurs in young patients. The mean age at diagnosis in a literature review series was 37 years, though it was 48 years (range, 22-81 years) in our familial HPT series. In the series reported by Barry et al. [7], the mean age at the time of diagnosis of FIHPT was 39 years, with 11 patients being first seen before 30 years of age. By contrast, patients with sporadic HPT are typically seen later, in the fifth and sixth decades. Renal stones developed in 47% of the patients with FIHPT in the literature review series, and 16% of them had bone diseases, whereas 86% of the patients in our familial HPT series had renal stones, and 57% of them had bone diseases. A serum calcium level of 15 mg/dL or greater was recorded in 41% of the patients reported in the literature, as opposed to a 0% incidence of profound hypercalcemia in our series. Multiple abnormal parathyroid glands were present in 56% of the patients reported in the literature and in 57% of the patients in our series. Supernumerary glands were found in 7% of cases

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H. Takami et al.

Table II. Comparison of current series and the literature. Variable

Age (yr) Sex ratio Manifestations (%) Renal stones Bone diseases CA > 15 mg/dl Multiple abnormal glands (_>2) (%) Supernumerary glands (%) Persistent or recurrent hypercalcemia (%)

Current series (N = 8)

Literature review (N = 132)

48 (22-81) 1:1.3

37 (11-82) 1:1.3

86 57 0 57

47 16 4I 56

29

7

0

34

reported in the literature, and in 29% of patients in our series. Barry [7] reported finding multiple-gland d i s e a s e in 20 p a t i e n t s ( 6 7 % ) in an F I H P T g r o u p . D o u b l e adenomas were found in four (13%) of these 20 patients, and hyperplastic glands were present in 16 (54%). Nine of the patients had ectopic glands, and three had supernumerary glands, which contributed to the high incidence of persistent or recurrent disease. Persistent or recurrent hypercalcemia occurred in 34% of the cases reported in the literature, but in 0% of the patients in our series. A shorter duration of follow-up and mild M E N 1-related clinical course may account for the lower incidence of recurrence in our familial H P T series. The most striking feature of familial HPT is the high incidence of persistence or recurrent hypercalcemic disease. These results are unsatisfactory and d e m a n d a more appropriate operative strategy.

Surgical treatment The more aggressive biologic behavior of the parathyroid disease in FIHPT patients, their high incidence of multiple abnormal glands and supernumerary glands, and high recurrence rate warrant a s o m e w h a t more aggressive surgical approach [8]. Although the hypercalcemia in most M E N 1 patients is usually mild, patients with HPT and M E N 1 usually have multiple abnormal parathyroid glands, with a high incidence of supernumerary glands [9]. We r e c o m m e n d a similar operative

strategy for patients with H P T and M E N 1 and for patients with FIHPT [ 10]. While most authorities in this field recommended subtotal parathyroidectomy or total parathyroidectomy with autotransplantation [2], we believe the latter procedure increases the frequency of hypoparathyroidism, and thus we prefer the former procedure. For patients with recurrent or persistent disease, we recommend total parathyroidectomy with autotransplantation and cryopreservation in centers with experience in the management of multiple abnormal glands. Judicious use of intraoperative rapid PTH monitoring and sestamibi-guided surgery must also be considered in these patients whose initial operation was unsuccessful. Because parathyroid remains or supernumerary glands are often present in the thymus or perithymic tissue, we adovocate routine bilateral dissection of the central zone with bilateral cervical thymectomy.

REFERENCES 1 Goldman L, Smyth FS. Hyperparathyroidism in sibling. Ann Surg 1936 ; 104 : 971-81. 2 Huang SM. Familial hyperparathyroidism. In: Clark OH, Duh QY. eds. Textbook of endocrine surgery. Philadelphia: W.B. Saunders Co: 1997. p. 385. 3 Heath H III. Familial benign (hypocalciuric) hypercalcemia. Endocrinol Metab Clin North Am 1889 ; 18 : 723-40. 4 Chandrasekharappa SC, Guru SC, Manickam P. Olufemi S, Collins FS, Emmert-Buck MR, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997 ; 276 : 404-7. 5 Fujimori M, Shirahama S, Sakurai A, Hashizume K, HamaY, lto K, et al. Novel M E N 1 germline mutations in the Japanese kindred with familial hyperparathyroidism. Am J Med Genet 1998 ; 80 : 221-2. 6 Trump D, Farren B, Wooding C, et al. Clinical studies of multiple endocrine neoplasia type 1 ( M E N 1). Q J Med 1996 : 89 : 653-9. 7 Barry MK, van Heerden JA, Grant CS, Thompson GB, Khosla S. Is familial hyperparathyroidism a unique disease'? Surgery 1997 : 122 : 1028-33. 8 Huang SM, Duh QY, Shaver J, Siperstein AE, Kraimps JL, Clark OH. Familial hyperparathyroidism without multiple endocrine neoplasia. World J Surg 1997 : 21 : 22-9. 9 Malmaeus J, Benson L, Johansson H, et al. Parathyroid surgery in the multiple endocrine neoplasia type I syndrome: choice of surgical procedure. World J Surg 1986 ; 10 : 668-71. 10 Kraimps JL, Duh QY, Demeure M, Clark OH. Hyperparathyroidism in multiple endocrine neopolasia syndrome. Surgery 1992 ; 112 : 1080-6.