The hyperparathyroidism-jaw tumour (HPT-JT) syndrome

Introduction

Primary hyperparathyroidism (HPT) represents the commonest cause of hypercalcaemia in the general population, with an es­timated incidence of 1 to 3 per 1000 individuals. The parathyroid tumours which cause primary HPT are found at histology to be adenomas in 85% of patients, hyperplastic in <15% of patients, and carcinomas in <1% of patients, and these most commonly arise as a non-familial i.e. sporadic, con­dition that increases with age and shows a female predomi­nance. However, primary HPT may occur as an inherited disorder in approximately 20% of patients. These inherit­ed forms (Table I) may either arise as an isolated endocrinopathies, such as familial isolated hyperparathyroidism (FIHP) and neonatal severe primary hyperparathyroidism (NSHPT), or as part of more complex syndromes such as mul­tiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A (MEN2A) or the hyperparathyroidism-jaw tu­mour syndrome (HPT-JT). These inherited forms of HPT typically present at an earlier age than the non-heritable forms and occur with equal frequencies in both sexes. This review will focus on the HPT-JT syndrome which is associated with the occurrence of parathyroid carcinomas in approximately 15% of patients.

Figure 1 - Occurrence of tumours

Figure 1 – Occurrence of tumours in patients with the HPT-JT syndrome. A review of the published reports of 34 kindreds with HRPT2 mutations was undertaken and the frequency of occurrence of each type of tumour calculated. Tumours showing a frequency of Z15% are shown. These consist of: parathyroid tumours leading to primary HPT which occurred in 97% of 132 individuals affected with HPT-JT; parathyroid carcinomas (PC) which occurred in 15% of 128 HPT-JT patients with parathyroid tumours; ossifying jaw fibromas (JT) which occurred in 28% of 132 patients with HPT-JT; renal abnormalities (Re) which occurred in 16% of 132 HPT-JT patients; and uterine lesions (Ut) which occurred in 74% of 27 women affected with HPT-JT. Over 75% of the renal abnormalities consisted of multiple renal cysts, and over 85% of the uterine abnormalities consisted of benign lesions such as endometrial hyperplasia, adenomyosis, leiomyomas and adenofibromas. Inclusion of data from from 11 HPT-JT families without reported HRPT2 mutations did not significantly alter these frequencies; thus the frequencies of primary HPT, parathyroid carcinomas, ossifying jaw fibromas, renal abnormalities and uterine lesions were 94% (n=196), 14% (n=185), 31% (n=196), 16% (n=196) and 79% (n=39), respectively. Tumours that have been reported to occur in <2% patients (Table II), such as Hurthle cell thyroid adenomas, papillary thyroid carcinomas, pancreatic adenocarcinomas, testicular mixed germ cell tumours, breast cancer, prostate cancer and colonic cancer are not shown.

Clinical features of the HPT-JT syndrome

The HPT-JT syndrome is an autosomal dominant disorder that is characterised primarily by the occurrence of parathyroid tumours in association with maxillary and/or mandibular ossifying fibromas. In addition, some patients may develop renal abnor­malities and uterine lesions (Fig. 1). Tumours involving other or­gans have also been reported in a few patients (Table II).
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Table I – Genes involved causing Parathyroid tumours.

Disorder3

Proteinb

Chromosomal location

OMINc

Ref. #d

Inherited forms of parathyroid disease

MEN1

MENIN

11q13

131100

40, 41

MEN2A

RET

10q11.2

171400

4, 42

HPT-JT

PARAFIBROMIN

1q31.2

145001

11, 12

FIHP

MENIN

11q13

43, 44

PARAFIBROMIN

1q31.2

145000

11, 23, 45

CaSR

3q21.1

13, 18, 45

NSHPT

CaSR

3q21.1

239200

4, 46

Non-inherited forms of parathyroid disease

Adenomas

PRAD1/CCND1

11q13

168461

4, 47-49

RB1

13q14

36, 50, 51

p53

17p13

52

Unknown

1p

51, 53-55

Hyperplasia (CRF)

Unknown

Xp11

56

Carcinoma

PARAFIBROMIN

1q31.2

6, 15, 20, 30

PRAD1/CCND1

11q13

48, 49, 57

RB1

13q14

36, 48, 58

p53

17p13

59

Table II – Tumours reported in < 2% of HPT-JT patients.

Tumour

Number

Ref. #a

of patients

Thyroid

Goitre

2

12, 24

Hurthle cell adenoma

1

25

Papillary carcinoma

1

11, 12, 22

Pancreatic adenocarcinoma

1

25

Lipoma

2

11, 12, 22

Testicular mixed germ cell tumour

1

25

Colonic carcinoma

3

11-14, 26

Prostate carcinoma

3 I

3, 11, 12, 14, 26

Breast cancer

2

11-14