Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications.(Original Article)

Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor (CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP.

J Med Genet 2004;41:155-160. doi: 10.1136/jmg.2003.016725

INTRODUCTION

The term familial hyperparathyroidism encompasses a spectrum of disorders in which primary hyperparathyroidism (persistent hypercalcaemia in the presence of inappropriately normal or elevated parathyroid hormone) (1) is inherited, usually in autosomal dominant fashion. It occurs either alone or as part of a syndrome including tumours of other tissues. The spectrum includes multiple endocrine neoplasia types 1 (MEN1) and 2A (MEN2A), hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH) (also known as familial benign hypercalcaemia), and familial isolated hyperparathyroidism (FIHP). (2) (3)

As the management and prognosis of these conditions vary considerably, the ability to accurately categorise a patient's familial hyperparathyroidism is crucial. In only a proportion, however, will a definitive diagnosis be apparent simply from the clinical findings and family history. The discovery of genes associated with MEN1, (4) MEN2A, (5) HPT-JT (6) and FHH (7) has allowed accurate diagnosis in more cases as well as screening of family members of patients with mutations identified in these genes. Nevertheless, approximately 13% of patients with MEN1, (8) 2% with MEN2A, (9) 40% with HPT-JT (6) and 40% with FHH (10) (11) phenotypes do not have sequence variations demonstrable in the protein coding regions of known genes by standard PCR-based mutation detection methods.

Gene discovery has also revealed that mutant MEN1, (12) (13) CASR (14) (15), or HRPT2 (6) genotypes may express only the FIHP phenotype. The relative proportions of these are still being elucidated, however, the cost and limited availability of genetic diagnostic tests currently preclude the option of testing all genes known to be associated with inherited hyperparathyroidism in all patients with familial hyperparathyroidism in clinical practice.

FIHP is essentially a diagnosis of exclusion. The clinical picture is of familial primary hyperparathyroidism in the absence of sufficient clinical, radiological or biochemical evidence for diagnoses of MEN 1, MEN2A, HPT-JT, or FHH to be made. Its incidence has been estimated to be about 1% of all cases of primary hyperparathyroidism. (14) Histologically, parathyroid chief cell hyperplasia, (16) single (17) and multiple gland adenomata (17) (18) as well as parathyroid carcinomata (17) (18) have been implicated.

FHH, usually caused by heterozygous inactivating mutations of CASR on chromosome 3q, (3) (19) is the most difficult of the familial hyperparathyroidism syndromes to distinguish clinically from FIHP. The prevalence of typical FHH in the west of Scotland has been estimated to be 1 in 78 000 (20) which makes it about as common as FIHP (14) Characteristic features of mild to moderate hypercalcaemia (21) non-suppressed parathyroid hormone (PTH), relative hypocalciuria while hypercalcaemic (calcium/creatinine clearance ratio <0.01 or 24 h urine calcium <6.25 mmol) (1) (21) almost 100% penetrance of the gene for hypercalcaemia from birth, absence of complications, persistence of hypercalcaemia following subtotal parathyroidectomy, (21) and normal parathyroid size, weight, and histology at surgery (22) facilitate the diagnosis when present. However, atypical presentations with severe hypercalcaemia, (23) hypercalciuria (with or without nephrolithiasis or nephrocalcinosis), (15) kindreds with affected members displaying either hypercalciuria or hypocalciuria, (14) (24) normocalcaemia resulting from surgery (15) (21) and pancreatitis (25) have all been described. A further limitation in the discriminating between FHH and primary hyperparathyroidism of other aetiologies is that about 1/3 of subjects with mild primary hyperparathyroidism have been shown to have relative hypocalciuria when hypercalcaemic. (26)

The general recommendation is that if a diagnosis of FHH is suspected, the kindred should be investigated. This may resolve diagnostic uncertainty, however if there are atypical features in the kindred, it may not. Furthermore, access to a sufficiently large kindred may not be possible if only a small one exists or for privacy or other reasons. In addition, if the index case presents with atypical features, the diagnosis may reasonably be regarded unlikely.

At present, no gene has been associated exclusively with the FIHP phenotype. We have taken advantage of the recent discovery of HRPT2 to combine mutation analysis of MEN1, CASR, and HRPT2 in 22 apparently unrelated patients with clinical diagnoses of FIHP. We report the prevalence of sequence variations in the group, discuss their implications for patient management, and confirm the need for further investigation to clarify the genetic basis of FIHP.

SUBJECTS AND METHODS

Subjects

Subjects were referred to this centre by clinicians in eastern Australia for genetic testing for inherited hyperparathyroidism as part of their clinical management. Informed consent was obtained from each subject by the referring clinician.

For a diagnosis of FIHP to be made, patients were required to have hypercalcaemia with a non-suppressed …