ORIGINAL ARTICLE

Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications

J Warner^1,2, M Epstein³, A Sweet^1,2, D Singh², J Burgess⁴, S Stranks⁵, P Hill⁶, D Perry-Keene^2,7, D Learoyd⁸, B Robinson⁸, P Birdsey⁹, E Mackenzie¹, B T Teh¹⁰, J B Prins^1,2, J Cardinal¹

¹ Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Ipswich Rd, Woolloongabba 4102, Qld, Australia
² University of Queensland, 4072, Qld, Australia
³ John Hunter Hospital, Newcastle, 2300, NSW, Australia
⁴ Department of Medicine, University of Tasmania, Hobart, Tas., Australia
⁵ Ashford Medical Center, Ashford, SA, Australia
⁶ Wickham Tce, Brisbane, Qld, Australia
⁷ Department of Endocrinology, Royal Brisbane Hospital, Qld, Australia
⁸ Department of Endocrinology and Cancer Genetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, NSW, Australia
⁹ Midhurst Ave, Christie Downs, 5164, SA, Australia
¹⁰ Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI, USA

Correspondence to:
Correspondence to:
Prof J B Prins
Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, 4102, Qld, Australia; jprins{at}soms.uq.edu.au

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.

Keywords: familial isolated hyperparathyroidism; familial hypocalciuric hypercalcaemia; calcium-sensing receptor; MEN1; HRPT2

Abbreviations: CASR, calcium-sensing receptor; FHH, familial hypocalciuric hypercalcaemia; FIHP, familial isolated hyperparathyroidism; HPT-JT, hyperparathyroidism-jaw tumour syndrome; MEN1, multiple endocrine neoplasia type 1; MTC, medullary thyroid carcinoma; PTH, parathyroid hormone

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