Endocrine Abstracts

Case history: Case 1: 18-year-old female referred with asymptomatic hypercalcaemia (adjusted calcium 2.69 mmol/l), phosphate 0.96 mmol/l, parathyroid hormone 2.6 pmol/l and total 25 hydroxyvitamin D 37 nmol/l. No evidence of end organ damage. Initial calcium: creatinine clearance ratio 0.0033 but the patient had a vitamin D 24 nmol/l. Case 2: A 53-year-old female referred with asymptomatic incidental hypercalcaemia (adjusted calcium 2.73–2.87 mmol/l), raised parathyroid hormone (7.4 pmol/l), normal vitamin D. Parathyroid imaging at the time suggested parathyroid hyperplasia as an underlying cause. Bone densitometry showed osteoporosis at the spine. The patient was diagnosed with primary hyperparathyroidism and discharged. She was referred back to the endocrinology clinic four years later.

Investigations: Ultrasound scan (USS) thyroid and parathyroid, nuclear medicine (NM) parathyroids, repeat calcium: creatinine ratio and subsequent genetic testing for FHH.

Results and treatment: Case 1: Normal USS and NM parathyroid scan, calcium: creatinine clearance ratio 0.0106 (normal vitamin D). Genetic testing revealed a G to A nucleotide substitution in Exon 7 of calcium-sensing receptor gene (CASR) (c. 1979G>A) which is predicted to result in replacement of the amino acid cysteine with tyrosine at residue 660 (p. Cys660Tyr). Case 2: US thyroid and parathyroid - all four parathyroids similar in size with measurements of right superior 4×4×3 mm, right inferior 4×3×3 mm, left inferior 4×3×2 mm and left superior 5×4×3 mm. Parathyroid hyperplasia more likely than adenoma. Genetic analysis of CASR (Exons 2–7) found a C to G nucleotide substitution in exon 7 of CASR (c. 2617C>G), which is predicted to result in replacement of the amino acid arginine with glycine at residue 873 (p. Arg873Gly).

Conclusions and points for discussion: We present two cases of FHH with novel mutations in the CASR gene - namely nucleotide substitution in Exon 7 of CASR. Neither variant is present on the Online Mendelian Inheritance in Man (OMIM), Mutation Discovery or 1000 genome databases. FHH is an autosomal dominant genetic condition characterised by usually moderate hypercalcaemia associated with inappropriate PTH and urinary calcium excretion. The patient in case 2 presented with likely parathyroid hyperplasia with FHH. It is often an incidental finding, but rarely patients may experience symptoms of hypercalcaemia (thirst, fatigue, weakness. We have not been able to study other members of the family tree for ethical reasons. Further research is needed to characterize the mutated gene function.