Endocrine Abstracts

Case history: A 28-year-old female was investigated for hypocalcaemia. Her calcium level was checked because her mother was found to be hypocalcaemic post thyroidectomy for recurrence of Graves disease. Further detailed history taking revealed that the patient’s grandmother often complained of hand cramps on kneading dough. The patient’s aunt was believed to have a parathyroid disorder; no further details were available. On further investigation, it was apparent that her mother’s hypocalcaemia pre-dated the thyroidectomy and was long standing. The patient had a history of seizures between the ages of 5–8 years during which her calcium levels were not available. She also had a history of paraesthesiae in her hands and feet. The patient’s Trousseau sign was negative at 3 minutes and there were no abnormal phenotypic findings on examination.

Investigations: Her corrected calcium varied between 1.87 and 2.07 mmol/l (2.2–2.6 mmol/l). Her PTH level was 2.9 pmol/l (1.3–9.3 pmol/l) when her serum calcium was 2.01 mmol/l, thus confirming hypoparathyroidism. Her 25-OH Vitamin D level was 38.1 nmol/l and her serum magnesium levels were normal. As she had a family history in keeping with a likely monogenic cause for her hypoparathyroidism, sequence analyses of AIRE, GATA3, CASR, GCM2, GNA11and PTHgenes were undertaken.

Results and treatment: Before the mutational analysis results, the patient had been commenced on alfacalcidol, which did not have an effect on her calcium levels at relatively high doses. The mutational analysis revealed that she was heterozygous for CASR c.452C>T p.(Thr151Met). This variant has been described in a Norwegian kindred of 61 individuals, segregating with hypocalcaemia. The change was absent in normal controls. This confirmed a diagnosis of autosomal dominant hypocalcaemia (ADH).

Conclusions and points for discussion: ADH is a rare disorder due to pathogenic gain of function mutations in the calcium sensing receptor (CASR), increasing sensitivity of the CASR to extracellular ionised calcium. In the kidney, less calcium is reabsorbed regardless of the calcium level, therefore patients are hypercalciuric. Patients do not often respond to alfacalcidol and the treatment may exacerbate the hypercalciuria, making them prone to nephrocalcinosis and nephrolithiasis. Although high quality evidence is lacking, asymptomatic patients can be monitored in the long term, without active treatment. Diagnosing monogenic calcium disorders is also of value for members of the family, as it can result in avoidance of unnecessary investigations and treatment.