Endocrine Abstracts

Case history: A 38-year-old woman presented with blepharospasm, cramping of the hands, and paraesthesia primarily affecting the face and hands. Symptoms had been present for 10 years but had been progressive over the previous 12 months. Symptoms were consistent with neuromuscular instability. Hypocalcaemia and elevated Parathyroid hormone (PTH) were confirmed. Past medical history was notable for anorexia nervosa in remission. Family history was non-contributary. Hypocalcaemia was resistant to oral calcium supplementation and symptoms persisted despite treatment with high doses of vitamin D (cholecalciferol). The patient had normal intelligence and was morphologically unremarkable with normal facies, stature, and metacarpal length. Following full biochemical assessment with a pattern of PTH resistance in the absence of overt skeletal defects, a diagnosis of pseudohypoparathyroidism type 1B (PHP1B) was suspected.

Investigations: On serial testing serum calcium was persistently low [1.6–1.8 mmol/l(ref, 2.2–2.6)]. PTH was elevated at 57.4 pmol/l (ref, 1.6–7.2). Phosphate was 1.41 mmol/l (ref, 0.7–1.45). 25 (OH) vitamin D was replete at 79 nmol/l(ref, ≥50). 1,25 (di-OH) vitamin D was low at 51 pmol/l (ref, 55–139). 24-hour urinary excretion was 1.2 mmol/24hr(ref, 2.4–6.5). Renal function and thyroid function tests were normal. Genetic analysis was undertaken to establish a diagnosis of PHP1B.

Results and treatment: The guanine nucleotide-binding protein alpha-stimulating (GNAS) gene locus on chromosome 20q13.3 displayed almost complete loss of maternal methylation pattern at all four differentially methylated regions (DMRs) analysed. A diagnosis of PHP1B was thus confirmed. The patient was commenced on high doses of alfacalcidol (3 mcg/day) and calcium supplementation (1g/day). Serum calcium level improved significantly (2.08 mmol/l) and the patient has been symptom free for 12 months.

Conclusions and points for discussion: PHP comprise a group of disorders with an estimated prevalence of 0.3–1.1 per 100,000 and are characterised by end-organ resistance to PTH. This is classically associated with the Albright hereditary osteodystrophy (AHO) phenotype of brachydactyly, rounded facies, short stature, central obesity, heterotopic subcutaneous ossifications, and cognitive impairment. Genetic molecular analysis secures a diagnosis in up to 90% of clinically confirmed cases. PHP1B occurs due to methylation defects of the GNAS locus, and manifests as renal resistance to PTH action. Inheritance is autosomal dominant, but most cases present as sporadic. Patients with PHP1B do not typically display features of AHO, respond to high dose activated vitamin D supplementation with alfacalcidol or calcitriol, and have an excellent prognosis. Therefore, it is important to diagnose the condition early and optimize patient care to prevent complications due to long term PTH resistance.