Endocrine Abstracts

Section 1: Case history: A 23-year-old female presented to the Emergency Department with a 3-month history of intermittent chest pain and palpitations. She was found to be hypokalaemic and hypocalcaemic. On direct-questioning she reported 3 weeks of perioral paraesthesia and muscle spasms. She had an unrestricted diet and no other personal or family history of note. She was normotensive with a sinus tachycardia and normal QT-interval, Chvostek’s negative, with no features to suggest growth retardation. She was admitted for intravenous electrolyte replacement.

Section 2: Investigations: Hypocalcaemia 1.58mmol/l, normal serum phosphate 1.29mmol/l and elevated parathyroid hormone (PTH) levels 127pmol/l were detected on admission. 25-OH Vitamin-D3 was deficient (22mmol/l) with a normal serum magnesium 0.8mmol and elevated ALP 944U/L. A spot urine calcium:creatinine ratio was low (0.0028). She was osteoporotic at the lumbar spine (T-score -2.8) and osteopaenic at the femoral neck (T-score -1.4). With a hypokalaemia (2.9-3.3mmol/l), there was kaliuria (urine potassium 68mmol), a detectable aldosterone (226pmol/l) and elevated renin (7nmol/l). Renal function was preserved with normal serum bicarbonate 24.9mmol/l. An ultrasound renal tract was normal.

Section 3: Results and treatment: Despite vitamin-D loading, an ongoing requirement for electrolyte replacement with highly elevated PTH levels prompted genetic and epigenetic testing for syndromes associated with PTH-resistance and renal tubulopathies. A loss of maternal methylation pattern in GNAS was detected. This, alongside a negative family history was consistent with the diagnosis of sporadic pseudohypoparathyroidism type-1b. A renal tubulopathy screen was negative. The patient was commenced on alfacalcidol, Vitamin-D3 and oral potassium. A sustained resolution of her symptoms and improvement in her biochemistry was seen at 4-months; PTH 54.1pmol/l, Ca 2.32mmol/l, Phosphate 0.9mmol/l, ALP 377U/L, K 4.3mmol/l.

Section 4: Conclusions and points for discussion: Pseudohypoparathyroidism type-1b is characterised by PTH-resistance in proximal renal tubules due to epigenetic changes in the differential methylated regions in the GNAS gene (chromosome 20q13.2). The loss of maternal-specific methylation of GNAS has been associated with downregulation of Gsα expression and cAMP dependent signalling pathways necessary for PTH action. Interestingly, our patient was normophosphataemic and hypokalaemic on presentation which is very unusual with only 2 other reported cases. It is possible that renal peritubular potassium channels are also governed by Gsα/cAMP pathways, and downregulation may promote renal potassium loss. More research into epigenetic regulation of GNAS/Gsα/cAMP related pathways is required to elucidate the intricate relationship between PTH-dependent calcium, phosphate and potassium handling in the kidneys.