Pseudohypoparathyroidism Type 1A

Hypocalcaemia is a hallmark of pseudohypoparathyroidism type 1A (PHP1A), characterised by parathyroid hormone (PTH) resistance and features of Albright Hereditary Osteodystrophy. We report 3 individuals with a consistent phenotype highly specific for a non-truncating GNAS single base exchange who presented to a district general hospital. Patient A with mild learning disability was referred in 2013 by a rheumatologist after noticing shortened 4th and 5th metacarpals and hypocalcaemia (serum adjusted calcium 1.84 (normal range 2.20-2.60mmol/l)). PTH was raised at 82 (15-65 pg/mL), as was phosphate 1.52 (0.8-1.5mmol/L). Magnesium was normal. There was end organ resistance with raised luteinising hormone (LH) 8.8 (1.7-8.6u/L) and thyroid stimulating hormone (TSH) 5.03 (0.3-4.5mU/L). Follicle-stimulating hormone (FSH) was normal. Investigations suggested PHP1A. The patient reported his mother and brother had a similar appearance. Genetic testing revealed a novel GNAS polymorphism. His relatives did not attend for requested genetic screening. In 2016 patient B with moderate learning disability was re-referred to endocrinology. In 2009 he attended for exclusion of Cushing’s syndrome but was lost to follow up. The patient appeared familiar and it became clear he was patient A’s half-brother (different surname). Calcium levels were, however, normal at 2.25mmol/L, with raised PTH (138pg/mL), LH (8.8iU/L), and TSH (5.94 mU/L), but normal FSH. He has the same polymorphism as his half-brother. Given their phenotype we suspect this mutation to be pathogenic. Obtaining a complete family history is important in calcium homeostasis disorders. Screening for GNAS mutations should be considered in suspected PHP1A, even if biochemistry is not typical.