25-year-old Ms P presented to the Emergency Department following an abnormal blood test result, arranged by Ms P’s general practitioner for assessment of muscle cramps with associated paraesthesiae and spasms. Chvostek and Trousseau signs were positive, but examination was otherwise unremarkable. Biochemistry revealed severe hypocalcaemia (corrected calcium 1.00 mmol/L) with elevated PTH 28.6 pmol/L (RR 0.8-5.5) and normal 25-hydroxy vitamin D 88 nmol/L (RR 50-150).
Genetic testing with analysis of the GNAS1 locus demonstrated multiple abnormalities in methylation, consistent with the diagnosis of sporadic pseudohypoparathyroidism 1b (PHP 1b), although uniparental disomy cannot be excluded.
PHP 1b is differentiated from other subtypes by the absence of AHO phenotype and other hormonal resistance syndromes. However, some overlap between PHP subtypes appears to occur [1,2]. Hypocalcaemia and hyperphosphatemia are due to renal proximal tubule resistance to PTH, while hypercalciuria and renal stones are not a feature as the distal tubules retain PTH-responsiveness.
The GNAS gene encodes the α-subunit of the Gsα subtype of G-protein coupled receptors . Various loci of GNAS undergo imprinting, with only maternal GNAS expressed in the kidneys. While hormone resistance in PHP 1a is caused by inactivating mutations affecting GNAS exons encoding Gsα, PHP 1b is due to methylation defects affecting one or more of the other loci . Sporadic cases of PHP 1b exhibit broad loss of methylation at multiple sites across the GNAS locus .
A small proportion of PHP1b cases are caused by paternal uniparental disomy (patUPD) of chromosome 20 . The identification of patUPD is reassuring for having low recurrence risk , whereas the molecular mechanisms underlying the range of imprinting defects in the remainder of sporadic cases of PHP 1b are still not understood, making genetic counselling regarding recurrence risk challenging.