Pseudohypoparathyroidism type 1b (PHPT1b) is a rare disorder due to resistance to parathyroid hormone (PTH) and subsequent hypocalcaemia, hyperphosphataemia and normal or raised PTH levels. Sufferers usually present in childhood with seizures or tetany due to hypocalcaemia. Typically, PHPT1b is associated with defects on the long-arm of chromosome 20 in the form of uniparental (paternal) disomy of 20q or genetic mutations or sporadic epigenetic changes in GNAS gene. Genomic imprinting is well recognised to influence the inheritance pattern of PHPT1b as only maternal versions of the gene are expressed in offspring1. Our patient represented in 2014, having been lost to follow-up, with the following biochemistry: Corrected Calcium 2.00 mmol/l (2.202.60 mmol/l); Phosphate 1.46 mmol/l (0.801.45 mmol/l); spot urinary calcium:creatinine 0.39 and PTH 978 ng/l (1472 ng/l consistent with her previously held diagnosis of PHPT1b. We consider her an index case for what has eventually been identified as a family of three affected siblings. Although initial genetic assessments in our patients childhood was unremarkable, reassessment in 2016 revealed a novel pattern of hypomethylation to the maternal 20q region affecting GNAS-AS, GNAS-XL and GNAS-ex1a common amongst all three siblings. No microdeletions were found and uniparental (paternal) disomy was also excluded. This epigenetic defect has caused down-regulation in the function of the GNAS gene subsequently leading to the typical pseudohypoparathyroidism type 1b phenotype. This is the first report of a case of an epigenetic cause for PHPT1b following a familial pattern, although sporadic epigenetic cases are well recognised2. The exact epigenetic origin in this family is yet to be identified.
References: 1. Pseudohypoparathyroidism Type 1b Rare diseases website https://rarediseases.info.nih.gov/diseases/10680/pseudohypoparathyroidism-type-1b [accessed 18/06/2019].
2. Colson et al., High frequency of paternal iso or heterodisomy at chromosome 20 associated with sporadic pseudohypoparathyroidism 1B; Bone, Elsevier June 2019.