Background: Pseudohypoparathyroidism (PHP) is characterized by proximal tubular resistance to PTH and, in some disease variants, by Albright osteodystrophy. PHP is caused either by mutations in those regions of GNAS encoding Gsα (PHP1A and PseudoPHP) or by GNAS methylation defects (autosomal dominant (AD) and sporadic (spor) PHP1B). Phenotypic differences in fetal growth, post-natal growth and metabolism are observed in the different PHP types.
Objective and Hypotheses: Our study aimed at understanding the contribution of the different GNAS transcripts to the growth pattern.
Method: We recorded height and weight (birth-18y) of patients with PHP and GNAS mutations or epimutations. GNAS methylation and transcript expressions were measured through pyrosequencing and qRT-PCR from blood and fibroblasts of patients, respectively.
Results: Fetal growth (median(min;max)) was severely and moderately impaired in patients with PseudoPHP and PHP1A. In contrast, it was normal or enhanced in patients with AD-PHP1B and sporPHP1B, and these displayed postnatal overgrowth. Birth length correlated with the methylation at the four differentially methylated GNAS regions, whereas weight correlated with A/B and XLαs promoter methylation. In addition, we showed that methylation of the A/B promoter controls the quantitative expression of A/B transcripts in patients fibroblasts and lymphocytes.
|PseudoPHP (n=4)||PHP1A (n=38)||AD-PHP1B (n=9)||sporPHP1B (n=22)|
|Birth length (SDS)||−2.89 (−3.04; −1.52)||−0.94 (−2.09; 1.01)||0.00 (−1.16; 0.85)||0.24 (−1.09; 3.26)|
|Height at 1y (SDS)||−0.79 (−1.79; 1.13)||−0.64 (−3.04; 1.54)||1.36 (0.96; 2.58)||2.16 (0.56; 3.83)|
|BMI at 1y (SDS)||−0.76 (−2.19; 0.39)||2.62 (−3.25; 5.12)||1.5 (0.22; 2.75)||1.74 (−1.74; 5.02)|
|Height at 18y (SDS)||−1.64 (−3.25; −0.04)||−3.25 (−4.23; −2.18)||0.57 (−0.25; 1.39)||0.17 (−1.67; 3.83)|
Conclusion: Our data suggest that the relative expression of the GNAS transcripts is critical for fetal and postnatal growth.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology