Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib
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Pseudohypoparathyroidism (PHP) is associated with compromised signal transductions via PTH receptor (PTH-R) and other G-protein-coupled receptors including GHRH-R. To date, while GH deficiency (GHD) has been reported in multiple patients with PHP-Ia caused by mutations on the maternally expressed <i>GNAS</i> coding regions and in two patients with sporadic form of PHP-Ib accompanied by broad methylation defects of maternally derived <i>GNAS</i> differentially methylated regions (DMRs), it has not been identified in a patient with an autosomal dominant form of PHP-Ib (AD-PHP-Ib) accompanied by an <i>STX16</i> microdeletion and an isolated loss of methylation (LOM) at exon A/B-DMR. We studied 5 4/12-year-old monozygotic twins with short stature (both -3.4 SD) and GHD (peak GH values, <6.0 μg/L after arginine and clonidine stimulations). Molecular studies revealed maternally derived <i>STX16</i> microdeletions and isolated LOMs at exon A/B-DMR in the twins, confirming the diagnosis of AD-PHP-Ib. <i>GNAS</i> mutation was not identified, and neither mutation nor copy number variation was detected in <i>GH1</i>, <i>POU1F1</i>, <i>PROP1</i>, <i>GHRHR</i>, <i>LHX3</i>, <i>LHX4</i>, and <i>HESX1</i> in the twins. The results, in conjunction with the previous finding that <i>GNAS</i> shows maternal expression in the pituitary, suggest that GHD of the twins is primarily ascribed to compromised GHRH-R signaling caused by AD-PTH-Ib. Thus, resistance to multiple hormones including GHRH should be considered in AD-PHP-Ib.
- Endocrine Journal
Endocrine Journal 62(6), 523-529, 2015
The Japan Endocrine Society