title: Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib.
abstract: 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 GNAS coding regions and in two patients with sporadic form of PHP-Ib accompanied by broad methylation defects of maternally derived GNAS 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 STX16 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 STX16 microdeletions and isolated LOMs at exon A/B-DMR in the twins, confirming the diagnosis of AD-PHP-Ib. GNAS mutation was not identified, and neither mutation nor copy number variation was detected in GH1, POU1F1, PROP1, GHRHR, LHX3, LHX4, and HESX1 in the twins. The results, in conjunction with the previous finding that GNAS 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.
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Sano
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwata
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsubara
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.forename: Masayo
authors.initials: M
authors.lastname: Kagami
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
mesh_terms: D002675:Child, Preschool; D002872:Chromosome Deletion; D019175:DNA Methylation; D004200:Diseases in Twins / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D004393:Dwarfism, Pituitary / Q000209:etiology*; D005260:Female; D019382:Human Growth Hormone / Q000097:blood / Q000172:deficiency*; D006801:Humans; D007564:Japan; D009035:Mothers; D011547:Pseudohypoparathyroidism / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D051438:Syntaxin 16 / Q000235:genetics*; D014430:Twins, Monozygotic
chemical_list: C496118:STX16 protein, human; D051438:Syntaxin 16; D019382:Human Growth Hormone