The Prevalence of GNAS Deficiency-Related Diseases in a Large Cohort of Patients Characterized by the EuroPHP Network

Media type: E-Article
Title: The Prevalence of GNAS Deficiency-Related Diseases in a Large Cohort of Patients Characterized by the EuroPHP Network
Contributor: Elli, Francesca Marta; Linglart, Agnès; Garin, Intza; de Sanctis, Luisa; Bordogna, Paolo; Grybek, Virginie; Pereda, Arrate; Giachero, Federica; Verrua, Elisa; Hanna, Patrick; Mantovani, Giovanna; Perez de Nanclares, Guiomar
Published: The Endocrine Society, 2016
Published in: The Journal of Clinical Endocrinology & Metabolism
Extent: 3657-3668
Language: English
DOI: 10.1210/jc.2015-4310
ISSN: 0021-972X; 1945-7197
Keywords: Biochemistry (medical) ; Clinical Biochemistry ; Endocrinology ; Biochemistry ; Endocrinology, Diabetes and Metabolism
Abstract: <jats:sec> <jats:title>Context:</jats:title> <jats:p>The term pseudohypoparathyroidism (PHP) was coined to describe the clinical condition resulting from end-organ resistance to parathormone (rPTH), caused by genetic and/or epigenetic alterations within or upstream of GNAS. Although knowledge about PHP is growing, there are few data on the prevalence of underlying molecular defects.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p>The purpose of our study was to ascertain the relative prevalence of PHP-associated molecular defects.</jats:p> </jats:sec> <jats:sec> <jats:title>Design:</jats:title> <jats:p>With a specially designed questionnaire, we collected data from all patients (n = 407) clinically and molecularly characterized to date by expert referral centers in France, Italy, and Spain.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Isolated rPTH (126/407, 31%) was caused only by epigenetic defects, 70% of patients showing loss of imprinting affecting all four GNAS differentially methylated regions and 30% loss of methylation restricted to the GNAS A/B:TSS-DMR. Multihormone resistance with no Albright’s hereditary osteodystrophy (AHO) signs (61/407, 15%) was essentially due to epigenetic defects, although 10% of patients had point mutations. In patients with rPTH and AHO (40/407, 10%), the rate of point mutations was higher (28%) and methylation defects lower (about 70%). In patients with multihormone resistance and AHO (155/407, 38%), all types of molecular defects appeared with different frequencies. Finally, isolated AHO (18/407, 4%) and progressive osseous heteroplasia (7/407, 2%) were exclusively caused by point mutations.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>With European data, we have established the prevalence of various genetic and epigenetic lesions in PHP-affected patients. Using these findings, we will develop objective criteria to guide cost-effective strategies for genetic testing and explore the implications for management and prognosis.</jats:p> </jats:sec>
Description: <jats:sec>
<jats:title>Context:</jats:title>
<jats:p>The term pseudohypoparathyroidism (PHP) was coined to describe the clinical condition resulting from end-organ resistance to parathormone (rPTH), caused by genetic and/or epigenetic alterations within or upstream of GNAS. Although knowledge about PHP is growing, there are few data on the prevalence of underlying molecular defects.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Objective:</jats:title>
<jats:p>The purpose of our study was to ascertain the relative prevalence of PHP-associated molecular defects.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Design:</jats:title>
<jats:p>With a specially designed questionnaire, we collected data from all patients (n = 407) clinically and molecularly characterized to date by expert referral centers in France, Italy, and Spain.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results:</jats:title>
<jats:p>Isolated rPTH (126/407, 31%) was caused only by epigenetic defects, 70% of patients showing loss of imprinting affecting all four GNAS differentially methylated regions and 30% loss of methylation restricted to the GNAS A/B:TSS-DMR. Multihormone resistance with no Albright’s hereditary osteodystrophy (AHO) signs (61/407, 15%) was essentially due to epigenetic defects, although 10% of patients had point mutations. In patients with rPTH and AHO (40/407, 10%), the rate of point mutations was higher (28%) and methylation defects lower (about 70%). In patients with multihormone resistance and AHO (155/407, 38%), all types of molecular defects appeared with different frequencies. Finally, isolated AHO (18/407, 4%) and progressive osseous heteroplasia (7/407, 2%) were exclusively caused by point mutations.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusion:</jats:title>
<jats:p>With European data, we have established the prevalence of various genetic and epigenetic lesions in PHP-affected patients. Using these findings, we will develop objective criteria to guide cost-effective strategies for genetic testing and explore the implications for management and prognosis.</jats:p>
</jats:sec>
Footnote:
Access State: Open Access

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