Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption
Sanctis et al. Italian Journal of Pediatrics
Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption
L. de Sanctis 0 4
F. Giachero 2
G. Mantovani 1
G. Weber 8
M. Salerno 7
G. I. Baroncelli 6
M. F. Elli 1
P. Matarazzo 5
M. Wasniewska 10
L. Mazzanti 9
G. Scirè 3
D. Tessaris 0 4
On behalf of the Study Group Endocrine diseases due to altered function of Gs
protein of the Italian Society of Pediatric Endocrinology
Diabetology (ISPED)
0 Department of Public Health and Pediatric Sciences, University of Turin - Regina Margherita Children's Hospital - Health and Science City, Subintensiva Allargata Prima Infanzia , Piazza Polonia 94, 10126 Torino , Italy
1 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community Health, University of Milan , Milan , Italy
2 Kinderklinik, Evangelisches Krankenhaus Oberhausen , Oberhausen , Germany
3 Endocrinology Ward, Bambin Gesù Children's Hospital , Rome , Italy
4 Department of Public Health and Pediatric Sciences, University of Turin - Regina Margherita Children's Hospital - Health and Science City, Subintensiva Allargata Prima Infanzia , Piazza Polonia 94, 10126 Torino , Italy
5 Pediatric Endocrinology and Diabetology Unit, Regina Margherita Children's Hospital - Health and Science City , Turin , Italy
6 Department of Obstetrics, Gynecology and Pediatrics, I Pediatric Division, University Hospital , Pisa , Italy
7 Pediatric Endocrine Unit, Department of Translational Medical Sciences, University of Naples Federico II , Naples , Italy
8 Department of Pediatrics, San Raffaele Hospital, University of Milan , Milan , Italy
9 Pediatric Endocrinology and Rare Diseases, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna , Bologna , Italy
10 Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, University of Messina , Messina , Italy
Background: Genetic and epigenetic alterations in the GNAS locus are responsible for the Gsα protein dysfunctions causing Pseudohypoparathyroidism (PHP) type Ia/c and Ib, respectively. For these heterogeneous diseases characterized by multiple hormone resistances and Albright's Hereditary Osteodystrophy (AHO) the current classification results inadequate because of the clinical overlap between molecular subtypes and a standard clinical approach is still missing. In the present paper several members of the Study Group Endocrine diseases due to altered function of Gsα protein of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) have reviewed and updated the clinical-molecular data of the largest case series of (epi)/genetically characterized AHO/PHP patients; they then produced a common healthcare pathway for patients with these disorders. Methods: The molecular analysis of the GNAS gene and locus identified the causal alteration in 74 subjects (46 genetic and 28 epigenetic mutations). The clinical data at the diagnosis and their evolution during up to 15 years follow-up were collected using two different cards. Results: In patients with genetic mutations the growth impairment worsen during the time, while obesity prevalence decreases; subcutaneous ossifications seem specific for this group. Brachydactyly has been detected in half of the subjects with epigenetic alterations, in which the disease overts later in life, often with symptomatic hypocalcaemia, and also early TSH and GHRH resistances have been recorded. Conclusions: A dedicated healthcare pathway addressing all these aspects in a systematic way would improve the clinical management, allowing an earlier recognition of some PHP features, the optimization of their medical treatment and a better clinical-oriented molecular analysis. Furthermore, standardized follow-up data would provide new insight into less known aspects.
GNAS gene; GNAS locus; Pseudohypoparathyroidism; Albright Hereditary Osteodystrophy; PTH resistance
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Background
Pseudohypoparathyroidism (PHP) defines a group of rare
heterogeneous metabolic disorders, characterized by
resistance to the peripheral action of PTH, the most
important hormone regulating the calcium and phosphorus
homeostasis [1, 2]. Several mutations of the GNAS gene
(20q13.32) and epigenetic alterations within its locus have
been described as causes of the different forms of PHP
type I (i.e. PHP-Ia, PHP-Ib, PHP-Ic). They all induce an
impaired function of the Gsα protein (the α-subunit of the
heterotrimeric stimulatory G protein), which regulates the
adenylate cyclase activity in the signaling pathway of
various peptide hormones binding the G-protein-coupled
receptors (GPCR): PTH, TSH, GHRH, gonadotropins,
ACTH, and calcitonin among others [1, 3].
Inactivating mutations in exons 1–13 of the maternal
copy of the GNAS gene lead to PHP-Ia, whose phenotype
encompasses the Albright Hereditary Osteodystrophy
(AHO) signs including short (...truncated)