title: Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption.
abstract: 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.
authors.affiliation: 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. luisa.desanctis@unito.it.
authors.forename: L
authors.initials: L
authors.lastname: de Sanctis
authors.affiliation: Kinderklinik, Evangelisches Krankenhaus Oberhausen, Oberhausen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Giachero
authors.affiliation: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Mantovani
authors.affiliation: Department of Pediatrics, San Raffaele Hospital, University of Milan, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Weber
authors.affiliation: Pediatric Endocrine Unit, Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Salerno
authors.affiliation: Department of Obstetrics, Gynecology and Pediatrics, I Pediatric Division, University Hospital, Pisa, Italy.
authors.forename: G I
authors.initials: GI
authors.lastname: Baroncelli
authors.affiliation: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: M F
authors.initials: MF
authors.lastname: Elli
authors.affiliation: Pediatric Endocrinology and Diabetology Unit, Regina Margherita Children's Hospital - Health and Science City, Turin, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Matarazzo
authors.affiliation: Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, University of Messina, Messina, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Wasniewska
authors.affiliation: Pediatric Endocrinology and Rare Diseases, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Mazzanti
authors.affiliation: Endocrinology Ward, Bambin Gesù Children's Hospital, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Scirè
authors.affiliation: 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.
authors.forename: D
authors.initials: D
authors.lastname: Tessaris
mesh_terms: D002648:Child; D002675:Child, Preschool; D002864:Chromogranins / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D007223:Infant; D007558:Italy; D008297:Male; D009154:Mutation; D011547:Pseudohypoparathyroidism / Q000235:genetics*
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: Albright Hereditary Osteodystrophy; GNAS gene; GNAS locus; PTH resistance; Pseudohypoparathyroidism