{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T05:42:54Z","timestamp":1793338974146,"version":"4.5.0"},"reference-count":29,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,17]],"date-time":"2021-04-17T00:00:00Z","timestamp":1618617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministery of Health","award":["08C724"],"award-info":[{"award-number":["08C724"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine\u2013Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal H19\/IGF2:IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes. Thus far, about 40% of SRS remains undiagnosed, pointing to the need to define the rare mechanisms in such a consistent fraction of unsolved patients. Within a cohort of 176 SRS with an NH-CSS \u2265 3, a molecular diagnosis was disclosed in about 45%. Among the remaining patients, we identified in 3 probands (1.7%) with UPD(20)mat (Mulchandani\u2013Bhoj\u2013Conlin syndrome, OMIM #617352), a molecular mechanism deregulating the GNAS locus and described in 21 cases, characterized by severe feeding difficulties associated with failure to thrive, preterm birth, and intrauterine\/postnatal growth retardation. Our patients share prominent forehead, feeding difficulties, postnatal growth delay, and advanced maternal age. Their clinical assessment and molecular diagnostic flowchart contribute to better define the characteristics of this rare imprinting disorder and to rank UPD(20)mat as the fourth most common pathogenic molecular defect causative of SRS.<\/jats:p>","DOI":"10.3390\/genes12040588","type":"journal-article","created":{"date-parts":[[2021,4,18]],"date-time":"2021-04-18T22:15:13Z","timestamp":1618784113000},"page":"588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1367-9860","authenticated-orcid":false,"given":"Pierpaola","family":"Tannorella","sequence":"first","affiliation":[{"name":"Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20095 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1963-6538","authenticated-orcid":false,"given":"Daniele","family":"Minervino","sequence":"additional","affiliation":[{"name":"Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20095 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Guzzetti","sequence":"additional","affiliation":[{"name":"Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20095 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Vimercati","sequence":"additional","affiliation":[{"name":"Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20095 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4283-0988","authenticated-orcid":false,"given":"Luciano","family":"Calzari","sequence":"additional","affiliation":[{"name":"Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20095 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppa","family":"Patti","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"},{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7183-5238","authenticated-orcid":false,"given":"Mohamad","family":"Maghnie","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"},{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Elsa Maria","family":"Allegri","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3087-8514","authenticated-orcid":false,"given":"Donatella","family":"Milani","sequence":"additional","affiliation":[{"name":"Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulietta","family":"Scuvera","sequence":"additional","affiliation":[{"name":"Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Medical Genetics Unit, Woman-Child-Newborn Department, Fondazione IRCCS Ca\u2019 Granda-Ospedale Maggiore Policlinico, via Francesco Sforza 28, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Mariani","sequence":"additional","affiliation":[{"name":"UOC Pediatria, ASST Lariana, 22100 Como, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piergiorgio","family":"Modena","sequence":"additional","affiliation":[{"name":"SOS-ID Laboratorio di Genetica, ASST Lariana, 22100 Como, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Selicorni","sequence":"additional","affiliation":[{"name":"UOC Pediatria, ASST Lariana, 22100 Como, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1367-7227","authenticated-orcid":false,"given":"Lidia","family":"Larizza","sequence":"additional","affiliation":[{"name":"Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20095 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5893-0193","authenticated-orcid":false,"given":"Silvia","family":"Russo","sequence":"additional","affiliation":[{"name":"Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20095 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nrendo.2016.138","article-title":"Diagnosis and management of Silver-Russell syndrome: First international consensus statement","volume":"13","author":"Wakeling","year":"2017","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cerrato, F., Sparago, A., Ariani, F., Brugnoletti, F., Calzari, L., Coppede, F., De Luca, A., Gervasini, C., Giardina, E., and Gurrieri, F. (2020). DNA Methylation in the Diagnosis of Monogenic Diseases. Genes, 11.","DOI":"10.3390\/genes11040355"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1210\/clinem\/dgaa856","article-title":"Role of imprinting disorders in short children born SGA and Silver-Russell syndrome spectrum","volume":"106","author":"Fuke","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.21926\/obm.genet.1803031","article-title":"Uniparental Disomy and Imprinting Disorders","volume":"2","author":"Eggermann","year":"2018","journal-title":"OBM Genetics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"103671","DOI":"10.1016\/j.ejmg.2019.103671","article-title":"Contribution of GRB10 to the prenatal phenotype in Silver-Russell syndrome? Lessons from 7p12 copy number variations","volume":"62","author":"Eggermann","year":"2019","journal-title":"Eur. J. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1002\/ajmg.a.37492","article-title":"Microdeletions of the 7q32.2 imprinted region are associated with Silver-Russell syndrome features","volume":"170","author":"Carrera","year":"2016","journal-title":"Am. J. Med Genet. Part A"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"955","DOI":"10.3389\/fgene.2019.00955","article-title":"Molecular Etiology Disclosed by Array CGH in Patients with Silver-Russell Syndrome or Similar Phenotypes","volume":"10","author":"Crippa","year":"2019","journal-title":"Front. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/gim.2017.105","article-title":"Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction","volume":"20","author":"Brioude","year":"2018","journal-title":"Genet. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/sj.ejhg.5200287","article-title":"Maternal UPD 20 in a hyperactive child with severe growth retardation","volume":"7","author":"Chudoba","year":"1999","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1136\/jmg.38.2.86","article-title":"Identification of interstitial maternal uniparental disomy (UPD) (14) and complete maternal UPD(20) in a cohort of growth retarded patients","volume":"38","author":"Eggermann","year":"2001","journal-title":"J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1002\/pd.158","article-title":"Maternal UPD 20 in an infant from a pregnancy with mosaic trisomy 20","volume":"21","author":"Salafsky","year":"2001","journal-title":"Prenat. Diagn."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/sj.ejhg.5200867","article-title":"Maternal uniparental isodisomy 20 in a foetus with trisomy 20 mosaicism: Clinical, cytogenetic and molecular analysis","volume":"10","author":"Velissariou","year":"2002","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1136\/jmedgenet-2014-102979","article-title":"A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome","volume":"52","author":"Azzi","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/gim.2015.103","article-title":"Maternal uniparental disomy of chromosome 20: A novel imprinting disorder of growth failure","volume":"18","author":"Mulchandani","year":"2016","journal-title":"Genet. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1210\/jc.2017-02780","article-title":"Maternal Uniparental Disomy for Chromosome 20: Physical and Endocrinological Characteristics of Five Patients","volume":"103","author":"Kawashima","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1002\/ccr3.1575","article-title":"Diagnostic exome sequencing identifies GLI2 haploinsufficiency and chromosome 20 uniparental disomy in a patient with developmental anomalies","volume":"6","author":"Sajan","year":"2018","journal-title":"Clin. Case Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1111\/cge.13727","article-title":"upd(20)mat is a rare cause of the Silver-Russell-syndrome-like phenotype: Two unrelated cases and screening of large cohorts","volume":"97","author":"Hjortshoj","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1002\/jbmr.3450","article-title":"Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity","volume":"33","author":"Hanna","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_19","first-page":"65","article-title":"GNAS locus and pseudohypoparathyroidism","volume":"63","author":"Bastepe","year":"2005","journal-title":"Horm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/s41574-018-0042-0","article-title":"Diagnosis and management of pseudohypoparathyroidism and related disorders: First international Consensus Statement","volume":"14","author":"Mantovani","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1172\/JCI8437","article-title":"Paternal versus maternal transmission of a stimulatory G-protein \u03b1 subunit knockout produces opposite effects on energy metabolism","volume":"105","author":"Yu","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/ng1397","article-title":"The imprinted signaling protein XL \u03b1 s is required for postnatal adaptation to feeding","volume":"36","author":"Plagge","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"18989","DOI":"10.1074\/jbc.M511752200","article-title":"The alternative stimulatory G protein \u03b1-subunit XLalphas is a critical regulator of energy and glucose metabolism and sympathetic nerve activity in adult mice","volume":"281","author":"Xie","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1210\/jc.2006-1497","article-title":"Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity","volume":"92","author":"Long","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/(SICI)1097-0223(200002)20:2<103::AID-PD761>3.0.CO;2-K","article-title":"Common trisomy mosaicism diagnosed in amniocytes involving chromosomes 13, 18, 20 and 21: Karyotype-phenotype correlations","volume":"20","author":"Wallerstein","year":"2000","journal-title":"Prenat. Diagn."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/BF03195686","article-title":"Uniparental disomy and the phenotype of mosaic trisomy 20: A new case and review of the literature","volume":"50","author":"Powis","year":"2009","journal-title":"J. Appl. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/ajmg.a.30586","article-title":"Trisomy 20 mosaicism caused by a maternal meiosis II error is associated with normal intellect but multiple congenital anomalies","volume":"134","author":"Ensenauer","year":"2005","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ball, S.T., Kelly, M.L., Robson, J.E., Turner, M.D., Harrison, J., Jones, L., Napper, D., Beechey, C.V., Hough, T., and Plagge, A. (2013). Gene Dosage Effects at the Imprinted Gnas Cluster. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0065639"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/432053a","article-title":"Resourceful imprinting","volume":"432","author":"Constancia","year":"2004","journal-title":"Nature"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/4\/588\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:49:11Z","timestamp":1760161751000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/4\/588"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,17]]},"references-count":29,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["genes12040588"],"URL":"https:\/\/doi.org\/10.3390\/genes12040588","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,17]]}}}