{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:47:35Z","timestamp":1787021255829,"version":"build-2736575974"},"reference-count":46,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Pituitary stalk interruption syndrome (PSIS) consists of a small\/absent anterior pituitary lobe, an interrupted\/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (&amp;lt;5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To provide further evidence for a non-Mendelian, polygenic etiology of PSIS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (&amp;lt;5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/jc.2017-01660","type":"journal-article","created":{"date-parts":[[2017,11,20]],"date-time":"2017-11-20T14:06:14Z","timestamp":1511186774000},"page":"415-428","source":"Crossref","is-referenced-by-count":54,"title":["Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients"],"prefix":"10.1210","volume":"103","author":[{"given":"Nitash","family":"Zwaveling-Soonawala","sequence":"first","affiliation":[{"name":"Department of Pediatric Endocrinology, Emma Children\u2019s Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle","family":"Alders","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"Jongejan","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidija","family":"Kova\u010di\u010d","sequence":"additional","affiliation":[{"name":"Novartis Ireland Ltd, Beech Hill Office Campus, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floor A","family":"Duijkers","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia M","family":"Maas","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Fliers","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A S Paul","family":"van Trotsenburg","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Emma Children\u2019s Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raoul C","family":"Hennekam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emma Children\u2019s Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2017,11,20]]},"reference":[{"issue":"11","key":"2020071623170967300_B1","doi-asserted-by":"crossref","first-page":"e0142354","DOI":"10.1371\/journal.pone.0142354","article-title":"Pituitary stalk interruption syndrome from infancy to adulthood: clinical, hormonal, and radiological assessment according to the initial presentation","volume":"10","author":"Bar","year":"2015","journal-title":"PLoS One"},{"issue":"4","key":"2020071623170967300_B2","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1097\/MOP.0000000000000378","article-title":"Pituitary stalk interruption syndrome: cause, clinical manifestations, diagnosis, and management","volume":"28","author":"Voutetakis","year":"2016","journal-title":"Curr Opin Pediatr"},{"issue":"7","key":"2020071623170967300_B3","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1210\/er.2009-0008","article-title":"Genetic regulation of pituitary gland development in human and mouse","volume":"30","author":"Kelberman","year":"2009","journal-title":"Endocr Rev"},{"issue":"6","key":"2020071623170967300_B4","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1111\/cen.12849","article-title":"Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort","volume":"83","author":"De Rienzo","year":"2015","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"9","key":"2020071623170967300_B5","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.1210\/jc.2005-2173","article-title":"Genetic screening of combined pituitary hormone deficiency: experience in 195 patients","volume":"91","author":"Reynaud","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2020071623170967300_B6","doi-asserted-by":"crossref","first-page":"E1068","DOI":"10.1210\/jc.2011-3056","article-title":"PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption","volume":"97","author":"Reynaud","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"2020071623170967300_B7","doi-asserted-by":"crossref","first-page":"E779","DOI":"10.1210\/jc.2012-3982","article-title":"Pituitary stalk interruption syndrome and isolated pituitary hypoplasia may be caused by mutations in holoprosencephaly-related genes","volume":"98","author":"Tatsi","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2020071623170967300_B8","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1210\/jc.2015-2995","article-title":"A nonsense mutation in the Hedgehog receptor CDON associated with pituitary stalk interruption syndrome","volume":"101","author":"Bashamboo","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2020071623170967300_B9","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1210\/er.2016-1101","article-title":"Genetics of combined pituitary hormone deficiency: roadmap into the genome era","volume":"37","author":"Fang","year":"2016","journal-title":"Endocr Rev"},{"issue":"4","key":"2020071623170967300_B10","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1111\/cen.12044","article-title":"Relatively high frequency of non-synonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly","volume":"78","author":"Fran\u00e7a","year":"2013","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"4","key":"2020071623170967300_B11","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1111\/cen.12565","article-title":"Sonic Hedgehog mutations are not a common cause of congenital hypopituitarism in the absence of complex midline cerebral defects","volume":"82","author":"Paulo","year":"2015","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"11","key":"2020071623170967300_B12","doi-asserted-by":"crossref","first-page":"E384","DOI":"10.1210\/jc.2010-1050","article-title":"Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly","volume":"95","author":"Fran\u00e7a","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2020071623170967300_B13","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1136\/jmedgenet-2013-102249","article-title":"Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly","volume":"51","author":"Bear","year":"2014","journal-title":"J Med Genet"},{"issue":"3","key":"2020071623170967300_B14","doi-asserted-by":"crossref","first-page":"R141","DOI":"10.1530\/JME-15-0009","article-title":"Role of GLI2 in hypopituitarism phenotype","volume":"54","author":"Arnhold","year":"2015","journal-title":"J Mol Endocrinol"},{"issue":"4","key":"2020071623170967300_B15","doi-asserted-by":"crossref","first-page":"E694","DOI":"10.1210\/jc.2011-2938","article-title":"Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia","volume":"97","author":"Raivio","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2020071623170967300_B16","doi-asserted-by":"crossref","first-page":"E547","DOI":"10.1210\/jc.2012-3067","article-title":"Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia","volume":"98","author":"McCabe","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2020071623170967300_B17","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1530\/EC-15-0015","article-title":"FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies","volume":"4","author":"Correa","year":"2015","journal-title":"Endocr Connect"},{"issue":"6","key":"2020071623170967300_B18","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1111\/cge.12722","article-title":"Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing","volume":"89","author":"Mouden","year":"2016","journal-title":"Clin Genet"},{"key":"2020071623170967300_B19","unstructured":"Guo\n              QH\n            , WangCZ, WuZQ, QinY, HanBY, WangAP, WangBA, DouJT, WuXS, MuYM. Multi-genic pattern found in rare type of hypopituitarism: a whole-exome sequencing study of Han Chinese with pituitary stalk interruption syndrome [published online ahead of print July 14, 2017]. J Cell Mol Med."},{"issue":"6","key":"2020071623170967300_B20","doi-asserted-by":"crossref","first-page":"3350","DOI":"10.1210\/jc.2004-2444","article-title":"Neonatal detection of congenital hypothyroidism of central origin","volume":"90","author":"van Tijn","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"issue":"9","key":"2020071623170967300_B21","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nrendo.2015.112","article-title":"Expert consensus document: European consensus statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment","volume":"11","author":"Boehm","year":"2015","journal-title":"Nat Rev Endocrinol"},{"issue":"6","key":"2020071623170967300_B22","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1093\/brain\/awt358","article-title":"Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes","volume":"137","author":"Edwards","year":"2014","journal-title":"Brain"},{"issue":"3","key":"2020071623170967300_B23","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","article-title":"Comparative protein modelling by satisfaction of spatial restraints","volume":"234","author":"\u0160ali","year":"1993","journal-title":"J Mol Biol"},{"issue":"11","key":"2020071623170967300_B24","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1038\/ng.2765","article-title":"Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development","volume":"45","author":"Cappello","year":"2013","journal-title":"Nat Genet"},{"issue":"45","key":"2020071623170967300_B25","doi-asserted-by":"crossref","first-page":"16011","DOI":"10.1073\/pnas.1418990111","article-title":"Giant cadherins Fat and Dachsous self-bend to organize properly spaced intercellular junctions","volume":"111","author":"Tsukasaki","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"issue":"11","key":"2020071623170967300_B26","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1016\/j.str.2015.09.005","article-title":"Structure and sequence analyses of clustered protocadherins reveal antiparallel interactions that mediate homophilic specificity","volume":"23","author":"Nicoludis","year":"2015","journal-title":"Structure"},{"issue":"3","key":"2020071623170967300_B27","doi-asserted-by":"crossref","first-page":"E567","DOI":"10.1210\/jc.2012-3224","article-title":"Functional characterization of a heterozygous GLI2 missense mutation in patients with multiple pituitary hormone deficiency","volume":"98","author":"Flemming","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"9","key":"2020071623170967300_B28","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1002\/ajmg.a.38330","article-title":"Variants in KAT6A and pituitary anomalies","volume":"173","author":"Zwaveling-Soonawala","year":"2017","journal-title":"Am J Med Genet A"},{"issue":"8","key":"2020071623170967300_B29","doi-asserted-by":"crossref","first-page":"2822","DOI":"10.1172\/JCI34538","article-title":"Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice","volume":"118","author":"Falardeau","year":"2008","journal-title":"J Clin Invest"},{"issue":"3","key":"2020071623170967300_B30","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1210\/jc.2005-2429","article-title":"An amino-terminal DAX1 (NROB1) missense mutation associated with isolated mineralocorticoid deficiency","volume":"92","author":"Verrijn Stuart","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"issue":"44","key":"2020071623170967300_B31","doi-asserted-by":"crossref","first-page":"17447","DOI":"10.1073\/pnas.0707173104","article-title":"Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism","volume":"104","author":"Pitteloud","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"issue":"7","key":"2020071623170967300_B32","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/ejhg.2008.15","article-title":"Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome","volume":"16","author":"Leroy","year":"2008","journal-title":"Eur J Hum Genet"},{"issue":"5","key":"2020071623170967300_B33","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.ajhg.2015.09.009","article-title":"Joubert syndrome in French Canadians and identification of mutations in CEP104","volume":"97","author":"Srour","year":"2015","journal-title":"Am J Hum Genet"},{"issue":"5","key":"2020071623170967300_B34","doi-asserted-by":"crossref","first-page":"e1004372","DOI":"10.1371\/journal.pgen.1004372","article-title":"Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma","volume":"10","author":"Carnes","year":"2014","journal-title":"PLoS Genet"},{"issue":"14","key":"2020071623170967300_B35","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1016\/j.cub.2014.05.067","article-title":"Regulation of neuronal migration by Dchs1-Fat4 planar cell polarity","volume":"24","author":"Zakaria","year":"2014","journal-title":"Curr Biol"},{"issue":"5","key":"2020071623170967300_B36","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1007\/s00429-015-1051-6","article-title":"Mammalian cadherins DCHS1-FAT4 affect functional cerebral architecture","volume":"221","author":"Beste","year":"2016","journal-title":"Brain Struct Funct"},{"key":"2020071623170967300_B37","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3389\/fphys.2016.00114","article-title":"Expression analysis of the hippo cascade indicates a role in pituitary stem cell development","volume":"7","author":"Lodge","year":"2016","journal-title":"Front Physiol"},{"issue":"5","key":"2020071623170967300_B38","doi-asserted-by":"crossref","first-page":"3439","DOI":"10.1007\/s12035-016-9925-z","article-title":"MicroRNA-338 attenuates cortical neuronal outgrowth by modulating the expression of axon guidance genes","volume":"54","author":"Kos","year":"2016","journal-title":"Mol Neurobiol"},{"issue":"4","key":"2020071623170967300_B39","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1086\/512735","article-title":"Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux","volume":"80","author":"Lu","year":"2007","journal-title":"Am J Hum Genet"},{"issue":"6","key":"2020071623170967300_B40","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.ygeno.2006.05.011","article-title":"Isolation and differential expression of two isoforms of the ROBO2\/Robo2 axon guidance receptor gene in humans and mice","volume":"88","author":"Yue","year":"2006","journal-title":"Genomics"},{"issue":"7","key":"2020071623170967300_B41","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1210\/jc.2016-1095","article-title":"Mutations in the human ROBO1 gene in pituitary stalk interruption syndrome","volume":"102","author":"Bashamboo","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2020071623170967300_B42","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1159\/000319859","article-title":"Disturbed Wnt signalling due to a mutation in CCDC88C causes an autosomal recessive non-syndromic hydrocephalus with medial diverticulum","volume":"1","author":"Ekici","year":"2010","journal-title":"Mol Syndromol"},{"issue":"3","key":"2020071623170967300_B43","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1111\/cge.12301","article-title":"Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype","volume":"86","author":"Filges","year":"2014","journal-title":"Clin Genet"},{"key":"2020071623170967300_B44","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.neuroscience.2014.06.011","article-title":"Cytoarchitecture of the olfactory bulb in the laggard mutant mouse","volume":"275","author":"Yunus","year":"2014","journal-title":"Neuroscience"},{"issue":"5","key":"2020071623170967300_B45","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1002\/humu.22048","article-title":"Next-generation sequencing demands next-generation phenotyping","volume":"33","author":"Hennekam","year":"2012","journal-title":"Hum Mutat"},{"issue":"7497","key":"2020071623170967300_B46","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nature13127","article-title":"Guidelines for investigating causality of sequence variants in human disease","volume":"508","author":"MacArthur","year":"2014","journal-title":"Nature"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/103\/2\/415\/23792221\/jc.2017-01660.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/103\/2\/415\/23792221\/jc.2017-01660.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T08:06:26Z","timestamp":1594973186000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/103\/2\/415\/4642964"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,20]]},"references-count":46,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2018,2,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2017-01660","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,2]]},"published":{"date-parts":[[2017,11,20]]}}}