{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:03Z","timestamp":1787027823549,"version":"build-2736575974"},"reference-count":67,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T00:00:00Z","timestamp":1656547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hellenic Foundation for Research and Innovation (HFRI)","award":["74156\/2017"],"award-info":[{"award-number":["74156\/2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Combined pituitary hormone deficiency (CPHD) is characterized by deficiency of growth hormone and at least one other pituitary hormone. Pathogenic variants in more than 30 genes expressed during the development of the head, hypothalamus, and\/or pituitary have been identified so far to cause genetic forms of CPHD. However, the etiology of around 85% of the cases remains unknown. The aim of this study was to unveil the genetic etiology of CPHD due to congenital hypopituitarism employing whole exome sequencing (WES) in two newborn patients, initially tested and found to be negative for PROP1, LHX3, LHX4 and HESX1 pathogenic variants by Sanger sequencing and for copy number variations by MLPA. In this study, the application of WES in these CPHD newborns revealed the presence of three different heterozygous gene variants in each patient. Specifically in patient 1, the variants BMP4; p.Ala42Pro, GNRH1; p.Arg73Ter and SRA1; p.Gln32Glu, and in patient 2, the SOX9; p.Val95Ile, HS6ST1; p.Arg306Gln, and IL17RD; p.Pro566Ser were identified as candidate gene variants. These findings further support the hypothesis that CPHD constitutes an oligogenic rather than a monogenic disease and that there is a genetic overlap between CPHD and congenital hypogonadotropic hypogonadism.<\/jats:p>","DOI":"10.3390\/cells11132088","type":"journal-article","created":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T20:53:02Z","timestamp":1656622382000},"page":"2088","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3648-3812","authenticated-orcid":false,"given":"Amalia","family":"Sertedaki","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, \u201cAghia Sophia\u201d Children\u2019s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7325-6195","authenticated-orcid":false,"given":"Elizabeth Barbara","family":"Tatsi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, \u201cAghia Sophia\u201d Children\u2019s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis Anargyros","family":"Vasilakis","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, \u201cAghia Sophia\u201d Children\u2019s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Fylaktou","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, \u201cAghia Sophia\u201d Children\u2019s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirini","family":"Nikaina","sequence":"additional","affiliation":[{"name":"Neonatology Unit, First Department of Pediatrics, Medical School, \u201cAghia Sophia\u201d Children\u2019s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Iacovidou","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Medical School, Aretaieion Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8991-0649","authenticated-orcid":false,"given":"Tania","family":"Siahanidou","sequence":"additional","affiliation":[{"name":"Neonatology Unit, First Department of Pediatrics, Medical School, \u201cAghia Sophia\u201d Children\u2019s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6942-6470","authenticated-orcid":false,"given":"Christina","family":"Kanaka-Gantenbein","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, \u201cAghia Sophia\u201d Children\u2019s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1515\/jpem-2020-0590","article-title":"Clinical characteristics and molecular genetic analysis of a cohort with idiopathic congenital hypogonadism","volume":"34","author":"Turkyilmaz","year":"2021","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.beem.2007.07.007","article-title":"Developmental disorders of the hypothalamus and pituitary gland associated with congenital hypopituitarism","volume":"22","author":"Mehta","year":"2008","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_3","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."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1097\/MED.0b013e32836318ba","article-title":"Neuroendocrine consequences of traumatic brain injury","volume":"20","author":"Munoz","year":"2013","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1097\/MOO.0b013e3282f4479d","article-title":"The need for patients endocrine function vigilance following treatment of head and neck cancer","volume":"16","author":"Lips","year":"2008","journal-title":"Curr. Opin. Otolaryngol. Head Neck Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/gim.2017.165","article-title":"Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency","volume":"20","author":"Simm","year":"2018","journal-title":"Genet. Med."},{"key":"ref_7","first-page":"175","article-title":"Genetic causes of pituitary hormone deficiencies","volume":"19","author":"Larson","year":"2015","journal-title":"Discov. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"368","DOI":"10.3389\/fendo.2020.00368","article-title":"SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD)","volume":"11","author":"Budny","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10985","DOI":"10.1038\/s41598-020-67715-x","article-title":"Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency","volume":"10","author":"Kinjo","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ghir.2019.10.002","article-title":"Unique near-complete deletion of GLI2 in a patient with combined pituitary hormone deficiency and post-axial polydactyly","volume":"50","author":"Elizabeth","year":"2020","journal-title":"Growth Horm. IGF Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1210\/jc.2017-01660","article-title":"Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients","volume":"103","author":"Alders","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"697549","DOI":"10.3389\/fgene.2021.697549","article-title":"Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic","volume":"12","author":"Jee","year":"2021","journal-title":"Front. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Brauner, R., Bignon-Topalovic, J., Bashamboo, A., and McElreavey, K. (2020). Pituitary stalk interruption syndrome is characterized by genetic heterogeneity. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0242358"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"E1709","DOI":"10.1210\/jc.2011-0454","article-title":"Novel FGF8 Mutations Associated with Recessive Holoprosencephaly, Craniofacial Defects, and Hypothalamo-Pituitary Dysfunction","volume":"96","author":"McCabe","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_15","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."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ka\u0142u\u017cna, M., Budny, B., Rabijewski, M., Ka\u0142u\u017cny, J., Dubiel, A., Trofimiuk-M\u00fcldner, M., Wrotkowska, E., Hubalewska-Dydejczyk, A., Rucha\u0142a, M., and Ziemnicka, K. (2021). Defects in GnRH Neuron Migration\/Development and Hypothalamic-Pituitary Signaling Impact Clinical Variability of Kallmann Syndrome. Genes, 12.","DOI":"10.3390\/genes12060868"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1126\/science.3201241","article-title":"Novel regulators of bone formation: Molecular clones and activities","volume":"242","author":"Wozney","year":"1988","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1242\/dev.125.6.1005","article-title":"Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary","volume":"125","author":"Ericson","year":"1998","journal-title":"Development"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1101\/gad.12.11.1691","article-title":"Multistep signaling requirements for pituitary organogenesis in vivo","volume":"12","author":"Treier","year":"1998","journal-title":"Genes Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.cytogfr.2009.10.007","article-title":"Recent advances in BMP receptor signaling","volume":"20","author":"Sieber","year":"2009","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/eos.12055","article-title":"Functional evaluation of a novel tooth agenesis-associated bone morphogenetic protein 4 prodomain mutation","volume":"121","author":"Huang","year":"2013","journal-title":"Eur. J. Oral Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.archoralbio.2019.05.012","article-title":"BMP4 mutations in tooth agenesis and low bone mass","volume":"103","author":"Yu","year":"2019","journal-title":"Arch. Oral Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.ajhg.2009.02.002","article-title":"Mutations in BMP4 Are Associated with Subepithelial, Microform, and Overt Cleft Lip","volume":"84","author":"Suzuki","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41431-018-0316-y","article-title":"Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler syndrome and renal dysplasia","volume":"27","author":"Nixon","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E1928","DOI":"10.1002\/humu.21376","article-title":"Evaluation of germline BMP4 mutation as a cause of colorectal cancer","volume":"32","author":"Lubbe","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.gendis.2014.07.005","article-title":"Bone Morphogenetic Protein (BMP) signaling in development and human diseases","volume":"1","author":"Wang","year":"2014","journal-title":"Genes Dis."},{"key":"ref_27","first-page":"495","article-title":"BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome","volume":"130","author":"Reis","year":"2011","journal-title":"Qual. Life Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ajhg.2007.09.023","article-title":"Mutations in BMP4 Cause Eye, Brain, and Digit Developmental Anomalies: Overlap between the BMP4 and Hedgehog Signaling Pathways","volume":"82","author":"Bakrania","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1472-6823-13-56","article-title":"Genetic analyses of bone morphogenetic protein 2, 4 and 7 in congenital combined pituitary hormone deficiency","volume":"13","author":"Breitfeld","year":"2013","journal-title":"BMC Endocr. Disord."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1002\/ajmg.a.61201","article-title":"Loss of function BMP4 mutation supports the implication of the BMP\/TGF-\u03b2 pathway in the etiology of combined pituitary hormone deficiency","volume":"179","author":"Heath","year":"2019","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nrendo.2015.112","article-title":"European Consensus Statement on congenital hypogonadotropic hypogonadism\u2014pathogenesis, diagnosis and treatment","volume":"11","author":"Boehm","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"11703","DOI":"10.1073\/pnas.0903449106","article-title":"GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism","volume":"106","author":"Chan","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1530\/EJE-18-0764","article-title":"New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism","volume":"181","author":"Amato","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1093\/humrep\/dew073","article-title":"Prevalence of KISS1 Receptor mutations in a series of 603 patients with normosmic congenital hypogonadotrophic hypogonadism and characterization of novel mutations: A single-centre study","volume":"31","author":"Francou","year":"2016","journal-title":"Hum. Reprod."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1515\/jpem-2020-0207","article-title":"Homozygous p.R31H GNRH1 mutation and normosmic congenital hypogonadotropic hypogonadism in a patient and self-limited delayed puberty in his relatives","volume":"33","author":"Brachet","year":"2020","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15140","DOI":"10.1073\/pnas.1009622107","article-title":"Oligogenic basis of isolated gonadotropin-releasing hormone deficiency","volume":"107","author":"Sykiotis","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1530\/EC-19-0010","article-title":"Next-generation sequencing refines the genetic architecture of Greek GnRH-deficient patients","volume":"8","author":"Varnavas","year":"2019","journal-title":"Endocr. Connect."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"125","DOI":"10.4274\/jcrpe.3248","article-title":"Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA","volume":"8","author":"Kotan","year":"2016","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1038\/s41431-018-0202-7","article-title":"Broad phenotypes in heterozygous NR5A1 46,XY patients with a disorder of sex development: An oligogenic origin?","volume":"26","author":"Camats","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16081","DOI":"10.1073\/pnas.192571399","article-title":"Distinct RNA motifs are important for coactivation of steroid hormone receptors by steroid receptor RNA activator (SRA)","volume":"99","author":"Lanz","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1042\/bj20020743","article-title":"A novel steroid receptor co-activator protein (SRAP) as an alternative form of steroid receptor RNA-activator gene: Expression in prostate cancer cells and enhancement of androgen receptor activity","volume":"369","author":"Kawashima","year":"2003","journal-title":"Biochem. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1016\/j.febslet.2010.02.024","article-title":"The protein encoded by the functional steroid receptor RNA activator is a new modulator of ER alpha transcriptional activity","volume":"584","author":"Vincett","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"33051","DOI":"10.1074\/jbc.M404930200","article-title":"An RNA-binding Domain in the Thyroid Hormone Receptor Enhances Transcriptional Activation","volume":"279","author":"Xu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.cca.2016.06.004","article-title":"Steroid receptor RNA activator: Biologic function and role in disease","volume":"459","author":"Liu","year":"2016","journal-title":"Clin. Chim. Acta"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1128\/MCB.01010-08","article-title":"Dax-1 and Steroid Receptor RNA Activator (SRA) Function as Transcriptional Coactivators for Steroidogenic Factor 1 in Steroidogenesis","volume":"29","author":"Xu","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"626","DOI":"10.3389\/fendo.2020.00626","article-title":"GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature","volume":"11","author":"Neocleous","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s12958-020-0568-6","article-title":"Expanding the mutational spectrum of monogenic hypogonadotropic hypogonadism: Novel mutations in ANOS1 and FGFR1 genes","volume":"18","author":"Gach","year":"2020","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.gendis.2014.09.004","article-title":"The versatile functions of Sox9 in development, stem cells, and human diseases","volume":"1","author":"Jo","year":"2014","journal-title":"Genes Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2907","DOI":"10.1073\/pnas.0707886105","article-title":"SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland","volume":"105","author":"Fauquier","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.stem.2013.07.006","article-title":"Mobilized Adult Pituitary Stem Cells Contribute to Endocrine Regeneration in Response to Physiological Demand","volume":"13","author":"Rizzoti","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.stem.2013.07.004","article-title":"Sox2+ Stem\/Progenitor Cells in the Adult Mouse Pituitary Support Organ Homeostasis and Have Tumor-Inducing Potential","volume":"13","author":"Andoniadou","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1038\/nature06944","article-title":"Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer","volume":"453","author":"Sekido","year":"2008","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/372525a0","article-title":"Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene","volume":"372","author":"Foster","year":"1994","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1177\/0022034517732538","article-title":"Ciliopathy Protein Tmem107 Plays Multiple Roles in Craniofacial Development","volume":"97","author":"Cela","year":"2018","journal-title":"J. Dent. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1002\/dvg.20717","article-title":"Sox9 function in craniofacial development and disease","volume":"49","author":"Lee","year":"2011","journal-title":"Genesis"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Zhang, F., Zheng, L., Cheng, S., Peng, Y., Fu, L., Zhang, X., and Linhardt, R. (2019). Comparison of the Interactions of Different Growth Factors and Glycosaminoglycans. Molecules, 24.","DOI":"10.3390\/molecules24183360"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1083\/jcb.200604035","article-title":"Interactions between heparan sulfate and proteins: The concept of specificity","volume":"174","author":"Kreuger","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"32616","DOI":"10.1074\/jbc.M204961200","article-title":"Heparin\/Heparan Sulfate Domains in Binding and Signaling of Fibroblast Growth Factor 8b","volume":"277","author":"Loo","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"11524","DOI":"10.1073\/pnas.1102284108","article-title":"Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism","volume":"108","author":"Tornberg","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","first-page":"38","article-title":"Exploring the Genetic Diversity of Isolated Hypogonadotropic Hypogonadism and Its Phenotypic Spectrum: A Case Series","volume":"22","author":"Danda","year":"2020","journal-title":"J. Reprod. Infertil."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"E646","DOI":"10.1210\/jc.2015-1080","article-title":"A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism","volume":"100","author":"Zhu","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.cyto.2016.12.023","article-title":"Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy","volume":"91","author":"Wright","year":"2017","journal-title":"Cytokine"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e2103","DOI":"10.1210\/clinem\/dgz184","article-title":"The Molecular Basis of Congenital Hypopituitarism and Related Disorders","volume":"105","author":"Gregory","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1210\/jc.2017-00332","article-title":"Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome","volume":"102","author":"McCormack","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"11703","DOI":"10.1111\/jcmm.15781","article-title":"Identification of novel candidate pathogenic genes in pituitary stalk interruption syndrome by whole-exome sequencing","volume":"24","author":"Fang","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_66","first-page":"77","article-title":"Genetics of congenital hypogonadotropic hypogonadism: Peculiarities and phenotype of an oligogenic disease","volume":"140","author":"Cangiano","year":"2021","journal-title":"Qual. Life Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000338706","article-title":"Genetic Overlap between Holoprosencephaly and Kallmann Syndrome","volume":"3","author":"Vaaralahti","year":"2012","journal-title":"Mol. Syndr."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/13\/2088\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:41:23Z","timestamp":1760139683000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/13\/2088"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,30]]},"references-count":67,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["cells11132088"],"URL":"https:\/\/doi.org\/10.3390\/cells11132088","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,30]]}}}