{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T09:40:04Z","timestamp":1784799604340,"version":"3.55.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T00:00:00Z","timestamp":1669939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009433","name":"Istituto Auxologico Italiano","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009433","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Congenital hypogonadotropic hypogonadism (CHH) is a condition with a strong genetic background, caused by a deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH). Published data on CHH cohorts indicate a male predominance, although this is not supported by our current understandings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims<\/jats:title><jats:p>In order to unravel the possible causes or contributors to such epidemiological sex difference, the aim of our study is to investigate differences in genetic background and clinical presentation between males and females in a large cohort of CHH patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>We enrolled 338 CHH patients with absent or arrested pubertal development, referred to our Center from 01\/2016. Data collection included clinical assessment at diagnosis and genetic analysis performed by next generation sequencing (NGS), employing a custom panel of 28 candidate genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 338 patients 94 were female (F) and 244 male (M), with a ratio of 1:2.6. We found that 36.09% (122\/338) of patients harbored potentially pathogenic rare genetic variants (RVs) with no significant differences between sexes; on the other hand, a significantly higher frequency of oligogenicity was observed in females (F 9,57% 9\/94 vs M 3,69% 9\/244, <jats:italic>P =<\/jats:italic> 0.034). The prevalence of non-reproductive phenotypic features was significantly higher (<jats:italic>P =<\/jats:italic> 0.01) in males (53\/228, 23.2%) than in females (10\/93, 10.8%): in particular, kidney abnormalities affected only male patients and midline defects had a significantly higher prevalence in males (<jats:italic>P =<\/jats:italic> 0.010). Finally, BMI SDS was -0.04 \u00b1 1.09 in females and 0.69 \u00b1 1.51 in males, with a statistically significant difference between groups (<jats:italic>P =<\/jats:italic> &amp;lt;0.001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data confirm the male predominance in CHH and identify some differences with regard to the clinical presentation between males and females that could indicate a variable expression of genetic rare variants and a dimorphic modulation of phenotype according to metabolic\/behavioral factors, which will need to be substantiated and investigated by further studies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.965074","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T05:00:41Z","timestamp":1669957241000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Genetic and phenotypic differences between sexes in congenital hypogonadotropic hypogonadism (CHH): Large cohort analysis from a single tertiary centre"],"prefix":"10.3389","volume":"13","author":[{"given":"Silvia","family":"Federici","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biagio","family":"Cangiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Goggi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Messetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta Veronica","family":"Munari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Amer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Giovanelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faris","family":"Hrvat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Vezzoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Persani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Bonomi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/jne.13094","article-title":"Neuroendocrine control of gonadotropin-releasing hormone: Pulsatile and surge modes of secretion","volume":"34","author":"Goodman","year":"2022","journal-title":"J Neuroendocrinol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s00439-020-02147-1","article-title":"Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease","volume":"140","author":"Cangiano","year":"2021","journal-title":"Hum Genet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1159\/000312700","article-title":"Complex genetics in idiopathic hypogonadotropic hypogonadism","volume":"39","author":"Pitteloud","year":"2010","journal-title":"Front Horm Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":":E136-44","DOI":"10.1210\/jc.2011-2041","article-title":"Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications","volume":"97","author":"Lewkowitz-Shpuntoff","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e220367","DOI":"10.1530\/EC-22-0367","article-title":"The genetic diagnosis of rare endocrine disorders of sex development and maturation: a survey among endo-ERN centres","volume":"11","author":"Persani","year":"2022","journal-title":"Endocr Connect"},{"key":"B6","article-title":"Impuberism and hypogonadism at induction into military service. statistical study","volume":"16","author":"Fromantin","year":"1973","journal-title":"Probl Actuels Endocrinol Nutr"},{"key":"B7","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/1750-1172-6-41","article-title":"Incidence, phenotypic features and molecular genetics of kallmann syndrome in Finland","volume":"6","author":"Laitinen","year":"2011","journal-title":"Orphanet J Rare Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.81.12.8954047","article-title":"The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human","volume":"81","author":"Waldstreicher","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2265.2001.01277.x","article-title":"Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization*","volume":"55","author":"Quinton","year":"2001","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.19.5.0344","article-title":"Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and kallmann\u2019s syndrome): pathophysiological and genetic considerations","volume":"19","author":"Seminara","year":"1998","journal-title":"Endocr Rev"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1530\/EC-17-0095","article-title":"Beyond hormone replacement: quality of life in women with congenital hypogonadotropic hypogonadism","volume":"6","author":"Dzemaili","year":"2017","journal-title":"Endocr Connect"},{"key":"B12","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1530\/EJE-17-0065","article-title":"Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH)","volume":"178","author":"Bonomi","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"B13","doi-asserted-by":"publisher","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":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/cen.13231","article-title":"Reversal of congenital hypogonadotropic hypogonadism in a man with kallmann syndrome due to SOX10 mutation","volume":"85","author":"Maione","year":"2016","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1530\/EC-19-0010","article-title":"Next-generation sequencing refines the genetic architecture of Greek GnRH-deficient patients","volume":"8","author":"Stamou","year":"2019","journal-title":"Endocr Connect"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2445\u201354","DOI":"10.1530\/endoabs.70.AEP807","article-title":"Predictors of reproductive and non-reproductive outcomes of gonadotropin mediated pubertal induction in male patients with congenital hypogonadotropic hypogonadism (CHH)","volume":"44","author":"Cangiano","year":"2021","journal-title":"J Endocrinol Invest."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-00131","article-title":"Functional hypothalamic amenorrhea: An endocrine society clinical practice guideline","volume":"102","author":"Gordon","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"B18","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1136\/adc.44.235.291","article-title":"Variations in pattern of pubertal changes in girls","volume":"44","author":"Marshall","year":"1969","journal-title":"Arch Dis Child"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: the human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"660","DOI":"10.2471\/blt.07.043497","article-title":"Development of a WHO growth reference for school-aged children and adolescents","volume":"85","author":"De Onis","year":"2007","journal-title":"Bull World Health Organ"},{"key":"B22","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.mce.2010.01.017","article-title":"Coming of age in the kisspeptin era: sex differences, development, and puberty","volume":"324","author":"Kauffman","year":"2010","journal-title":"Mol Cell Endocrinol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1038\/s41574-020-0363-7","article-title":"Metabolic regulation of kisspeptin \u2014 the link between energy balance and reproduction","volume":"16","author":"Navarro","year":"2020","journal-title":"Nat Rev Endocrinol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.brainres.2010.09.020","article-title":"Anatomy of the kisspeptin neural network in mammals","volume":"1364","author":"Lehman","year":"2010","journal-title":"Brain Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-4175","article-title":"Kisspeptin expression in the human infundibular nucleus in relation to sex, gender identity, and sexual orientation","volume":"101","author":"Taziaux","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B26","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1111\/j.1365-2826.2010.02030.x","article-title":"Gonadal and non-gonadal regulation of sex differences in hypothalamic Kiss1 neurons","volume":"22","author":"Kauffman","year":"2010","journal-title":"J Neuroendocrinol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2265.2001.01277.x","article-title":"Prioritizing genetic testing in patients with kallmann syndrome using clinical phenotypes","volume":"98","author":"Costa-Barbosa","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B28","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1210\/jc.2012-4116","article-title":"Is there a causal relationship between obesity and puberty","volume":"3","author":"Reinehr","year":"2019","journal-title":"Lancet Child Adolesc Heal"},{"key":"B29","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/S2352-4642(18)30306-7","article-title":"Evidence for a common genetic origin of classic and milder adult-onset forms of isolated hypogonadotropic hypogonadism","volume":"8","author":"Cangiano","year":"2019","journal-title":"J Clin Med"},{"key":"B30","doi-asserted-by":"publisher","first-page":":E566-76","DOI":"10.3390\/jcm8010126","article-title":"Expanding the phenotype and genotype of female GnRH deficiency","volume":"96","author":"Shaw","year":"2011","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.965074\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T05:00:44Z","timestamp":1669957244000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.965074\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,2]]},"references-count":30,"alternative-id":["10.3389\/fendo.2022.965074"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.965074","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,2]]},"article-number":"965074"}}