{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T18:07:58Z","timestamp":1766945278826,"version":"3.37.3"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T00:00:00Z","timestamp":1645574400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T00:00:00Z","timestamp":1645574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005774","name":"Universitat de Barcelona","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005774","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Reprod. Sci."],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Kallmann syndrome (KS) is an uncommon genetic disorder characterized by isolated congenital hypogonadotropic hypogonadism (CHH) and anosmia\/hyposmia. KS originates from abnormal embryonic migration of olfactory axons and gonadotropin-releasing hormone (GnRH)-synthesizing neurons. It can be challenging to diagnose due to its heterogeneous clinical presentation and genes implied. Herein, we report a rare phenotype of KS in two sisters accompanied by a variety of nonreproductive disorders such as hypoparathyroidism, hypercortisolism, atrophy of the cerebellum, intellectual disability, and remarkably, ovarian dysgenesis. Additionally, both subjects present muscle weakness, exercise intolerance, marked hypotonia and seizures, being suspected, although not fully confirmed, mitochondrial encephalomyopathy. These cases illustrate the heterogeneous clinical presentation and the diagnostic difficulties often found in patients suffering from this condition. These clinical features have never been described before as associated with KS; therefore, we decided to report this novel KS phenotype.<\/jats:p>","DOI":"10.1007\/s43032-022-00897-z","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T22:02:43Z","timestamp":1645653763000},"page":"2859-2863","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Two Sisters with Kallmann Syndrome, Gonadal Dysgenesis, and Multiple Neuromuscular and Endocrine Disorders: Report of Two Cases with Description of an Unusual Association"],"prefix":"10.1007","volume":"29","author":[{"given":"Marta","family":"Camacho","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9860-8318","authenticated-orcid":false,"given":"Camil","family":"Castelo-Branco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,2,23]]},"reference":[{"issue":"9","key":"897_CR1","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/nrendo.2015.112","volume":"11","author":"U Boehm","year":"2015","unstructured":"Boehm U, Bouloux PM, Dattani MT, De Roux N, Dod\u00e9 C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J. Expert consensus document: European consensus statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11(9):547\u201364. https:\/\/doi.org\/10.1038\/nrendo.2015.112.","journal-title":"Nat. Rev. Endocrinol"},{"key":"897_CR2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2013.00070","author":"ED Valle","year":"2013","unstructured":"Valle ED, Vezzani S, Rochira V, Granata ARM, Madeo B, Genovese E, Pignatti E, Marino M, Carani C, Simoni M. Prevalence of olfactory and other developmental anomalies in patients with central hypogonadotropic hypogonadism. Front Endocrinol. 2013. https:\/\/doi.org\/10.3389\/fendo.2013.00070.","journal-title":"Front Endocrinol"},{"key":"897_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2017.03.040","author":"MI Stamou","year":"2008","unstructured":"Stamou MI, Georgopoulos MA. Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism. Metabolism. 2008. https:\/\/doi.org\/10.1016\/j.physbeh.2017.03.040.","journal-title":"Metabolism"},{"key":"897_CR4","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/14.5.1207","author":"JW Persson","year":"1999","unstructured":"Persson JW, Humphrey K, Watson C, Taylor P, Leigh D, McDonald B, Fraser IS. Investigation of a unique male and female sibship with Kallmann\u2019s syndrome and 46, XX gonadal dysgenesis with short stature. Hum Reprod. 1999. https:\/\/doi.org\/10.1093\/humrep\/14.5.1207.","journal-title":"Hum Reprod"},{"key":"897_CR5","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33442","author":"JD Kaplan","year":"2010","unstructured":"Kaplan JD, Kwan A, Bernstein JA, Hudgins L. Clues to an early diagnosis of Kallmann syndrome. Am J Med Genet Part A. 2010. https:\/\/doi.org\/10.1002\/ajmg.a.33442.","journal-title":"Am J Med Genet Part A"},{"key":"897_CR6","doi-asserted-by":"publisher","DOI":"10.3803\/EnM.2015.30.4.456","author":"SH Kim","year":"2015","unstructured":"Kim SH. Congenital hypogonadotropic hypogonadism and Kallmann syndrome: past, present, and future. Endocrinol Metab. 2015. https:\/\/doi.org\/10.3803\/EnM.2015.30.4.456.","journal-title":"Endocrinol Metab"},{"key":"897_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/aja.2011.68","author":"M Bonomi","year":"2015","unstructured":"Bonomi M, Libri DV, Guizzardi F, Guarducci E, Maiolo E, Pignatti E, Asci R, Persani L. New understandings of the genetic basis of isolated idiopathic central hypogonadism. Asian J Androl. 2015. https:\/\/doi.org\/10.1038\/aja.2011.68.","journal-title":"Asian J Androl"},{"key":"897_CR8","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-4116","author":"FA Costa-Barbosa","year":"2013","unstructured":"Costa-Barbosa FA, Balasubramanian R, Keefe KW, Shaw ND, Al-Tassan N, Plummer L, Dwyer AA, Buck CL, Choi JH, Seminara SB, Quinton R, Monies D, Meyer B, Hall JE, Pitteloud N, Crowley WF. Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes. J Clin Endocrinol Metab. 2013. https:\/\/doi.org\/10.1210\/jc.2012-4116.","journal-title":"J Clin Endocrinol Metab"},{"key":"897_CR9","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-020-02147-1","author":"B Cangiano","year":"2021","unstructured":"Cangiano B, Swee DS, Quinton R, Bonomi M. Genetics of congenital hypogonadotropic hypogonadism: pecularities and phenotype of an oligogenic disease. Hum Genet. 2021. https:\/\/doi.org\/10.1007\/s00439-020-02147-1.","journal-title":"Hum Genet"},{"key":"897_CR10","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-019-02048-y","author":"L Sagi-Dain","year":"2019","unstructured":"Sagi-Dain L, Goldberg Y, Peleg A, Sukenik-Halevy R, Sofrin-Druker E, Appelman Z, Josefsberg B, Ben-Sachar S, Vinkler C, Basel-Salmon L, Maya I. The rare 13q33-q34 microdeletions: eight new patients and review of the literature. Hum Genet. 2019. https:\/\/doi.org\/10.1007\/s00439-019-02048-y.","journal-title":"Hum Genet"},{"key":"897_CR11","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.0059","author":"W Ma","year":"2020","unstructured":"Ma W, Mao J, Wang X, Duan L, Song Y, Lian X, Zheng J, Liu Z, Nie M, Wu X. Novel microdeletion in the X chromosome leads to Kallmann syndrome, ichthyosis, obesity, and strabismus. Front Genet. 2020. https:\/\/doi.org\/10.3389\/fgene.2020.0059.","journal-title":"Front Genet"},{"key":"897_CR12","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/1687-9856-2011-11","volume":"1","author":"S Jain","year":"2011","unstructured":"Jain S, Kim HG, Lacbawan F, Meliciani I, Wenzel W, Kurth I, Sharma J, Schoeneman M, Ten S, Layman LC, Jacobson-Dickman E. Unique phenotype in a patient with CHARGE syndrome. Int J Pediatr Endocrinol. 2011;1:11.","journal-title":"Int J Pediatr Endocrinol"},{"key":"897_CR13","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1007\/s13311-018-00674-4","volume":"15","author":"ST Ahmed","year":"2018","unstructured":"Ahmed ST, Craven L, Russell OM, Turnbull DM, Vincent AE. Diagnosis and treatment of mitochondrial myopathies. 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Loss of smell but not taste in adult women with Turner\u2019s syndrome and other congenital hypogonadisms. Maturitas. 2012. https:\/\/doi.org\/10.1016\/j.maturitas.2012.07.012.","journal-title":"Maturitas"},{"key":"897_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-323-03247-6.X1000-3","author":"C Ros","year":"2013","unstructured":"Ros C, Alobid I, Balasch J, Mullol J, Castelo-Branco C. Turner\u2019s syndrome and other forms of congenital hypogonadism impair quality of life and sexual function. Am J Obstet Gynecol. 2013. https:\/\/doi.org\/10.1016\/B978-0-323-03247-6.X1000-3.","journal-title":"Am J Obstet Gynecol"},{"issue":"12","key":"897_CR18","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1080\/09513590.2016.1241229","volume":"32","author":"MF Garrido","year":"2016","unstructured":"Garrido MF, Castelo-Branco C. Sexuality and quality of life in congenital hypogonadisms. Gynecol Endocrinol. 2016;32(12):947\u201350. https:\/\/doi.org\/10.1080\/09513590.2016.1241229.","journal-title":"Gynecol. 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The study was approved by the Local Ethical Committee before the enrollment.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Both patients gave their written consent to participate and agreed for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Both patients gave their written consent to participate and agreed for publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}