{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:28:09Z","timestamp":1784820489288,"version":"3.55.0"},"reference-count":8,"publisher":"The Endocrine Society","issue":"11","license":[{"start":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:00:00Z","timestamp":1729641600000},"content-version":"vor","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"University Hospitals Leuven"},{"DOI":"10.13039\/501100003130","name":"Research Foundation Flanders","doi-asserted-by":"publisher","award":["1800923N"],"award-info":[{"award-number":["1800923N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Biallelic pathogenic variants in RNF216 cause a syndrome characterized by hypogonadotropic hypogonadism, cerebellar ataxia, chorea, and cognitive impairment, a combination first described as Gordon Holmes syndrome (MIM 212840). We report 2 siblings who were referred due to absent or delayed puberty. The older sibling, a 17-year-old male, presented with absence of secondary sexual characteristics and a high-pitched voice. He had normal cognitive development and no anosmia. Clinical examination revealed Tanner stage P1\/G1 and bilateral gynecomastia. Blood tests showed low gonadotropin and morning testosterone levels. His 15-year-old sister was referred due to primary amenorrhea. She had spontaneous thelarche and presented with Tanner stage P3\/B3. Pituitary magnetic resonance imaging was performed on the brother due to suspicion of Kallmann syndrome, revealing a normal anterior pituitary, a hypoplastic posterior pituitary, and an extensive supratentorial leuko-encephalopathy. Whole-exome sequencing revealed a homozygous pathogenic variant in RNF216 in both affected siblings. Both parents were heterozygous carriers. RNF216 pathogenic variants cause a disorder characterized by combined neurodegeneration and reproductive dysfunction. Although neurological symptoms are typically recognized first, they often seem to follow the onset of hypogonadism. This highlights the need for awareness, as hypogonadotropic hypogonadism may be the initial manifestation of this severe neuroendocrine disorder, especially in males.<\/jats:p>","DOI":"10.1210\/jcemcr\/luae195","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T13:37:06Z","timestamp":1729690626000},"source":"Crossref","is-referenced-by-count":3,"title":["Hypogonadotropic Hypogonadism as First Presentation of the Severe Neuroendocrine Disorder Caused by RNF216"],"prefix":"10.1210","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3266-9126","authenticated-orcid":false,"given":"Anne","family":"Rochtus","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University Hospitals Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willeke","family":"Asscherickx","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospitals Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marijke","family":"Timmers","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, University Hospitals Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Vermeer","sequence":"additional","affiliation":[{"name":"Department of Genetics, University Hospitals Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1079-2860","authenticated-orcid":false,"given":"Leen","family":"Antonio","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, University Hospitals Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2024,10,23]]},"reference":[{"issue":"5","key":"2024110705250491100_luae195-B1","first-page":"430","article-title":"Clinical and genetic spectrum of RNF216-related disorder: a new case and literature review","volume":"61","author":"Wu","year":"2024","journal-title":"J Med Genet"},{"issue":"17","key":"2024110705250491100_luae195-B2","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1212\/WNL.0000000000001521","article-title":"RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder","volume":"84","author":"Santens","year":"2015","journal-title":"Neurology"},{"issue":"21","key":"2024110705250491100_luae195-B3","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1056\/NEJMoa1215993","article-title":"Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination","volume":"368","author":"Margolin","year":"2013","journal-title":"N Engl J Med"},{"key":"2024110705250491100_luae195-B4","doi-asserted-by":"crossref","first-page":"106763","DOI":"10.1016\/j.clineuro.2021.106763","article-title":"Gordon Holmes syndrome caused by two novel mutations in the PNPLA6 gene","volume":"207","author":"Locci","year":"2021","journal-title":"Clin Neurol Neurosurg"},{"issue":"2","key":"2024110705250491100_luae195-B5","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1007\/s12311-023-01549-x","article-title":"Ataxia and hypogonadism: a review of the associated genes and syndromes","volume":"23","author":"De Michele","year":"2024","journal-title":"Cerebellum"},{"issue":"8","key":"2024110705250491100_luae195-B6","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1002\/mdc3.12839","article-title":"Overt hypogonadism may not be a sentinel sign of RING finger protein 216: two novel mutations associated with ataxia, chorea, and fertility","volume":"6","author":"Lieto","year":"2019","journal-title":"Mov Disord Clin Pract"},{"issue":"5","key":"2024110705250491100_luae195-B7","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1093\/biolre\/ioz006","article-title":"RNF216 is essential for spermatogenesis and male fertility\u2020","volume":"100","author":"Melnick","year":"2019","journal-title":"Biol Reprod"},{"issue":"4","key":"2024110705250491100_luae195-B8","doi-asserted-by":"crossref","first-page":"e21460","DOI":"10.1096\/fj.202002294RR","article-title":"RNF216 regulates meiosis and PKA stability in the testes","volume":"35","author":"Li","year":"2021","journal-title":"FASEB J"}],"container-title":["JCEM Case Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcemcr\/article-pdf\/2\/11\/luae195\/60396586\/luae195.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcemcr\/article-pdf\/2\/11\/luae195\/60396586\/luae195.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T05:25:35Z","timestamp":1730957135000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcemcr\/article\/doi\/10.1210\/jcemcr\/luae195\/7832243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,18]]},"references-count":8,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,10,18]]}},"URL":"https:\/\/doi.org\/10.1210\/jcemcr\/luae195","relation":{},"ISSN":["2755-1520"],"issn-type":[{"value":"2755-1520","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,11]]},"published":{"date-parts":[[2024,10,18]]},"article-number":"luae195"}}