{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:18:59Z","timestamp":1783523939056,"version":"3.55.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"\n Background<\/jats:title>\n \n Pathogenic loss-of-function variants in the\n KMT2B<\/jats:italic>\n gene cause a rare autosomal dominant disorder with two major phenotypes:\n KMT2B<\/jats:italic>\n -related dystonia (DYT-\n KMT2B<\/jats:italic>\n ) and\n KMT2B<\/jats:italic>\n -related neurodevelopmental disorder (\n KMT2B<\/jats:italic>\n -NDD). Central precocious puberty (CPP) has been documented as a comorbidity in patients with DYT-\n KMT2B<\/jats:italic>\n , but has not been reported as the primary clinical manifestation of the disorder in patients without dystonia. Deletions or pathogenic variants in the\n STS<\/jats:italic>\n gene cause X-linked ichthyosis (XLI). Concurrent\n KMT2B<\/jats:italic>\n and\n STS<\/jats:italic>\n alterations have not been well characterised, and GnRH analogue therapy for CPP in\n KMT2B<\/jats:italic>\n -related disorders has not been previously described.\n <\/jats:p>\n <\/jats:sec>\n \n Case presentation<\/jats:title>\n \n An 8-year-10-month-old male presented with a 1-2\u2212year history of progressive increase in penile length and girth. Physical examination revealed distinctive craniofacial dysmorphism, classic ichthyotic scaling, pubertal changes consistent with precocious puberty, and normal muscle tone without dystonic features. Biochemical testing confirmed markedly elevated serum total testosterone, a positive gonadotropin-releasing hormone (GnRH) stimulation test consistent with CPP, and bone age advanced by 1.2 years relative to chronological age. Neurocognitive assessment identified mild intellectual disability. Family-based whole-exome sequencing and copy number variation (CNV) analysis identified a\n de novo<\/jats:italic>\n heterozygous pathogenic nonsense variant in\n KMT2B<\/jats:italic>\n (NM_014727.3: c.4213del, p.Leu1405Ter) and a hemizygous pathogenic full-coding deletion of\n STS<\/jats:italic>\n . The patient was treated with leuprorelin acetate for CPP and topical emollients for XLI. At 3\u2212month follow\u2212up, physical signs of puberty remained stable. GnRHa stimulation test showed indicating but incomplete suppression of the hypothalamic-pituitary-gonadal axis. The ichthyotic skin lesions improved markedly with topical therapy. The leuprorelin acetate dose was subsequently increased. The patient is continuing on the current regimen with close monitoring.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Precocious puberty has been reported in eleven patients with\n KMT2B<\/jats:italic>\n \u2212related dystonia. This case documents the co\u2212occurrence of a\n KMT2B<\/jats:italic>\n \u2212related disorder and XLI in a patient, and provides documentation of GnRH analogue therapy and structured endocrine follow\u2212up for CPP in this population.\n KMT2B<\/jats:italic>\n haploinsufficiency may contribute to premature activation of the hypothalamic\u2212pituitary\u2212gonadal axis through disruption of ER\u03b1\u2212mediated transcriptional regulation and altered epigenetic programming at key hypothalamic developmental genes. Clinically, children with\n KMT2B<\/jats:italic>\n \u2212related disorders should undergo comprehensive endocrine assessment to facilitate early diagnosis and timely intervention.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fendo.2026.1869758","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:46:59Z","timestamp":1781671619000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Central precocious puberty as the initial manifestation of multisystem involvement caused by de novo heterozygous KMT2B mutation and STS hemizygous deletion: a case report"],"prefix":"10.3389","volume":"17","author":[{"given":"Yaqin","family":"Feng","sequence":"first","affiliation":[{"name":"Jiangxi Provincial Children's Hospital; JXHC Key Laboratory of Precise Prevention and Treatment for Childhood Diabetes","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yang","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Children's Hospital; JXHC Key Laboratory of Precise Prevention and Treatment for Childhood Diabetes","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Bo","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Children's Hospital; JXHC Key Laboratory of Precise Prevention and Treatment for Childhood Diabetes","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan-Fang","family":"Cao","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Children's Hospital; JXHC Key Laboratory of Precise Prevention and Treatment for Childhood Diabetes","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.03431-21","article-title":"GRWD1-WDR5-MLL2 epigenetic complex mediates H3K4me3 mark and is essential for kaposi\u2019s sarcoma-associated herpesvirus-induced cellular transformation","volume":"12","author":"Wei","year":"2021","journal-title":"mBio"},{"key":"B2","article-title":"KMT2B-related disorders","volume-title":"GeneReviews\u00ae","author":"Abela","year":"1993"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.81454","article-title":"Clinical presentation of KMT2B-related dystonia: a case report","volume":"17","author":"Onoprishvili","year":"2025","journal-title":"Cureus"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2024.107172","article-title":"The clinical spectrum and pathogenesis associated with KMT2B variants in chinese pediatric patients","volume":"129","author":"Ding","year":"2024","journal-title":"Park Relat Disord"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa304","article-title":"KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation","volume":"143","author":"Cif","year":"2020","journal-title":"Brain: J Neurol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/s41598-024-84701-9","article-title":"Dysregulation of STS in keratinocytes promotes calcium signaling and differentiation","volume":"15","author":"Kwon","year":"2025","journal-title":"Sci Rep"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcaf070","article-title":"X-linked ichthyosis","volume":"118","author":"Cao","year":"2025","journal-title":"QJM: Mon J Assoc Physicians"},{"key":"B8","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1111\/ijd.17396","article-title":"Revisiting X-linked congenital ichthyosis","volume":"64","author":"Zhou","year":"2025","journal-title":"Int J Dermatol"},{"key":"B9","article-title":"X-linked ichthyosis","volume-title":"StatPearls","author":"Crane","year":"2026"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2026.1727854","article-title":"KMT2B-related disorders in Austria: clinical features and long-term outcome after deep brain stimulation","volume":"17","author":"Indelicato","year":"2026","journal-title":"Front Neurol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s11033-025-11210-x","article-title":"Novel heterozygous mutation in KMT2B causing an unusual phenotypic presentation: a comprehensive clinical and bioinformatic analysis","volume":"53","author":"Iravani","year":"2025","journal-title":"Mol Biol Rep"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.prdoa.2025.100314","article-title":"Bi-pallidal deep brain stimulation as an effective therapy in atypical two-stage evolution adult-onset KMT2B-related dystonia","volume":"12","author":"Kahwagi","year":"2025","journal-title":"Clin Park Relat Disord"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-026-03153-9","article-title":"Clinical, imaging and genetic profile of KMT2B-related dystonia: a review of published cases","author":"Mahale","year":"2026","journal-title":"J Neural Transm"},{"key":"B14","doi-asserted-by":"publisher","first-page":"823","DOI":"10.3390\/life11080823","article-title":"Structure, activity and function of the MLL2 (KMT2B) protein lysine methyltransferase","volume":"11","author":"Klonou","year":"2021","journal-title":"Life (Basel)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1186\/s13148-021-01145-y","article-title":"Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile","volume":"13","author":"Ciolfi","year":"2021","journal-title":"Clin Epigenetics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"fcac276","DOI":"10.1093\/braincomms\/fcac276","article-title":"Adult-onset KMT2B-related dystonia","volume":"4","author":"Monfrini","year":"2022","journal-title":"Brain Commun"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1516","DOI":"10.1002\/mds.27771","article-title":"Frequency and phenotypic spectrum of KMT2B dystonia in childhood: a single-center cohort study","volume":"34","author":"Carecchio","year":"2019","journal-title":"Mov Disord"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e0166090","DOI":"10.1371\/journal.pone.0166090","article-title":"Regulation of IL-20 expression by estradiol through KMT2B-mediated epigenetic modification","volume":"11","author":"Su","year":"2016","journal-title":"PLoS One"},{"key":"B19","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/1756-8935-2-5","article-title":"The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis","volume":"2","author":"Glaser","year":"2009","journal-title":"Epigenet Chromatin"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e1000453","DOI":"10.1371\/journal.pbio.1000453","article-title":"MLL2 is required in oocytes for bulk histone 3 lysine 4 trimethylation and transcriptional silencing","volume":"8","author":"Andreu-Vieyra","year":"2010","journal-title":"PLoS Biol"},{"key":"B21","unstructured":"Kmt2b phenotypes for Amhr2\u2011cre conditional deletion (MGI:4867492)\n \n \n Mouse Genome Informatics"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1414","DOI":"10.1172\/JCI111552","article-title":"Stratum corneum lipids in disorders of cornification. Steroid sulfatase and cholesterol sulfate in normal desquamation and the pathogenesis of recessive X-linked ichthyosis","volume":"74","author":"Elias","year":"1984","journal-title":"J Clin Invest"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1876","DOI":"10.1093\/ced\/llaf221","article-title":"The importance of cardiac screening in X-linked ichthyosis: a plea","volume":"50","author":"Davies","year":"2025","journal-title":"Clin Exp Dermatol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.00596","article-title":"Novel microdeletion in the X chromosome leads to kallmann syndrome, ichthyosis, obesity, and strabismus","volume":"11","author":"Ma","year":"2020","journal-title":"Front Genet"},{"key":"B25","article-title":"Fibrous dysplasia \/ McCune-albright syndrome","volume-title":"GeneReviews\u00ae [Internet]","author":"Szymczuk","year":"1993"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.1056\/NEJMcp0800459","article-title":"Clinical practice. Precocious puberty","volume":"358","author":"Carel","year":"2008","journal-title":"N Engl J Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.1056\/NEJM199112123252403","article-title":"Activating mutations of the stimulatory G protein in the McCune-albright syndrome","volume":"325","author":"Weinstein","year":"1991","journal-title":"N Engl J Med"},{"key":"B28","article-title":"Kabuki syndrome","volume-title":"GeneReviews\u00ae [Internet]","author":"Adam","year":"1993"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2024.1346044","article-title":"Diagnostic utility of DNA methylation episignature analysis for early diagnosis of KMT2B-related disorders: case report","volume":"15","author":"Bouhamdani","year":"2024","journal-title":"Front Genet"},{"key":"B30","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.ajhg.2017.11.013","article-title":"Histone lysine methylases and demethylases in the landscape of human developmental disorders","volume":"102","author":"Faundes","year":"2018","journal-title":"Am J Hum Genet"},{"key":"B31","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/j.ejmg.2012.03.002","article-title":"19q13 microdeletion syndrome: further refining the critical region","volume":"55","author":"Forzano","year":"2012","journal-title":"Eur J Med Genet"},{"key":"B32","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.parkreldis.2020.06.002","article-title":"Clinical phenotypes, genotypes and treatment in chinese dystonia patients with KMT2B variants","volume":"77","author":"Li","year":"2020","journal-title":"Park Relat Disord"}],"updated-by":[{"DOI":"10.3389\/fendo.2026.1911609","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000}}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1869758\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T14:36:02Z","timestamp":1783521362000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1869758\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":32,"alternative-id":["10.3389\/fendo.2026.1869758"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1869758","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]},"article-number":"1869758"}}