{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:32:52Z","timestamp":1784327572157,"version":"3.55.0"},"reference-count":8,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Tessadori\u2013Bicknell\u2013van Haaften syndrome (OMIM #619759) is a rare autosomal dominant neurodevelopmental disorder associated with heterozygous variants in genes encoding histone H4 proteins. The condition is characterized by global developmental delay, craniofacial dysmorphism, hypotrophy, intellectual disability, and ophthalmologic anomalies. More than 30 individuals with variants in histone H4 genes have been reported to date, reflecting the genetic heterogeneity of this emerging disorder. According to OMIM, the association between the H4C11 gene and Tessadori\u2013Bicknell\u2013van Haaften syndrome 2 is currently considered provisional. Methods: We report the case of a 5-year-old female presenting with expressive language delay, social interaction difficulties, and craniofacial features including microcephaly, exophthalmos, and periorbital fullness (\u201cpuffy eyes\u201d). Family history revealed two sisters with borderline intellectual functioning who have not undergone genetic testing. The patient\u2019s father carried the same heterozygous H4C11 variant (c.97C &gt; T), while maternal testing was negative. Results: Neuropsychological evaluation revealed borderline intellectual functioning (IQ 73 at first assessment, 85 at follow-up) with persistent expressive language impairment. Ophthalmologic examination confirmed congenital exophthalmos and hypermetropic astigmatism. Laboratory investigations showed low ferritin and mildly elevated TSH levels, which may have contributed to the observed growth delay. At follow-up, the patient showed an increase in IQ score (73 to 85); however, test\u2013retest variability cannot be excluded. Conclusions: This case highlights the importance of careful clinical assessment and cautious interpretation of genetic findings in children with neurodevelopmental delay. Familial segregation of a variant of uncertain significance (VUS), in the absence of functional evidence, should be interpreted conservatively and integrated with detailed phenotypic evaluation to guide clinical management and follow-up.<\/jats:p>","DOI":"10.3390\/jcm15072505","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T10:07:13Z","timestamp":1774433233000},"page":"2505","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Pediatric Case of Neurodevelopmental Delay with a Familial H4C11 Variant: Clinical Course and Diagnostic Challenges"],"prefix":"10.3390","volume":"15","author":[{"given":"Elena","family":"Tudorache","sequence":"first","affiliation":[{"name":"Dr. Constantin Gorgos Psychiatry Hospital, 030442 Bucharest, Romania"},{"name":"Department of Genetics, Carol Davila University of Medicine and Pharmacy, 020027 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea","family":"Giurgiuveanu","sequence":"additional","affiliation":[{"name":"Dr. Constantin Gorgos Psychiatry Hospital, 030442 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3901-615X","authenticated-orcid":false,"given":"Emilia","family":"Severin","sequence":"additional","affiliation":[{"name":"Department of Genetics, Carol Davila University of Medicine and Pharmacy, 020027 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina-Ioana","family":"Iord\u0103nescu","sequence":"additional","affiliation":[{"name":"Department of Genetics, Carol Davila University of Medicine and Pharmacy, 020027 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela Anca","family":"Bulf","sequence":"additional","affiliation":[{"name":"Dr. Constantin Gorgos Psychiatry Hospital, 030442 Bucharest, Romania"},{"name":"Psychology Major, Faculty of Psychology and Education Sciences, University of Bucharest, 050663 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"ref_1","unstructured":"OMIM (2025, November 10). Available online: https:\/\/omim.org\/entry\/619759."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1038\/ng.3956","article-title":"Deciphering Developmental Disorders Study Germline mutations affecting the histone H4 core cause a developmental syndrome by altering DNA damage response and cell cycle control","volume":"49","author":"Tessadori","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_3","unstructured":"HPO (2025, November 10). Available online: https:\/\/hpo.jax.org\/browse\/disease\/OMIM:619759."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/s41431-019-0552-9","article-title":"A de novo variant in the human HIST1H4J gene causes a syndrome analogous to the HIST1H4C-associated neurodevelopmental disorder","volume":"28","author":"Tessadori","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.ajhg.2022.02.003","article-title":"Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome","volume":"109","author":"Tessadori","year":"2022","journal-title":"Am. J. Hum. Genet."},{"key":"ref_6","unstructured":"(2025, November 17). Gene Curation Coalition (GenCC), H4C11\u2014Curated Gene\u2013Disease Relationship: Neurodevelopmental Disorder, Autosomal Dominant. Available online: https:\/\/search.thegencc.org\/genes\/HGNC:4785."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1101\/gr.190629.115","article-title":"The Mendelian disorders of the epigenetic machinery","volume":"25","author":"Bjornsson","year":"2015","journal-title":"Genome Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s40246-025-00734-9","article-title":"Molecular and clinical aspects of histone-related disorders","volume":"19","author":"Banimortada","year":"2025","journal-title":"Hum. Genom."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/7\/2505\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T10:49:27Z","timestamp":1774435767000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/7\/2505"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":8,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["jcm15072505"],"URL":"https:\/\/doi.org\/10.3390\/jcm15072505","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]}}}