{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:12:50Z","timestamp":1770815570703,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T00:00:00Z","timestamp":1643587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Despite high survival, paediatric optic pathway hypothalamic gliomas are associated with significant morbidity and late mortality. Those youngest at presentation have the worst outcomes. We aimed to assess presenting disease, tumour location, and treatment factors implicated in the evolution of neuroendocrine, metabolic, and neurobehavioural morbidity in 90 infants\/children diagnosed before their third birthday and followed-up for 9.5 years (range 0.5\u201325.0). A total of 52 (57.8%) patients experienced endo-metabolic dysfunction (EMD), the large majority (46) of whom had hypothalamic involvement (H+) and lower endocrine event-free survival (EEFS) rates. EMD was greatly increased by a diencephalic syndrome presentation (85.2% vs. 46%, p = 0.001)), H+ (OR 6.1 95% CI 1.7\u201321.7, p 0.005), radiotherapy (OR 16.2, 95% CI 1.7\u2013158.6, p = 0.017) and surgery (OR 4.8 95% CI 1.3\u201317.2, p = 0.015), all associated with anterior pituitary disorders. Obesity occurred in 25% of cases and was clustered with the endocrinopathies. Neurobehavioural deficits occurred in over half (52) of the cohort and were associated with H+ (OR 2.5 95% C.I. 1.1\u20135.9, p = 0.043) and radiotherapy (OR 23.1 C.I. 2.9\u2013182, p = 0.003). Very young children with OPHG carry a high risk of endo-metabolic and neurobehavioural comorbidities which deserve better understanding and timely\/parallel support from diagnosis to improve outcomes. These evolve in complex, hierarchical patterns over time whose aetiology appears predominantly determined by injury from the hypothalamic tumour location alongside adjuvant treatment strategies.<\/jats:p>","DOI":"10.3390\/cancers14030747","type":"journal-article","created":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T09:59:21Z","timestamp":1643709561000},"page":"747","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A 40-Year Cohort Study of Evolving Hypothalamic Dysfunction in Infants and Young Children (&lt;3 years) with Optic Pathway Gliomas"],"prefix":"10.3390","volume":"14","author":[{"given":"Stefania","family":"Picariello","sequence":"first","affiliation":[{"name":"Neuro-Oncology Unit, Department of Paediatric Oncology, Santobono-Pausilipon Children\u2019s Hospital, 80123 Naples, Italy"},{"name":"Department of Woman, Child and General and Specialized Surgery, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Cerbone","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK"},{"name":"Section of Molecular Basis of Rare Disease, University College London Great Ormond Street Hospital Institute of Child Health, London WC1N 1EH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felice","family":"D\u2019Arco","sequence":"additional","affiliation":[{"name":"Department of Radiology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hoong-Wei","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK"},{"name":"Section of Molecular Basis of Rare Disease, University College London Great Ormond Street Hospital Institute of Child Health, London WC1N 1EH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"O\u2019Hare","sequence":"additional","affiliation":[{"name":"Department of Oncology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristian","family":"Aquilina","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Great Ormond Street Hospital for Children, London WC1N 3JH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8483-1618","authenticated-orcid":false,"given":"Enrico","family":"Opocher","sequence":"additional","affiliation":[{"name":"Department of Oncology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK"},{"name":"Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darren","family":"Hargrave","sequence":"additional","affiliation":[{"name":"Department of Oncology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen A.","family":"Spoudeas","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK"},{"name":"Section of Molecular Basis of Rare Disease, University College London Great Ormond Street Hospital Institute of Child Health, London WC1N 1EH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,31]]},"reference":[{"key":"ref_1","unstructured":"CBTRUS (2008). Statistical Report: Primary Brain Tumors in the United States, 2000\u20132004, Central Brain Tumor Registry of the United States."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Pritchard-Jones, K. (2007). Childhood cancer in Britain: Incidence, survival and mortality. Br. J. Cancer, 96.","DOI":"10.1038\/sj.bjc.6603800"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.1097\/WNO.0000000000000550","article-title":"Optic Pathway Gliomas in Neurofibromatosis Type 1: An Update: Surveillance, Treatment Indications, and Biomarkers of Vision","volume":"37","author":"Fisher","year":"2017","journal-title":"J. Neuroophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1093\/neuonc\/noq178","article-title":"Survival and long-term health and cognitive outcomes after low-grade glioma","volume":"13","author":"Armstrong","year":"2011","journal-title":"Neuro-Oncology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1136\/bjophthalmol-2017-311305","article-title":"Visual outcomes after chemotherapy for optic pathway glioma in children with and without neurofibromatosis type 1: Results of the International Society of Paediatric Oncology (SIOP) Low-Grade Glioma 2004 trial UK cohort","volume":"102","author":"Falzon","year":"2018","journal-title":"Br. J. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1093\/neuonc\/noaa153","article-title":"NF1 optic pathway glioma: Analyzing risk factors for visual outcome and indications to treat","volume":"23","author":"Azizi","year":"2021","journal-title":"Neuro-Oncology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s11060-019-03264-2","article-title":"Long-term visual acuity outcomes after radiation therapy for sporadic optic pathway glioma","volume":"144","author":"Acharya","year":"2019","journal-title":"J. Neurooncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4190","DOI":"10.1002\/cncr.29649","article-title":"Long-term visual outcome after chemotherapy for optic pathway glioma in children: Site and age are strongly predictive","volume":"121","author":"Dodgshun","year":"2015","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3787","DOI":"10.1210\/jc.2015-2028","article-title":"Neuroendocrine Morbidity After Pediatric Optic Gliomas: A Longitudinal Analysis of 166 Children Over 30 Years","volume":"100","author":"Gan","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1227\/00006123-199002000-00010","article-title":"Management of hypothalamic gliomas in children: An analysis of 33 cases","volume":"26","author":"Rodriguez","year":"1990","journal-title":"Neurosurgery"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s11060-005-9091-z","article-title":"Late sequela after treatment of childhood low-grade gliomas: A retrospective analysis of 69 long-term survivors treated between 1983 and 2003","volume":"78","author":"Benesch","year":"2006","journal-title":"J. Neurooncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1046\/j.1365-2265.1997.2211032.x","article-title":"Endocrine outcome in long-term survivors of low-grade hypothalamic\/chiasmatic glioma","volume":"47","author":"Sernyak","year":"1997","journal-title":"Clin. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3691","DOI":"10.1200\/JCO.2008.21.2738","article-title":"Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: Prospective evaluation of cognitive, endocrine, and hearing deficits","volume":"27","author":"Merchant","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1136\/adc.79.4.334","article-title":"Long-term follow up of 69 patients treated for optic pathway tumours before the chemotherapy era","volume":"79","author":"Cappelli","year":"1998","journal-title":"Arch. Dis. Child."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1067\/mpd.2003.234","article-title":"Adult height after cranial irradiation for optic pathway tumors: Relationship with neurofibromatosis","volume":"142","author":"Huguenin","year":"2003","journal-title":"J. Pediatrics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1007\/s00381-006-0086-7","article-title":"Optic pathway glioma: Outcome and prognostic factors in a surgical series","volume":"22","author":"Ahn","year":"2006","journal-title":"Childs Nerv. Syst."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1159\/000028996","article-title":"Optic pathway hypothalamic gliomas in children under three years of age: The role of chemotherapy","volume":"33","author":"Silva","year":"2000","journal-title":"Pediatr. Neurosurg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s11060-013-1284-2","article-title":"Favorable survival and metabolic outcome for children with diencephalic syndrome using a radiation-sparing approach","volume":"116","author":"Kilday","year":"2014","journal-title":"J. Neurooncol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rakotonjanahary, J., De Carli, E., Delion, M., Kalifa, C., Grill, J., Doz, F., Leblond, P., Bertozzi, A.I., and Rialland, X. (2015). Mortality in Children with Optic Pathway Glioma Treated with Up-Front BB-SFOP Chemotherapy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127676"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1055\/a-0889-8256","article-title":"SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma","volume":"231","author":"Gnekow","year":"2019","journal-title":"Klin. Padiatr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s11060-011-0783-2","article-title":"Characterization and outcomes of optic nerve gliomas: A population-based analysis","volume":"107","author":"Mishra","year":"2012","journal-title":"J. Neurooncol."},{"key":"ref_22","first-page":"1257","article-title":"A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: A population-based cohort study (CCLG CNS9702)","volume":"12","author":"Stokland","year":"2010","journal-title":"Neuro-Oncology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/BF02072067","article-title":"Growth and endocrine disorders in optic glioma","volume":"149","author":"Brauner","year":"1990","journal-title":"Eur. J. Pediatrics"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Binning, M.J., Liu, J.K., Kestle, J.R., Brockmeyer, D.L., and Walker, M.L. (2007). Optic pathway gliomas: A review. Neurosurg. Focus, 23.","DOI":"10.3171\/foc.2007.23.5.3"},{"key":"ref_25","first-page":"1499","article-title":"Diencephalic syndrome: Clinical features and imaging findings","volume":"18","author":"Poussaint","year":"1997","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Santoro, C., Perrotta, S., Picariello, S., Scilipoti, M., Cirillo, M., Quaglietta, L., Cinalli, G., Cioffi, D., Di Iorgi, N., and Maghnie, M. (2020). Pretreatment Endocrine Disorders Due to Optic Pathway Gliomas in Pediatric Neurofibromatosis Type 1: Multicenter Study. J. Clin. Endocrinol. Metab., 105.","DOI":"10.1210\/clinem\/dgaa138"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1210\/jc.2016-2046","article-title":"Cancer Risks in Patients Treated with Growth Hormone in Childhood: The SAGhE European Cohort Study","volume":"102","author":"Swerdlow","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1080\/08035250600577889","article-title":"Recurrence of brain tumours in patients treated with growth hormone: Analysis of KIGS (Pfizer International Growth Database)","volume":"95","author":"Darendeliler","year":"2006","journal-title":"Acta Paediatr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1159\/000284358","article-title":"Analyses of treatment variables for patients with childhood craniopharyngioma\u2014Results of the multicenter prospective trial KRANIOPHARYNGEOM 2000 after three years of follow-up","volume":"73","author":"Gebhardt","year":"2010","journal-title":"Horm. Res. Paediatr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1200\/JCO.2001.19.2.480","article-title":"Growth hormone replacement therapy in children with medulloblastoma: Use and effect on tumor control","volume":"19","author":"Packer","year":"2001","journal-title":"J. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1210\/jc.2018-01175","article-title":"Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline","volume":"103","author":"Sklar","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1159\/000458525","article-title":"Endocrine Long-Term Follow-Up of Children with Neurofibromatosis Type 1 and Optic Pathway Gliomas","volume":"87","author":"Sani","year":"2017","journal-title":"Horm. Res. Paediatr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1007\/s00381-020-04697-1","article-title":"Neurofibromatosis 1-associated optic pathway gliomas","volume":"36","author":"Shofty","year":"2020","journal-title":"Childs Nerv. Syst."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Papini, C., Dineen, R.A., Walker, D.A., Thomas, S., and Pitchford, N.J. (2020). Neuropsychological outcomes of children with Optic Pathway Glioma. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-59896-2"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1002\/cncr.31918","article-title":"Treatment burden and long-term health deficits of patients with low-grade gliomas or glioneuronal tumors diagnosed during the first year of life","volume":"125","author":"Liu","year":"2019","journal-title":"Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1002\/cncr.32186","article-title":"Neuropsychological and socioeconomic outcomes in adult survivors of pediatric low-grade glioma","volume":"125","author":"Ris","year":"2019","journal-title":"Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1259\/bjr\/65246351","article-title":"Radiological classification of optic pathway gliomas: Experience of a modified functional classification system","volume":"81","author":"Taylor","year":"2008","journal-title":"Br. J. Radiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3972","DOI":"10.1210\/jc.2014-1680","article-title":"Diencephalic syndrome in childhood craniopharyngioma--results of German multicenter studies on 485 long-term survivors of childhood craniopharyngioma","volume":"99","author":"Hoffmann","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1210\/jc.2006-0322","article-title":"Diencephalic syndrome due to hypothalamic tumor: A model of the relationship between weight and puberty onset","volume":"91","author":"Brauner","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1136\/adc.75.2.108","article-title":"Growth and endocrine sequelae of craniopharyngioma","volume":"75","author":"DeVile","year":"1996","journal-title":"Arch. Dis. Child."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1007\/s00381-021-05060-8","article-title":"Neurosurgical experience of managing optic pathway gliomas","volume":"37","author":"Hill","year":"2021","journal-title":"Child\u2019s Nerv. Syst."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/3\/747\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:12:07Z","timestamp":1760134327000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/3\/747"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,31]]},"references-count":41,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["cancers14030747"],"URL":"https:\/\/doi.org\/10.3390\/cancers14030747","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,31]]}}}