{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T14:02:55Z","timestamp":1774015375712,"version":"3.50.1"},"reference-count":16,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AORN Santobono Pausilipon, Naples, Italy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by an impaired ventilatory response to hypercapnia and hypoxia, particularly during sleep, and frequently associated with autonomic dysfunction. It is caused by pathogenic variants in the PHOX2B gene. Although CCHS is typically diagnosed in the neonatal period, milder forms may present later in infancy or childhood, often triggered by respiratory infections. Case presentation: We report the case of 16-month-old male diagnosed with CCHS following an episode of hypoxemic\u2013hypercapnic respiratory failure during respiratory syncytial virus (RSV) infection. His medical history included neonatal respiratory distress requiring oxygen therapy and recurrent wheezing. At 15 months, he developed acute respiratory distress with severe hypercapnia (PaCO2 70 mmHg), requiring admission to the Pediatric Intensive Care Unit and invasive mechanical ventilation. Persistent sleep-related hypercapnia and hypoxemia prompted evaluation for central hypoventilation, confirmed by means of transcutaneous capnography and nocturnal pulse oximetry. Genetic testing revealed a de novo nonsense mutation in exon 1 of PHOX2B (p.Tyr14Ter). Brain magnetic resonance imaging showed diffuse white matter changes suggestive of gliosis. Further investigations identified early-onset systemic hypertension, requiring antihypertensive therapy. The patient was discharged on nocturnal non-invasive ventilation and enrolled in a neurodevelopmental rehabilitation program. Conclusions: This case highlights the phenotypic variability of CCHS and the importance of considering this diagnosis in children presenting with unexplained hypercapnia and sleep-related hypoxemia. It underscores the need for comprehensive autonomic evaluation, including blood pressure monitoring. The p.Tyr14Ter variant may allow partial protein function, potentially accounting for the relatively mild phenotype.<\/jats:p>","DOI":"10.3390\/children13030425","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T15:38:01Z","timestamp":1773934681000},"page":"425","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PHOX2B Tyr14Ter Mutation Might Be Associated with Sustained Diurnal Hypertension: Case Report and Review of the Literature"],"prefix":"10.3390","volume":"13","author":[{"given":"Fabio","family":"Antonelli","sequence":"first","affiliation":[{"name":"Unit of Pediatric Pneumology and UTSIR, AORN Santobono-Pausilipon Children\u2019s Hospital, 80129 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7293-9629","authenticated-orcid":false,"given":"Simona","family":"Sottili","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emergency University of Bari, 70126 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Giovanna","family":"Paglietti","sequence":"additional","affiliation":[{"name":"Pediatric Pulmonology & Cystic Fibrosis Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6527-0317","authenticated-orcid":false,"given":"Alessandro","family":"Onofri","sequence":"additional","affiliation":[{"name":"Pediatric Pulmonology & Cystic Fibrosis Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7711-5672","authenticated-orcid":false,"given":"Renato","family":"Cutrera","sequence":"additional","affiliation":[{"name":"Pediatric Pulmonology & Cystic Fibrosis Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5024-2999","authenticated-orcid":false,"given":"Martina","family":"Mazzoni","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, Pediatrics Section, University of Salerno, 84081 Baronissi, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1807-3884","authenticated-orcid":false,"given":"Alessandro","family":"Rossi","sequence":"additional","affiliation":[{"name":"Unit of Pediatric Pneumology and UTSIR, AORN Santobono-Pausilipon Children\u2019s Hospital, 80129 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierluigi","family":"Vuilleumier","sequence":"additional","affiliation":[{"name":"Unit of Pediatric Pneumology and UTSIR, AORN Santobono-Pausilipon Children\u2019s Hospital, 80129 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4685-7205","authenticated-orcid":false,"given":"Annalisa","family":"Allegorico","sequence":"additional","affiliation":[{"name":"Unit of Pediatric Pneumology and UTSIR, AORN Santobono-Pausilipon Children\u2019s Hospital, 80129 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1186\/s13023-020-01460-2","article-title":"Guidelines for diagnosis and management of congenital central hypoventilation syndrome","volume":"15","author":"Trang","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/cge.13633","article-title":"Causative and common PHOX2B variants define a broad phenotypic spectrum","volume":"97","author":"Bachetti","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E421","DOI":"10.1002\/humu.20923","article-title":"In Vitro studies of non poly alanine PHOX2B mutations argue against a loss-of-function mechanism for congenital central hypoventilation","volume":"30","author":"Trochet","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_4","unstructured":"American Academy of Sleep Medicine (2023). The AASM Manual for the Scoring of Sleep and Associated Events: Terminology and Technical Specifications (Version 3), AASM."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1164\/rccm.200602-266CR","article-title":"Brainstem Anomalies in Two Patients Affected by Congenital Central Hypoventilation Syndrome","volume":"174","author":"Bachetti","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_6","unstructured":"Hall, J.E. (2020). Guyton and Hall Textbook of Medical Physiology, Elsevier. [14th ed.]. Chapter 18: Nervous Regulation of the Circulation and Rapid Control of Arterial Pressure."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1042\/CS20040282","article-title":"Short-term blood pressure and heart rate variability in congenital central hypoventilation syndrome (Ondine\u2019s curse)","volume":"108","author":"Trang","year":"2005","journal-title":"Clin. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1164\/rccm.202103-0732OC","article-title":"Cerebral Autoregulation during Orthostatic Challenge in Congenital Central Hypoventilation Syndrome","volume":"205","author":"Vu","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1203\/00006450-199203000-00020","article-title":"Heart Rate Variability in Congenital Central Hypoventilation Syndrome","volume":"31","author":"Woo","year":"1992","journal-title":"Pediatr. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1038\/s41436-021-01178-x","article-title":"Paired-like homeobox gene (PHOX2B) nonpolyalanine repeat expansion mutations (NPARMs): Genotype\u2013phenotype correlation in congenital central hypoventilation syndrome (CCHS)","volume":"23","author":"Zhou","year":"2021","journal-title":"Genet. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1002\/ajmg.a.38162","article-title":"Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome","volume":"173","author":"Cain","year":"2017","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/humu.9516","article-title":"Parental origin and somatic mosaicism of PHOX2B mutations in Congenital Central Hypoventilation Syndrome","volume":"29","author":"Parodi","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s11325-014-0996-7","article-title":"Late-onset congenital central hypoventilation syndrome and a rare PHOX2B gene mutation","volume":"19","author":"Madureira","year":"2015","journal-title":"Sleep Breath."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1002\/ajmg.a.38218","article-title":"Variable phenotype in a novel mutation in PHOX2B","volume":"173","author":"Lombardo","year":"2017","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1002\/ajmg.a.38720","article-title":"Atypical presentations associated with non-polyalanine repeat PHOX2B mutations","volume":"176","author":"Katwa","year":"2018","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1164\/ajrccm.155.1.9001336","article-title":"Peripheral chemoreceptors in congenital central hypoventilation syndrome","volume":"155","author":"Cutz","year":"1997","journal-title":"Am. J. Respir. Crit. Care Med."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/13\/3\/425\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T11:51:52Z","timestamp":1774007512000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/13\/3\/425"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,19]]},"references-count":16,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["children13030425"],"URL":"https:\/\/doi.org\/10.3390\/children13030425","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,19]]}}}