{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T08:01:09Z","timestamp":1783065669587,"version":"3.54.6"},"reference-count":16,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2018,4,28]],"date-time":"2018-04-28T00:00:00Z","timestamp":1524873600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000069","name":"NIAMS","doi-asserted-by":"publisher","award":["1R01AR068429\u201001"],"award-info":[{"award-number":["1R01AR068429\u201001"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"NICHD","doi-asserted-by":"publisher","award":["U19HD077671"],"award-info":[{"award-number":["U19HD077671"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"NIGMS","doi-asserted-by":"publisher","award":["T32GM007753"],"award-info":[{"award-number":["T32GM007753"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2018,7]]},"abstract":"<jats:p>Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired\u2010like homeobox 2B (<jats:italic>PHOX2B)<\/jats:italic> gene. The majority of CCHS cases are caused by polyalanine repeat mutations (PARMs) in <jats:italic>PHOX2B<\/jats:italic>; however, in rare cases, non\u2010polyalanine repeat mutations (NPARMs) have been identified. Here, we report two patients with NPARMs in <jats:italic>PHOX2B<\/jats:italic>. Patient 1 has a mild CCHS phenotype seen only on polysomnogram, which was performed for desaturations and stridor following a bronchiolitis episode, and characterized by night\u2010time hypoventilation and a history of ganglioneuroblastoma. She carried a novel <jats:italic>de novo<\/jats:italic> missense variant, p.R102S (c.304C\u2009&gt;\u2009A), in exon 2. Patient 2 has an atypical CCHS phenotype including micrognathia, gastroesophageal reflux, stridor, hypopnea, and intermittent desaturations. Sleep study demonstrated that Patient 2 had daytime and night\u2010time hypercarbia with obstructive sleep apnea, requiring tracheostomy. On <jats:italic>PHOX2B<\/jats:italic> sequencing, she carried a recently identified nonsense variant, p.Y78* (c.234C\u2009&gt;\u2009G), in exon 1. In summary, we present two patients with CCHS and identified NPARMs in <jats:italic>PHOX2B<\/jats:italic> who have distinct differences in phenotype severity, further elucidating the range of clinical outcomes in CCHS and illustrating the necessity of considering <jats:italic>PHOX2B<\/jats:italic> mutations when encountering atypical CCHS presentations.<\/jats:p>","DOI":"10.1002\/ajmg.a.38720","type":"journal-article","created":{"date-parts":[[2018,4,28]],"date-time":"2018-04-28T07:36:52Z","timestamp":1524901012000},"page":"1627-1631","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Atypical presentations associated with non\u2010polyalanine repeat <i>PHOX2B<\/i> mutations"],"prefix":"10.1002","volume":"176","author":[{"given":"Umakanth","family":"Katwa","sequence":"first","affiliation":[{"name":"Division of Pulmonology Boston Children's Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2482-5328","authenticated-orcid":false,"given":"Alissa M.","family":"D'Gama","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita E.","family":"Qualls","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine Boston Children's Hospital and Harvard Medical School Boston Massachusetts"},{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas M.","family":"Donovan","sequence":"additional","affiliation":[{"name":"Division of Pulmonology Boston Children's Hospital and Harvard Medical School Boston Massachusetts"},{"name":"Department of Medicine, Division of Pulmonary and Sleep Medicine Beth Israel Deaconess Medical Center Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jody","family":"Heffernan","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine Boston Children's Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahai","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences City University of Hong Kong Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj B.","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital and Harvard Medical School Boston Massachusetts"},{"name":"Division of Newborn Medicine Boston Children's Hospital and Harvard Medical School Boston Massachusetts"},{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,4,28]]},"reference":[{"key":"e_1_2_6_2_1","volume-title":"The AASM manual for the scoring of sleep and associated events: Rules, terminology and technical specifications","author":"Berry R. 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