{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:50:45Z","timestamp":1791561045163,"version":"4.3.4"},"reference-count":26,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Heterozygous germline variants in\n                    <jats:italic>CBL<\/jats:italic>\n                    disrupt its function as a negative regulator of the Ras\/MAPK pathway, classically predisposing to Juvenile myelomonocytic leukemia (JMML) and moyamoya. We describe two affected siblings carrying a paternally inherited\n                    <jats:italic>CBL<\/jats:italic>\n                    variant (c.1210 T&gt; C, p. Cys404Arg) who exhibited markedly divergent phenotypes, uncovering novel neuroinflammatory and systemic vascular fragility manifestations. The older sibling, a previously healthy 4\u2010year\u2010old girl, presented with acute, rapidly progressive acute disseminated encephalomyelitis (ADEM)\u2013like neuroinflammatory disease post\u2010febrile illness, accompanied by optic neuritis, and severe dystonia\u2010parkinsonism. She had mild splenomegaly and thrombocytopenia. Brain MRI demonstrated extensive bilateral basal ganglia and diffuse white matter abnormalities, without evidence of moyamoya. Cerebrospinal fluid analysis showed pleocytosis and elevated protein, with extensive infectious and metabolic workups returning negative. Conversely, her 2\u2010year\u2010old sister presented with hematologic myeloproliferation and was diagnosed with JMML at 12\u2009months. At 21\u2009months, following an intercurrent viral infection, she presented with recurrent, bilateral arterial ischemic stroke and was diagnosed with severe, bilateral moyamoya. Vessel wall Imaging showed no enhancement. During hospitalization, she demonstrated profound systemic vascular fragility, manifested by a radial artery pseudoaneurysm post\u2010puncture and a femoral artery pseudoaneurysm post\u2010angiography, which required surgical repair. Bilateral encephaloduroarteriosynangiosis led to clinical stabilization. These cases extend the phenotypic spectrum of\n                    <jats:italic>CBL<\/jats:italic>\n                    \u2010related disorders to include severe central nervous system immune dysregulation and systemic vascular fragility with recurrent peripheral arterial pseudoaneurysms. These findings demonstrate that CBL loss of function drives tissue\u2010level proliferative and inflammatory remodeling, highlighting a novel intersection between dysregulated Ras\/MAPK signaling, neuroinflammation, and structural vascular vulnerability.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70232","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:14:27Z","timestamp":1782270867000},"page":"2568-2574","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Severe ADEM\u2010Like Neuroinflammatory Disease and Cerebrovascular Fragility With Recurrent Pseudoaneurysms and Moyamoya in a Familial Germline\n                    <i>CBL<\/i>\n                    Mutation: Expanding the Clinical Phenotype"],"prefix":"10.1002","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4478-7074","authenticated-orcid":false,"given":"Michal","family":"Bar\u2010Hakim","sequence":"first","affiliation":[{"name":"Pediatric Neurology Institute, Dana\u2010Dwek Children's Hospital Tel Aviv Sourasky Medical Center  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anat","family":"Abramovich","sequence":"additional","affiliation":[{"name":"Pediatric Neurology and Development Center Shamir Medical Center  Be'er Ya'akov Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Via\u2010Dorembus","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, The Edmond and Lily Safra Children's Hospital Sheba Medical Center  Ramat Gan 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Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0961-2567","authenticated-orcid":false,"given":"Assaf A.","family":"Barg","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medical and Health Sciences Tel Aviv University  Tel Aviv Israel"},{"name":"Division of Pediatric Hematology and Oncology, the Edmond and Lily Safra Children's Hospital Sheba Medical Center  Ramat Gan Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Roth","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medical and Health Sciences Tel Aviv University  Tel Aviv Israel"},{"name":"Department of Pediatric Neurosurgery, Dana Children's Hospital Tel Aviv Medical Center  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basheer","family":"Sheick\u2010Yousif","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medical and Health Sciences Tel Aviv University  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