Severe ADEM-Like Neuroinflammatory Disease and Cerebrovascular Fragility With Recurrent Pseudoaneurysms and Moyamoya in a Familial Germline CBL Mutation: Expanding the Clinical Phenotype.

Abstract

Heterozygous germline variants in CBL 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 CBL variant (c.1210 T> C, p. Cys404Arg) who exhibited markedly divergent phenotypes, uncovering novel neuroinflammatory and systemic vascular fragility manifestations. The older sibling, a previously healthy 4-year-old girl, presented with acute, rapidly progressive acute disseminated encephalomyelitis (ADEM)-like neuroinflammatory disease post-febrile illness, accompanied by optic neuritis, and severe dystonia-parkinsonism. 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-year-old sister presented with hematologic myeloproliferation and was diagnosed with JMML at 12 months. At 21 months, 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-puncture and a femoral artery pseudoaneurysm post-angiography, which required surgical repair. Bilateral encephaloduroarteriosynangiosis led to clinical stabilization. These cases extend the phenotypic spectrum of CBL-related 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-level proliferative and inflammatory remodeling, highlighting a novel intersection between dysregulated Ras/MAPK signaling, neuroinflammation, and structural vascular vulnerability.