Session Type: Abstract Submissions
Session Time: 5:30PM-7:00PM
Methods: We identified two unrelated cases of TA developing in children with Noonan-like syndrome and juvenile myelomonocytic leukemia (JMML) due to germline mutations in the CBL gene. We performed flow cytometry studies to assess T cell phenotype and function in one patient.
Results: Both patients were female. Patient 1 presented with massive splenomegaly and thrombocytopenia, being diagnosed with JMML at 1.5 years of age. She had delayed growth, developmental delay, optic atrophy, cardiomyopathy, hypertension, and was diagnosed with TA at 9 years of age. Angiography revealed severe stenoses of descending aorta and major branches. She underwent stenting of major arteries but died 9 months after diagnosis of TA. Genotyping showed a homozygous p.384C>R mutation in the CBL gene in granulocytes. Patient 2 had delayed growth, mild developmental delay, and congenital heart disease (atrial septal defect, patent ductus arteriosus, pulmonary stenosis). She was admitted at 14 months of age with massive splenomegaly, mild lymphadenopathy, bicytopenia, and fever. Extensive diagnostic studies showed normal bone marrow and liver biopsies, negative infectious disease work-up, hypergammaglobulinemia, and moderate T cell lymphopenia. She had mild positive anticardiolipin IgM antibodies, low C3 and C4, but negative ANA and ANCA. Lymph node biopsy showed interfollicular histiocytosis, but no malignancy or other specific diagnoses. Contrast-enhanced MRI revealed thickening of the thoracic aorta, suprarenal abdominal aorta, and proximal third of the celiac trunk and superior mesenteric artery, all of which had T2-hyperintensity and progressive contrast enhancement. PET-CT showed increased 18-F FDG uptake in the common carotid arteries, thoracic and abdominal aorta, celiac trunk, and superior mesenteric artery. Whole exome sequencing revealed a p.396C>R mutation in the CBL gene of 88% of reads from blood DNA suggesting loss of heterozygosity of a germline mutation. The father is a heterozygote for this mutation. PHA-induced CD4+ T cell proliferation and PMA/Ionomycin-induced expansion of Th17 cells were increased in the patient compared to normal controls. Regulatory T cells and double-negative T cells were normal. The patient was started on prednisone and azathioprine and is currently in good state of health.
Conclusion: The E3 ligase CBL inhibits angiogenesis and cytokine and T cell receptor signaling. This negative regulation is lost in the case of germline loss-of-function CBL mutations and consecutive loss of heterozygosity, thereby resulting in JMML and autoimmunity. CBL mutations are associated with the development of childhood-onset TA, possibly mediated by increased T cell responses and Th17 cell expansion.
To cite this abstract in AMA style:Borzutzky A, Niemeyer C, Pérez-Mateluna G, Mellado C, Erlacher M, Niewisch M, Aracena M, García C. Childhood-onset Takayasu Arteritis Associated with Mutations in CBL [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 4). https://acrabstracts.org/abstract/childhood-onset-takayasu-arteritis-associated-with-mutations-in-cbl/. Accessed September 30, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/childhood-onset-takayasu-arteritis-associated-with-mutations-in-cbl/