Multi-organ disease associated with nfkb1 mutation

SESSION TITLE: Genetic and Developmental Disorders Global Case Report Posters 1 SESSION TYPE: Global Case Reports PRESENTED ON: 10/10/2023 12:00 pm - 12:45 pm INTRODUCTION: A 36-year-old female with a history of chronic axonal neuropathy and liver cirrhosis of unclear etiology presented to the emergency department with leg weakness and acute hypoxic respiratory failure with diffuse ground glass opacities. She had a prolonged hospital course with multiple intubations, and an extensive infectious and rheumatologic workup was unrevealing for a unifying diagnosis. She was treated with antibiotics, steroids and IVIG and ultimately improved. Whole genome sequencing revealed a NFKB1 gene mutation associated with common variable immunodeficiency (CVID). CASE PRESENTATION: A 36-year-old female with a history of chronic axonal neuropathy, liver cirrhosis, pancreatic cystic lesions and macrocytic anemia presented to the emergency department with complaints of acute onset lower extremity weakness for several days. In the emergency department she was found to have severe sepsis with acute hypoxic respiratory failure, enterocolitis, and acute on chronic liver failure. Her respiratory status worsened and she required intubation.Computed tomography showed ground glass and reticular opacities throughout the parenchyma. She underwent bronchoscopy with cultures that were negative for bacteria, AFB and fungus, and had a negative viral panel. Bronchoalveolar lavage cell differential showed elevated neutrophils. She had markedly elevated ESR and CRP but an extensive rheumatological workup was unrevealing, including normal immunoglobulin levels, negative ANA, and negative myositis panel.Magnetic resonance imaging (MRI) of her brain showed diffuse cerebral volume loss greater than expected for age. Electromyography (EMG) showed worsened chronic diffuse sensorimotor axonal neuropathy. A sural nerve biopsy confirmed the same finding.Due to difficulty weaning respiratory support, and multiple failed attempts at extubation, she underwent tracheostomy one month into her hospitalization. She was then started on high dose steroids with marked improvement in her hypoxemia and pulmonary infiltrates. Although anti-ganglioside antibodies were negative for Guillian-Barre, a decision was made to treat with IVIG since she had responded well in the past. She received 3 days of IVIG infusions with improvement in her weakness and respiratory status.Given her constellation of idiopathic pulmonary infiltrates, neuropathy, and liver disease, there was concern for an underlying genetic abnormality. Low serum high-density lipoprotein (HDL) and apolipoprotein A1 raised concern for Tangier disease, but genetic testing was negative. The patient ultimately underwent whole genome sequencing which revealed a missense mutation in the NFKB1 gene c.2742G>T, which is associated with common variable immunodeficiency (CVID) type XII with autoimmunity. DISCUSSION: Our report describes a patient who presented with multiorgan failure who was ultimately found to have a NFKB1 gene mutation. Background mutations in NFKB1 (nuclear factor of kappa light polypeptide gene enhancers in B cells) are associated with a variety of clinical presentations including lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, arthralgia, recurrent respiratory tract infections (1). It is also associated with increased risk of cardiovascular disease and malignancies (2). Peripheral neuropathy has been associated with CVID but is a rare complication with only several cases documented (3). CVID is treated with IVIG, corticosteroids, and immunotherapy (1). Our patient ultimately responded to high dose steroids and IVIG, and was discharged to rehab. CONCLUSIONS: NKBI mutation is associated with CVID REFERENCE #1: Mandola, A., Sharfe, N., Nagdi, Z., Ngan, B., & Roifman, C. (2020). Combined immunodeficiency caused by a novel homozygous NFKB1 mutation. The Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2020.08.040 REFERENCE #2: Czauderna, C., Castven, D., Mahn, F.L., Marquardt, J.U (2019). Context Dependent Role of NF-κB Signaling in Primary Liver Cancer—from Tumor Development to Therapeutic Implications. Cancers 2019, 11, 1053. https://doi.org/10.3390/cancers11081053 REFERENCE #3: Long, C. P., Suzuki, H., & Vitale, K. (2019). Peripheral Neuropathy Due to Common Variable Immunodeficiency: Case Report and Narrative Review. Gerontology & geriatric medicine, 5, 2333721419850644. https://doi.org/10.1177/2333721419850644 DISCLOSURES: No disclosure on file for Easa Al-Ghandour No relevant relationships Added 12/04/2022 by Shambhu Aryal, source=Web Response, value=Consulting fee Removed 03/30/2023 by Shambhu Aryal, source=Web Response No relevant relationships by Tiffany Ghafouri No disclosure on file for Vikramjit Khangoora No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Honoraria Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Honoraria Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Christopher King, value=Consulting fee Removed 12/02/2022 by Christopher King, source=Web Response No relevant relationships by Nicholas Montano No relevant relationships by Anju Singhal No relevant relationships by Megan Terek No relevant relationships by Christopher Thomas No relevant relationships by VAUGHAN WASHCO No disclosure on file for Fasika Weldearegay No relevant relationships by Sharon Zhao