2019 CIS Annual Meeting: Immune Deficiency & Dysregulation North American Conference: (151) Submission ID#601626: A 29-year-old Woman with History of Hypogammaglobulinemia and Acute Liver Failure

A 29-year-old woman with a 7-month history of nausea, vomiting, and abdominal pain was admitted to an outside hospital with new onset of jaundice and anasarca. Liver biopsy was thought most consistent with alcoholic steatohepatitis, and she was discharged with counseling on alcohol cessation and medical management of liver disease. She presented to our facility for a second opinion. Over the following days, she developed further rise in direct hyperbilirubinemia up to 19.2 mg/dL, new coagulopathy with an INR 2.06 and hypoalbuminemia to 1.7 mg/dL in the absence of ongoing alcohol consumption. Liver sonography revealed course echotexture and patent vessels. PCRs directed against multiple hepatotropic viruses were negative and copper studies were normal. Due to a history of moderate alcohol consumption, she was started on high-dose corticosteroids due to a presumptive diagnosis of alcoholic hepatitis. Additional history raised concern for a possible primary immunodeficiency, including idiopathic thrombocytopenic purpura at 11 years of age, multiple episodes of sinusitis treated with antibiotics and sinus surgery, one episode of suspected bacterial pneumonia, and one hospitalization for influenza A during which she developed neutropenia. In her 20s, she developed refractory genital warts, prompting infectious diseases evaluation. Initial immune evaluation had revealed low immunoglobulins (IgA <7 mg/dL, IgG 198 mg/dL, IgM 13 mg/dL) with very low responses to tetanus and diphtheria, despite a recent booster dose, and B and T cell lymphopenia (CD19+ 89 cells/μL, CD3+ 567 cells/μL, CD4+ 345v, CD 8+ 244 cells/μL, CD16/56+ 236 cells/μL); antigen and mitogen proliferation were not assessed. Intravenous immunoglobulin replacement was initiated but discontinued by the patient due to infusion-related adverse effects, and she was lost to follow up until she presented with liver failure. Both parents were deceased from cardiovascular disease in their 40s and she had no siblings. She had limited knowledge of family history but no known immune diseases. Due to suspicion for genetic etiology of immune disorder and liver disease, we performed next-generation sequencing of a panel of over 200 genes implicated in primary immune deficiencies. Patient was heterozygous for a nucleotide substation (c.1752+1G>A) within a splice site at the exon 16/intron 16 boundary of the NFKB1 gene. During the hospitalization, immunoglobulin replacement and trimethoprim-sulfamethoxazole prophylaxis were initiated. An attempt was made to refer the patient for additional immunological evaluation and transplantation evaluation but unfortunately, she developed worsening liver failure and multiple complications, including extended-spectrum beta-lactamase (ESBL)-producing E. coli bacteremia, hypotension requiring vasopressors and extensive bowel ischemia, and died in the hospital. In summary, this case highlights both the risk of diagnostic delay in adult patients presenting with a primary immune deficiency and potential for genetic testing to clarify the diagnosis. While the particular genetic change has not been described, other splice site and predicted loss-of-function mutations have been reported as pathogenic in this gene, which have been implicated in autosomal dominant common variable immunodeficiency. This case further expands on the genetic causes and spectrum of disease associated with changes in the NFKB1 gene.