Interstitial cystitis caused by immune dysregulation in LRBA deficiency: one among the rare urological manifestations in inborn errors of immunity

Inborn errors of immunity (IEI) rarely present with associated urological manifestations. Chronic cystitis and urethritis caused by ureaplasma and mycoplasma infection in hypogammaglobulinemia may result in bladder fibrosis. Papovaviridae such as BK or JC, can cause hemorrhagic cystitis in patients with T cell defects. Bladder granulomtata and urethral strictures can occur in chronic granulomatous disease. This is the first reported case of severe lymphocytic interstitial cystitis in a patient with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency. LRBA deficiency is known to impair CTLA-4 recycling, leading to decreased Treg cell function. A 13 year old male refugee presented with chronic recurrent debilitating suprapubic pain and dysuria, which progressed to extreme urinary frequency. He had a prior history of recurrent aseptic urinary tract infections, and one episode of gross hematuria. Extensive infectious investigations of urine (bacterial, mycobacterial cultures; viral PCRs), blood, and stool (Schistosoma) failed to isolate a pathogen. Bladder biopsy was positive for EBV by PCR but blood remained EBV-negative. Urinalysis showed microscopic hematuria while urodynamic studies were normal, and cystoscopy showed bladder and urethral irritation. Pathology confirmed lymphocytic interstitial cystitis, with primarily T cell infiltration. Immunological investigations revealed low IgG, IgA and IgM levels, B lymphopenia (1%), with low class-switched memory B cell development (3%) and absent response to protein and polysaccharide vaccine antigens. There were no signs of autoimmunity. Parents are consanguineous, and a sibling was likewise diagnosed with LRBA deficiency. Sanger sequencing of DNA confirmed the same homozygous family mutation in the LRBA gene, a likely pathogenic splice donor variant, c.2258+2T>G. The patient was started on immunoglobulin replacement. Trials of analgesics including NSAIDs, gabapentin, and morphine, and immunosuppression with corticosteroids and sirolimus, were unsuccessful in reducing urinary symptoms. Physiotherapy and antispasmodics were introduced when pelvic-floor dyssynergia with rectal pain developed. Subsequently-presenting enteropathy was managed with Abatacept (CTLA-4 IgG1 fusion protein), ultimately improving bladder symptoms after several months of therapy. Patient has since undergone HSCT and is now free of urinary tract symptoms. LRBA deficiency presents with hypogammaglobulinemia, infections, and immune dysregulation presenting with lymphocytic infiltration of non-lymphoid organs. This report highlights the phenotypic diversity of this disease.