Identification of compound heterozygous LRBA variants associated with Pneumocystis Jirovecii pneumonia and toxoplasmosis

ABSTRACT Background: Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency is an autosomal recessive primary immunodeficiency disorder, OMIM #614700. The LRBA protein is crucial for immune regulation, receptor recycling, and autophagy. LRBA deficiency is linked to various clinical manifestations, including autoimmunity, lymphoproliferation, and humoral immune deficiency. Aim: To describe the clinical course and diagnosis of a patient identified with LRBA deficiency. Methods: A thorough review of the patient’s medical chart was performed. Results: We report the case of a 42-year-old female born prematurely and diagnosed with Bartter syndrome, with features of immune dysregulation presenting during childhood, manifesting as recurrent bacterial and viral sinopulmonary infections, lymphadenopathy, pancytopenia, and atopy. Her clinical status deteriorated in adulthood with multi-organ involvement, including granulomatous lymphocytic interstitial lung disease, progressive hepatosplenomegaly with resultant portal hypertension; acute on chronic kidney disease with nephrocalcinosis; and severe immune dysfunction characterized by low T and B cells, recurrent bacterial, fungal and viral infections and susceptibility to opportunistic infections including Candida, Pneumocystis jirovecii and Toxoplasma gondii. Research-based analysis of the patient's clinical exome identified 2 variants in the LRBA gene, a rare missense c.6697G>A (p.Ala2233Thr) change and a novel intronic splice site c.4005-210G>C (p.?) change strengthening the acceptor splice site of a pseudo-exon, classified as variants of unknown significance. In addition to her genetic findings pertaining to Bartter syndrome (SLC12A1: c.596G>A (p.Arg199His), and c. 1543 G>T (p.Ala515Ser)), a heterozygous variant of uncertain significance in NOD2, c.866A>G (p.Asn289Ser), was identified. A positive pathogenic heterozygous mutation in DOCK8 was found, although follow-up functional testing for DOCK8 expression did not confirm a DOCK8 deficiency, with adequate expression of DOCK8 protein in T and NK cells. Based on the LRBA genetic variants identified by exome sequencing, add-on therapy with abatacept, a recombinant cytotoxic T lymphocyte-associated protein 4 (CTLA4) fusion protein, was initiated as a targeted therapy for LRBA deficiency. Conclusion: This case expands our knowledge of the clinical manifestations of LRBA deficiency and the potential associations across the spectrum of immune dysregulation. Early incorporation of genetic sequencing into the diagnostic evaluation, may play a beneficial role in early diagnosis and treatment, particularly in individuals at risk for life-threatening immunodeficiencies and rare disorders.