Lipopolysaccharide Responsive Beige-like Anchor Protein Deficiency in a Patient with Autoimmune Lymphoproliferative Syndrome-like Disease Phenotype: A Case Report and Literature Review

Abstract

LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by a mutation in the LRBA gene. Affected individuals present with a variety of clinical symptoms including hypogammaglobulinemia, recurrent infections, splenomegaly, hepatomegaly, and autoimmune cytopenias. Except for hypogammaglobulinemia, the remaining features resemble autoimmune lymphoproliferative syndrome (ALPS). Here, we report the case of a 14-year-old boy with the ALPS phenotype, eventually diagnosed with LRBA deficiency. He presented with lymphadenopathy and hepatosplenomegaly, along with autoimmune cytopenia. Due to recurrent infections and worsening gastrointestinal symptoms, whole-exome sequencing was conducted and revealed a novel homozygous pathogenic variant in the LRBA gene (c.534del; p.9Asp179IIef*16). The patient recently suffered from clinical deterioration due to SARS-COV-2 which appears to have triggered an acute worsening of his existing Cytomegalovirus colitis leading to an eventual demise. A literature search for reported LRBA deficient patients with ALPS-like phenotype revealed 11 patients. The most common clinical presentations in LRBA patients with ALPS-like phenotype included autoimmunity (100%), splenomegaly (91%), lymphadenopathy (36.4%), and respiratory tract infections (63.6%). LRBA deficiency is unique in the fact that it encompasses immune deficiency, autoimmunity, and lymphoproliferation. In children with multiple symptoms related to these domains, a genetic diagnosis is necessary to ensure tailored and precise medical therapy.

Severity of SARS-CoV-2 infection in children with inborn errors of immunity (primary immunodeficiencies): a systematic review

“…Immune dysregulatory diseases were the fourth most-common IEIs in children who experienced COVID-19 (n = 95, 13.4%) [ 6 , 9 , 19 , 29 , 32 , 35 , 38 , 40 , 43 , 44 , 46 , 48 , 50 , 52 , 54 , 57 , 58 , 62 , 63 , 65 , 67 , 72 – 74 , 79 , 81 , 82 , 84 , 86 , 88 , 93 – 97 , 99 , 100 , 102 , 109 , 110 , 113 , 115 , 118 , 121 , 125 , 130 ] (see Additional file 2 : Table S3). Among them, 25 have familial hemophagocytic lymphohistiocytosis (26.3% of all immune dysregulatory diseases) [ 6 , 19 , 29 , 48 , 62 , 65 , 67 , 72 , 73 , 79 , 81 , 82 , 84 , 88 , 99 , 110 , 125 ], 19 have autoimmune polyendocrine syndromes type-1 (APS-1) (20%) [ 35 , 38 , 73 , 86 , 94 , …”

“…The remaining 13 patients have NOTCH1 mutation (n = 1) [ 19 ]; ALPS-Caspase10 (n = 1) [ 19 ]; CD137 deficiency (n = 1) [ 73 ]; interleukin-37 deficiency (n = 1) [ 19 ]; IPEX syndrome (n = 1) [ 93 ]; prolidase deficiency (n = 1) [ 62 ]; PRKCD deficiency (n = 1) [ 95 ]; MAGT1 deficiency (n = 1) [ 99 ]; and unspecified immune dysregulatory disease (n = 5) [ 40 , 46 , 52 , 63 ]. The most frequent main genetic causes of immune dysregulatory diseases in children infected with SARS-CoV-2 were AIRE (n = 19) [ 35 , 38 , 73 , 86 , 94 , 102 , 113 ], LRBA deficiency (n = 6) [ 57 , 58 , 115 , 125 ], PRF1 (n = 6) [ 74 , 125 ], TPP2 (n = 5) [ 118 , 121 , 125 ], LYST (n = 4) [ 65 , 84 , 99 , 125 ], XIAP deficiency (n = 4) [ 43 , 65 , 95 , 100 ], SH2D1A deficiency (n = 4) [ 44 , 54 , 81 , 109 ], STXBP2 (n = 3) [ 19 , 73 , 125 ], UNC13D (n = 2) [ 19 , 125 ], SOCS1 deficiency (n = 2) [ 9 , 96 ], CTLA4 deficiency (n = 2) [ 32 , 95 ], and IL10RA deficiency (n = 2) [ 74 , 125 ]. For patients with immune dysregulatory diseases who acquired SARS-CoV-2, the median interquartile range (IQR) age was 108 months [60 to 168], with a male predominance [n = 55, 57.9%] [ 6 , 9 , 19 , 32 , 35 <...…”

“…The most frequent main genetic causes of immune dysregulatory diseases in children infected with SARS-CoV-2 were AIRE (n = 19) [ 35 , 38 , 73 , 86 , 94 , 102 , 113 ], LRBA deficiency (n = 6) [ 57 , 58 , 115 , 125 ], PRF1 (n = 6) [ 74 , 125 ], TPP2 (n = 5) [ 118 , 121 , 125 ], LYST (n = 4) [ 65 , 84 , 99 , 125 ], XIAP deficiency (n = 4) [ 43 , 65 , 95 , 100 ], SH2D1A deficiency (n = 4) [ 44 , 54 , 81 , 109 ], STXBP2 (n = 3) [ 19 , 73 , 125 ], UNC13D (n = 2) [ 19 , 125 ], SOCS1 deficiency (n = 2) [ 9 , 96 ], CTLA4 deficiency (n = 2) [ 32 , 95 ], and IL10RA deficiency (n = 2) [ 74 , 125 ]. For patients with immune dysregulatory diseases who acquired SARS-CoV-2, the median interquartile range (IQR) age was 108 months [60 to 168], with a male predominance [n = 55, 57.9%] [ 6 , 9 , 19 , 32 , 35 , 40 , 43 , 44 , 46 , 50 , 54 , 57 , 58 , 62 , 63 , 65 , 72 , 73 , 79 , 82 , 88 , 93 – …”

“…For patients with immune dysregulatory diseases who acquired SARS-CoV-2, the median interquartile range (IQR) age was 108 months [60 to 168], with a male predominance [n = 55, 57.9%] [ 6 , 9 , 19 , 32 , 35 , 40 , 43 , 44 , 46 , 50 , 54 , 57 , 58 , 62 , 63 , 65 , 72 , 73 , 79 , 82 , 88 , 93 – 95 , 99 , 100 , 102 , 109 , 113 , 115 , 125 , 130 ], and majority of the patients belonged to White (Caucasian) (n = 53, 55.8%) [ 6 , 9 , 32 , 35 , 38 , 43 , 46 , 50 , 52 , 62 , 63 , 67 , 73 , 81 , 82 , 84 , 86 , 94 , 95 , 97 , 100 , 109 , 110 , 113 , 115 , 118 ], Black (n = 12, 12.6%) [ 79 , 93 , 125 ] and Persian (n = 10, 10.5%) [ 19 , 48 , 54 , 74 , 88 ] ethnicity. In those immune dysregulatory diseases...…”

“…In those immune dysregulatory diseases patients, few studies reported on specific allele changes (n = 15, 15.8%) [ 32 , 35 , 38 , 58 , 62 , 84 , 86 , 94 , 96 , 99 , 100 , 109 , 113 , 121 , 125 ]. Reported modes of inheritance for the immune dysregulatory diseases in children were autosomal recessive (n = 64, 67.4%) [ 6 , 19 , 29 , 35 , 38 , 48 , 57 , 58 , 62 , 65 , 67 , 72 – 74 , 79 , 81 , 82 , 84 , 86 , 88 , 94 , 95 , 99 , 102 , 110 , 113 , 115 , 118 , 121 , 125 ], X-linked (n = 10, 10.5%) [ 43 , 44 , 54 , 65 , 81 , 93 , 95 , 99 , 100 , 109 ], or autosomal dominant (n = 7, 7.4%) [ 9 , 19 , 32 , 35 , 95 , 96 ], however, mode of inheritance in these immune dysregulatory diseases cases was unknown in a high percentage of patients (n = 14, 14.7%) [ 40 , 46 , 50 , …”