DISCUSSION
A mutation in the LRBA gene that encodes LRBA protein causes an autosomal recessive monogenic disorder named LRBA deficiency. The individuals that Lopez-Herrera et al. investigated, presented variable symptoms and phenotypes including recurrent infections, hypogammaglobulinemia, lymphadenopathy and hepatosplenomegaly, lymphoid follicular hyperplasia, granulomatous infiltration of the brain, chronic lung disease with bronchiectasis and obstruction of the small airways, recurrent chronic diarrhea (IBD-like syndrome), autoimmunity (idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), hypothyroidism, myasthenia gravis, and autoimmune enteropathy), allergic and inflammatory diseases (such as allergic dermatitis, asthma, and arthritis) and growth retardation (failure to thrive). They demonstrated that individuals with homozygous LRBA mutations could not produce any LRBA. They had severe defects in B cell development and activation and in plasmablast formation, reduced counts of switched-memory B cells, impaired immunoglobulin secretion, low proliferative responses, increased susceptibility to apoptosis, and severe defects in autophagy. All of these characteristics are associated with a clinical phenotype of early-onset hypogammaglobulinemia (reduced levels of at least two immunoglobulin isotypes (IgM, IgG, or IgA)) accompanied by autoimmunity in homozygous individuals. All heterozygous individuals in this study were healthy. Accordingly, they proposed that LRBA has unanticipated functions in B cells, which are essential for normal development and humoral immune responses 1.
Several novel mutations in the LRBA gene have been identified and reported in many cases of PID as well as in other disorders without hypogammaglobulinemia, since Lope-Herrera’s study 15. Liphaus et al. introduced a new LRBA mutation that was associated with Juvenile Systemic Lupus Erythematous (JSLE) 16. In another study, LRBA deficiency was reported in a patient with Juvenile Idiopathic Arthritis (JIA) and immune dysregulation17. Charbonnier et al. identified a loss of function mutation in LRBA in a patient who presented with Immune dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX)-like syndrome, and Severe TR cell deficiency. They proposed that LRBA deficiency results in depressed suppressive function and increased apoptosis of TR cells 18. Akarcan et al. also reported a novel LRBA mutation in two male siblings with IPEX syndrome 19. Another study performed by Taylan et al. in 2020 revealed LRBA deficiency in a patient with end-stage renal disease 20. Some other studies reported novel mutations in LRBA associated with Type 1 diabetes mellitus (T1DM) and immune dysregulation 21,22.
A study in 2015 showed LRBA’s interaction with the cytoplasmic tail of CTLA4 that protects and prevents CTLA4 from being degraded by the lysosomes 14. Therefore, a deficit in LRBA leads to a deficit in CTLA4. In addition, an autosomal dominant disorder caused by a heterozygote mutation in the CTLA4 gene called CTLA4 Haploinsufficiency with Autoimmune Infiltration (CHAI) has similar symptoms with LRBA deficiency, but LRBA deficiency causes lower levels of CTLA4, earlier onset of the disease and more severity than CHAI23. Different clinical and immunological characteristics have been found in more than 70 patients with LRBA deficiency, including hypogammaglobulinemia, autoimmune disorders, chronic diarrhea, recurrent infection, and organomegaly1,13,15.
Pulmonary manifestations of CTLA4 haploinsufficiency and LRBA deficiency have been compared. LRBA deficiency has been shown to be associated with more severe forms of pulmonary disease in terms of pulmonary symptoms, radiological findings and pulmonary function test (PFT)s. Cough was the most common respiratory symptom and more common in LRBA deficiency. Also, abnormalities in PFT and CT scan findings (mediastinal lymphadenopathy, bronchiectasis, and ground-glass opacification) were more frequent in LRBA deficiency 24.
In patients with LRBA deficiency, a history of infectious complications (with pneumonia and respiratory tract infections being the most common), autoimmunity (mostly autoimmune cytopenia) with early-onset hypogammaglobulinemia, and enteropathy must be considered. The mean age at which the first symptoms present and the time until diagnosis in LRBA deficiency cases is variable. In this study, we introduced a patient with the first manifestation of the disease and final diagnosis at the age of 5 and 9 years old, respectively. This patient presented with arthritis at first and then she developed pneumonia at the age of 8 with pulmonary consolidation on her chest X-ray at the time. In laboratory tests, low levels of Hb and also low levels of IgG, IgM, and IgA were found, which is suggestive of CVID. WES was ordered and DNA was extracted from whole blood. Analysis of exome data showed TCF3and LRBA as possible candidates that could explain the clinical history mentioned above.
The TCF3 gene has been reported to be associated with agammaglobulinemia in previous studies, whereas the LRBA gene was shown to be related to CVID with autoimmunity. Based on the clinical and paraclinical data in this patient, which is most compatible with CVID, the LRBA variant seems to be the responsible gene causing symptoms in this patient. However, further analysis including parental genotyping of the variant detected in TCF3 is essential in order to make a definitive conclusion. The presence of this variant in the asymptomatic parent(s) strongly supports the benign nature of the variant while confirming a de novo nature is in favor of its pathogenicity, which should be followed by further investigation.
Regarding the presence of hypogammaglobulinemia despite the normal number of total circulating B cells (CD19+), further analysis of memory B cells with flow cytometry could elaborate on whether hypogammaglobulinemia in this patient is due to a defect in isotype-switching (reduction of class-switched CD27+IgM-IgD- memory B cells) of memory B cells or not.