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.