Case Description
Our index child was a sixth-order child born to a third-degree
consanguineous couple with a birth weight of 3 kg. Two female siblings
succumbed to severe sepsis and meningitis before 1 year of age. A male
sibling had a history of recurrent episodes of severe anemia requiring
blood transfusion since the age of 18 months and finally succumbed by 2
years of age. The index child presented to us at 15 months of age with a
stormy infantile period with recurrent episodes of lower respiratory
tract infection, persistent diarrhea and failure to thrive since 9
months of age. None of the signature organisms pertaining to
immunodeficiency could be isolated during the evaluation of these
episodes. There was no organomegaly, lymphopenia, thrombocytopenia or
neutropenia. As part of workup for
failure to thrive, a duodenal biopsy was performed through upper
gastrointestinal endoscopy, which revealed features consistent with
eosinophilic enteritis. The colonic biopsy also revealed similar
results. Evaluation for immunodeficiency disorders was performed at 18
months of age. Lymphocyte subset analysis by flow cytometry revealed:
absolute lymphocyte count- 2700/µL, helper T cells-12% (322/µL),
cytotoxic T cells-43% (1154µL), B cells-7% (188/µL), NK cells-14%
(376/µL). Serum immunoglobulin evaluation by nephelometry showed:
IgG-18.6 g/L, IgM- 1.01g/L, IgA- <0.246g/L, IgE-
<4.4 IU/mL. Thus, the helper T cell count and serum
immunoglobulin A levels were reduced for his age. Human immunodeficiency
virus (HIV) ELISA was negative. A possibility of combined
immunodeficiency or Common Variable Immunodeficiency (CVID) was
considered. However, further evaluation for immunodeficiency could not
be performed as the child was lost to follow-up.
The child presented again at four years of age with severe pallor
(hemoglobin 3.6 gm/L) and congestive cardiac failure. There was
significant failure to thrive and hepatosplenomegaly. His mother
reported intermitted episodes of persistent diarrhea and
bronchopneumonia in the last three years, which were managed
conservatively by his primary care physician. There were features
suggestive of intravascular hemolysis (spherocytes in peripheral smear,
hemoglobinuria, elevated reticulocyte count and indirect
hyperbilirubinemia). Direct Coomb’s test was positive for IgG. Evans
syndrome was initially diagnosed in view of severe thrombocytopenia
(9000/µL) and autoimmune hemolytic anemia. The child also had stage-I
hypertension and proteinuria (1+) with low serum C3 levels (42 mg/dL).
Hence, a possibility of SLE was entertained and worked up. Serum
antinuclear antibody (ANA) and anti-double-stranded DNA (dsDNA) were
positive (4+ ). However, the serum albumin (3.3g/dL), serum cholesterol
(122 mg/dL), serum creatinine (0.53 mg/dL) and blood urea (39 mg/dL)
were within normal limits. Renal biopsy (done in view of hypertension
with sub-nephrotic proteinuria) showed evidence of class-II lupus
nephritis. He did not have other systemic manifestations of SLE i.e
cutaneous domain, arthritis, neurological domain, serositis domain,
antiphospholipid antibody domains were all negative. The absence of
cutaneous and neurological manifestations excluded complement
deficiency-induced lupus as our differential diagnosis. EULAR/ACR 2019
criteria to diagnose systemic lupus erythematosus (SLE) were satisfied
(score=25). The child was treated with intravenous methylprednisolone
pulse (30mg/kg/dose) for 3 days followed by oral prednisolone
(2mg/kg/day) with oral mycophenolate mofetil
(925mg/m2) for 4 weeks. Laboratory evaluation
(complete hemogram and urine analysis) after 4 weeks confirmed that the
child was under remission. The dose of prednisolone was tapered
gradually and mycophenolate mofetil was continued with oral
hydroxychloroquine.
During the third month of the steroid taper, there was a hematological
flare of SLE (hemoglobin- 3.3gm/L). Renal function tests and urine
analysis did not reveal any features suggestive of active nephritis. The
anti-ds DNA antibodies were negative. Treatment was initiated with
intravenous methylprednisolone pulses for 3 days and 4 weekly doses of
injection Rituximab (350mg/m2). Tapering dose of oral
prednisolone, mycophenolate mofetil, and hydroxychloroquine were
continued for the next 6 months. He was in clinical remission status
during this period.
Since the index child had presented with features of combined
immunodeficiency disorder initially and features of SLE later, further
evaluation was done to identify the immunodeficiency disorder. Flow
cytometric evaluation for Human Leucocyte Antigen (HLA)-DR expression on
monocytes was performed. 87% of the monocytes expressed HLA-DR antigen
(Fig. 1A and 1B). Whole-exome sequencing by Next Generation Sequencing
(NGS) was performed using the Illumina sequencing platform. The
sequences obtained were aligned to the human reference genome
(GRCh37/hg19) using the Sentieon aligner and analyzed.
Sentieon-haplotype-caller has been used to identify variants that were
relevant to the clinical indication. Gene annotation of the variants was
performed using VEP program against the Ensemble release 91 human gene
model. The NGS testing revealed a heterozygous missense
variation in exon 13 of the CIITA gene
(chr16:g.11004088G>C; Depth:73x) resulting in the amino
acid substitution of Leucine for Valine at codon 94 (p.val954Leu;
ENST00000324288.8). The child was initiated on monthly Intravenous
immunoglobulin (IVIG) replacement therapy, daily cotrimoxazole and
acyclovir prophylaxis for the past one year as a bridge till stem cell
transplantation is performed.