Case presentation:
Patient X is the index case, previously healthy 18 months old female,
the first child of healthy Saudi consanguineous parents, presented to
our Emergency Department with a five-day history of high-grade fever,
associated with diarrhea development lethargy, an anal lesion. Fever
reached a Tmax of 39 Celcius and was partially responsive to
antipyretics. Family History was positive for two childhood deaths at
two years of age, with fever of unknown origin from the paternal side.
One family member on the paternal side required intravenous
immunoglobulin with an unknown cause—positive maternal family history
of Behçet’s disease.
Physical Examination revealed a normal child with no findings apart from
the presence of oral aphthous ulcers along buccal mucosa and an anal
lesion, described to be 1cm x 1cm regular erythematous painless papule.
The child underwent diagnostic workup and the initial investigations
showed neutropenia and leukopenia, with white blood count (WBC) 4.58
10e9/L (reference range 4-11 10e9/L), ANC: 0.13 10e9/L, Hemoglobin: 10
g/dl, Platelet 154 10e9/L. Inflammatory markers showed increased CRP
148, ESR 120. Blood, urine, and cerebrospinal fluid cultures were
negative.
Throughout her hospital stay, fever persisted at four hourly intervals
reaching a T max of 40 Celsius for three months. Anal lesion progressed
to enlarge and was complicated by cutaneous perianal fistula formation
at 2’oclock and 9oclock position associated with exudative discharge.
Exudative discharge grew Pseudomonas and Escherichia coli. Multiple
Aphthous ulcers proceeded to develop in oral mucosa; oral scrapings
showed growth of candida tropicalis. Diarrhea progressed to include
hematochezia and blood clot passage requiring multiple blood
transfusions.
The patient continued to be persistently neutropenic 0 - 0.35,
leukopenic 0.22- 4.92, with thrombocytopenia development. Inflammatory
markers remained elevated CRP 310 – ESR 120 ferritin 15141. The
coagulation profile remained normal. Antinuclear antibodies (ANA) and
anti-double-stranded DNA (anti-dsDNA) were negative. Immunoglobulin
levels IgG 3.87 (2.9-10.7 g/L ), IgA 0.28 (0.40-1.20) and IgM 0.2
(0.3-1.5) remained unaffected along with post-vaccination titers.
Oxidate burst test was resulted negative. Extensive workup for virology,
fungemia, and mycobacterium all remained negative. C3 and C4 complement
factors were within the normal range.
The perianal abscess was complicated by growth in size; and failure of
formation of granulation tissue. Initially, stool for occult blood
resulted positive, with the development of microcytic hypochromic
anemia. Abscess depth progressed to involve vascular beddings resulting
in hematochezia and fresh blood passage. Hemoglobin reached a low of
4mg/dl, requiring multiple blood transfusions and fresh frozen plasma
(FFP). The Source of bleeding was not identified on a clinical basis.
Mickell’s scan resulted in being negative as well as RBC technetium
scan. Ultrasound was done, which was negative for intussusception and
organomegaly. Endoscopy, and colonoscopic findings from the rectum to
ascending colon were normal.
Intervention for neutropenia included methylprednisolone 10 mg/kg and
intravenous immunoglobulin therapy with no response. A trial of
Granulocyte colony-stimulating factor (GCSF) was initiated. She received
a continuous infusion of GCSF 200 units for one month, with a lack of
response. Furthermore, a trial of Human Leukocyte antigen typing was
performed on both parents for future bone marrow transplant (BMT).
Bone Marrow Aspiration was performed, showing hypocellular bone marrow
(50% cellularity), myeloid aplasia and extensive histiocytic
proliferation with significant hemophagocytosis. Flow cytometry was
performed on bone marrow aspirate showing severe lymphocytopenia
(absolute including all lymphocyte subsets (B-,T-, NK-). The overall
findings suggestive of primary or secondary immunodeficiency due to bone
marrow suppression.
Blood passage was daily with the presence of clots; about 50 ml. At the
time, fever continued, and tachycardia developed to reach a heart rate
of 200 bpm. The patient was admitted under the care of the Pediatric
Intensive Care Unit (PICU). Platelets declined to reach 1, despite
multiple trials of platelets transfusion, as well as continuous
infusion. After a multi-disciplinary meeting was conducted (involving
general pediatrics, immunology, hematology-oncology, infectious
diseases, gastroenterology, Rheumatology, Pediatric surgery, Pathology,
PICU), it was agreed upon to initiate a trial of Anakinra 10 mg/kg
interleukin (IL-1 receptor agonist); fever subsided for two days and
resumed. A chimeric monoclonal antibody, infliximab, was given with no
satisfactory outcome.
Whole Exome Sequencing demonstrated a homozygous pathogenic variant of
the ADA2 gene suggesting VIAHS. Persistent massive peri rectal bleeding
and tachycardia continued for a duration of two months. Cardiac ejection
fraction was reduced; she was started on inotropic support and
supportive management. She proceeded to develop acute kidney injury,
liver injury with abdominal distention. Respiratory status declined
secondary to abdominal compartment syndrome, and she was placed on
maximum respiratory support. Despite all interventions, the patient
arrested.