Our patient is an 8-year-old female who presented at five years of age with two months history of fever, erythematous rash over the forehead, fatigue, and poor appetite. The parents are consanguineous, and two siblings have a history of seizure disorder in the presence of normal brain MRI. Weight was on the 5th percentile, and height was below the 5th percentile. Physical examination showed enlarged and tender lymph nodes in the right anterior cervical and right inguinal areas with no hepatosplenomegaly. CBC showed pancytopenia with WBC 2.1 x 109/L, ANC 0.9 x 109/L, ALC 1.1 x109/L, Hb 6.8 g/dl, MCV 80 fl (normal 77-85), and platelet 67 x 109/L. The reticulocyte production index was 0.2%. A peripheral blood smear was significant for increased schistocytes, bilobulation of some neutrophils, few reactive lymphocytes, and occasional giant platelets. ESR was 17 mm/h, and CRP was 7 mg/L. PT and aPTT were normal. There was an increase in ALT (187 units/L, normal 20-65) and AST (318 units/L, normal 15-37). Otherwise, liver function tests were unremarkable. LDH was >1,000 units/L (normal 84-246). Fibrinogen was slightly low, 1.9 g/L (normal 2-4), and ferritin was >2,000 mcg/L. Triglycerides was 2.37 mmol/L (normal 0.34-1.13). The metabolic panel showed mild hypocalcemia 1.87 mmol/L (normal 2.1-2.55), hypophosphatemia 1.42 mmol/L (normal 1.45-1.78), normal urea and creatinine, and urine examination was normal. Immunoglobulin levels were normal, and quantitative lymphocyte subsets showed a slight decrease in B-cell 334/ul (normal 400-800/ul), and NK-cell 105/ul (normal 200-400/ul). ANA was 1:160 fine speckled with normal C3 and C4. Hemoglobin electrophoresis and G6PD level were normal. The infectious disease workup was negative which included negative blood and urine cultures, negative serology for CMV, EBV, HIV, HBV, and HCV, negative brucella culture, negative aspergillus galactomannan, and negative Quantiferon test for tuberculosis. Bone marrow examination showed hypocellular marrow with a marked increase in histiocytes, occasional hemophagocytic activity, and markedly reduced granulopoiesis. Echocardiogram was normal. Ultrasound abdomen showed mildly swollen kidneys with a mild increase in cortical echogenicity. The patient was diagnosed with hypothyroidism and was started on levothyroxine.
The fever persisted despite broad-spectrum antibiotics (piperacillin-tazobactam and amikacin) and anti-fungal therapy (amphotericin B). There were intermittent episodes of hypertension (maximum 138/84 stage II). Neurological assessment was normal. The ophthalmology exam was normal. A brain computerized tomography scan was performed because of headache. It showed a faint subcortical calcification at right frontal lobe and almost symmetrical calcification within the basal ganglia. Brain magnetic resonance imaging showed bilateral symmetrical globus pallidus, high T1 signal intensities, and a few scattered nonspecific fluid attenuated inversion recovery (FLAIR) hyperintensities in subcortical and deep white matter. There was mild generalized brain atrophy, Figure 1. The patient fulfilled the modified criteria of HLH 2009 but did not fulfill the diagnostic criteria for HLH-2004; only four criteria were present: fever, pancytopenia, Ferritin >= 500 mcg/L, and hemophagocytic activity in the bone marrow. However, there was no splenomegaly, triglycerides >=3 mmol/L, or low fibrinogen. NK-cell activity and soluble CD25 were not assessed. Thus, HLH therapy was not started. Nevertheless, immune dysregulation disorder was suspected, and we started IVIG (1 g/kg) as an immune modulating agent was administered starting on day 16 of admission and was repeated regularly every 3-4 weeks. This has led to the resolution of fever, improvement of blood count parameters and normalization of liver enzymes. However, the ferritin level remained relatively high at 735 mcg/L, Figure 2. CBC showed WBC 3.7 x 109/L, ANC 1.5 x 109/L, ALC 1.5 x109/L, Hb 9.9 g/dl, and platelet 306 x 109/L. The reticulocyte count was 2.1%. ALT was (56 units/L) and AST (was 79 units/L). The patient was discharged in stable condition with a plan to administer IVIG monthly. The child remained afebrile with no significant events for six months, then was again admitted with fever (38-39 C), oral ulcers, pancytopenia, ferritin >2,000 mcg/L, LDH >1,000 unit/L, ALT 147 units/L, AST 508 units/L, and normal fibrinogen. The infectious disease workup was again negative. The patient was started on pulse methylprednisolone 30 mg/kg for three days given the concerns of secondary HLH due to autoinflammatory disorder, then continued on 2 mg/kg. Subsequently, whole exome sequencing (WES) was requested given the concern of inherited immune dysregulation disorders or HLH which revealed a novel heterozygous missense TREX1 mutation NM_016381.3:c.223G > A p.(Glu75Lys) which is located in N-terminal catalytic domain and this amino acid change is predicted to impact the protein stability. This variant was not reported in the genome aggregation database, exome sequencing project, and 1,000 genome project. In silico prediction was performed to assess the effect of this variant; it is predicted to be pathogenic by Align-GVGD C55 and disease-causing by MutationTaster. Thus, a diagnosis of autosomal dominant TREX1-related disorder such as AGS was considered, and the patient was started on ruxolitinib, 5 mg orally twice daily as an emerging treatment option for interferonopathies. Steroids were tapered off, and the patient is no longer on IVIG for more than one year, Figure 2. The patient is still on ruxolitinib for more than two years. Most recent blood work while on ruxolitinib showed CBC: WBC 4.7 x 109/L, ANC 1.8 x 109/L, ALC 2.3 x109/L, Hb 12.8 g/dl, and platelet 438 x 109/L. Ferritin 90 mcg/L. Interferon signature was not measured. During treatment with ruxolitinib, no signs of autoinflammation were observed. The treatment was well tolerated, with no serious side effects. Segregation analysis of the family was not performed based on parental preference.