Epstein–Barr virus-related hemophagocytic lymphohistiocytosis complicated with coronary artery dilation and acute renal injury in a boy with a novel X-linked inhibitor of apoptosis protein (XIAP) variant: a case report

Abstract

Background X-linked lymphoproliferative disease (XLP) is a rare inherited X-linked primary immunodeficiency diseases (PID). One such disease, X-linked inhibitor of apoptosis protein (XIAP) deficiency, is characterized by Epstein–Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH). However, EBV-HLH with coronary artery dilation and acute renal injury (AKI) in children is unusual. Case presentation We report the case of a young boy aged 17 months with a novel XIAP variant. He was initially diagnosed with EBV-HLH based on the HLH-2004 diagnostic criteria and the condition was accompanied by coronary artery dilation and acute renal injury. The comprehensive genetic analysis of peripheral blood-derived DNA revealed a hemizygous variant of the XIAP gene [c.116G > C(p.G39A)], which was inherited from his mother (heterozygous condition). After combined treatment with rituximab, intravenous immunoglobulin, corticosteroids, antiviral drugs, and mycophenolate mofetil (MMF) in addition to supportive therapy, his clinical manifestations and laboratory indexes were improved. The patient achieved complete remission with MMF treatment in the 8-month follow-up. Conclusions We report the [c.116G > C(p.G39A)] variant in the XIAP gene for the first time in a case of XLP-2 associated with EBV-HLH. For male patients with severe EBV-HLH, the possibility of XLP should be considered and molecular genetic testing should be used early in auxiliary diagnosis. Reports of EBV-HLH with coronary artery dilation and AKI in children are rare. In the patients with EBV-HLH, color Doppler echocardiography and urine tests should be monitored regularly. If necessary, renal biopsy can be performed to clarify the pathology. Treatment with rituximab, immunosuppressors and supportive therapy achieved a good effect, but long-term follow-up is required.

An efficient diagnosis: A patient with X‐linked inhibitor of apoptosis protein (XIAP) deficiency in the setting of infantile hemophagocytic lymphohistiocytosis was diagnosed using high serum interleukin‐18 combined with common laboratory parameters

“…We previously reported the usefulness of common laboratory markers for early detection of FHL: patients with earlystage FHL have a high total lymphocyte percentage (>50%) on the hematology differential and a high sIL-2R (U/ml):ferritin (ng/ml) ratio (>10 3 ). 2 Our patient, as well as those in other published reports of XIAP deficiency-associated HLH, [16][17][18][19] had a relatively low total lymphocyte percentage and a low sIL-2R:ferritin ratio at presentation, indicating that FHL was less likely. In addition, extremely high serum IL-18 levels (typically >10 4 pg/ml) at the time of HLH flare are only reported in patients with a few specific genetic disorders.…”

Identification of Germline Non-coding Deletions in XIAP Gene Causing XIAP Deficiency Reveals a Key Promoter Sequence

“…X-linked inhibitor of apoptosis (XIAP) deficiency (OMIM #300635), also known as the X-linked lymphoproliferative syndrome type 2 (XLP-2), is a recessive inherited primary immunodeficiency estimated to affect approximately 1-3 males per million, although it may be underdiagnosed. XIAP deficiency is associated with a high risk to develop inflammatory symptoms including hemophagocytic lymphohistiocytosis (HLH) often in response to EBV infection, recurrent splenomegaly, inflammatory bowel disease (IBD) with the features of Crohn's disease [1][2][3][4][5][6]. Notably, heterozygous females can also develop symptoms as severe as in males due to abnormal X-inactivation [4,7].…”

Lentiviral Gene Transfer Corrects Immune Abnormalities in XIAP Deficiency

“…The cytokine profile reported in XIAP y/− mice recapitulates those observed in patients [ 32 , 34 , 60 ], and therefore our data suggests that we could improve the pro-inflammatory status and clinical manifestations of XIAP deficiency. Although the majority of HLH in patients reported in earlier series were triggered by EBV infections [ 70 – 72 ], the exact mechanism for the development of HLH in XIAP deficiency is currently poorly understood but is it likely that dysregulated innate immune responses and cytokine production play a role.…”