X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency disorder with immune dysregulation, caused by SH2D1A/SAP gene mutations. Clinical manifestations include fulminant infectious mononucleosis (FIM), hemophagocytic lymphohistiocytosis (HLH), lymphomas and dysgammaglo-bulinemia [1]. HLH in children can be primary/familial HLH or secondary/reactive HLH [2]. In 80% of familial HLH cases the genetic defect can be identified. To the best of our knowledge this is the first report of XLP1 in an infant with non-Epstein Barr virus (EBV) HLH in India.

An 11 months old male infant, born to third degree consanguineous parents presented with intermittent fever and loose stools for twenty days. There was no history of vomiting, blood in stools, bleeding manifestations, cough/cold, weight loss or past recurrent infections with an unremarkable family history. Child had normal nutritional status, some pallor and massive hepatosplenomegaly. Investigations revealed anemia with hemoglobin of 8.3 g/dL, neutrophilic leucocytosis, absolute neutrophil count of 1704/mm3, low normal platelet count and along with elevated liver enzymes (alanine transaminase: 210 U/dL; aspartate transaminase: 399 U/dL). He was started on antibiotics ceftriaxone and doxycycline. Further investigations including smear for malarial parasite, serology for scrub typhus, cytomegalovirus, EBV and retrovirus was negative. As his fever spikes persisted, ultrasound abdomen, echocardiogram and Immunoglobulin profile were done and found normal. .

Re-evaluation revealed decreasing neutrophil counts (ANC of 624/mm3), thrombocytopenia (platelet count of 0.49×109/L) and coagulopathy (INR of 1.6). Antibiotics were escalated to meropenem and vancomycin because of worsening clinical condition and laboratory parameters though the blood cultures remained sterile. In view of pancytopenia, deranged liver functions, organomegaly and persisting fever spikes, hemophagocytic lymphohistiocytosis (HLH) was considered. Follow up investigations showed elevated serum ferritin (5498 ng/mL), serum triglycerides (278 mg/dL), soluble CD 25 levels, decreased serum fibrinogen (175 mg/dL), bone marrow hemophagocytosis, and cerebrospinal fluid lymphocytic pleocytosis, all consistent with the diagnosis of HLH [2]. He was treated with intravenous immunoglobulin, dexamethasone and etoposide. Workup for primary HLH showed normal perforin protein expression and CD 107a. With the background of consanguinity and male sex, XLP was considered. Next generation sequencing revealed mutation in SH2D1 characteristic of XLP1. Unfortunately, the child had HLH progression and expired of fulminant hepatic dysfunction and coagulopathy. Parents were counseled regarding antenatal diagnosis of XLP in next pregnancy.

X-linked lymphoproliferative syndrome (XLP) is a rare inherited immunodeficiency affecting approximately one in 1,000,000 males. XLP patients have severe immune dysregulation often after viral infection (typically with Epstein-Barr virus [EBV]) [1]. However, a proportion of boys (approximately 10%) have immunological abnormalities before evidence of EBV infection [3] like in our case.

One of the manifestations of XLP1 is hemophagocytic lymphohistiocytosis (HLH) which is a multisystem inflam-matory disorder characterized by cytokine overproduction by activated lymphocytes and macrophages.

XLP arises from 2 different genetic defects in SH2D1A, in Xq25 gene (XLP1, the most common) and BIRC/XIAP gene (XLP2). SH2D1A encodes the cytoplasmic protein SAP (SLAM-associated protein) which is a key regulator of normal immune function in T cells and naturalkiller cells [4]. Defects in SAP lead to the varied immune defects in XLP1 patients. Our child had a mutation in SH2D1A confirming XLP1.

Hematopoietic stem cell transplantation (HSCT) remains the most effective curative treatment for XLP though IVIG and rituximab have been used previously in prevention with questionable benefit [4,5].

Any male child with HLH or FIM should undergo genetic testing for therapeutic implications like bone marrow transplant. Early genetic confirmation of diagnosis also plays a major role in prenatal diagnosis and genetic counselling for the next pregnancy.