A Novel BTK Gene Mutation in a Child With Atypical X-Linked Agammaglobulinemia and Recurrent Hemophagocytosis: A Case Report

Abstract

X-linked agammaglobulinemia (XLA), caused by a mutation in the Bruton's tyrosine kinase ( BTK ) gene, is rarely reported in patients with recurrent hemophagocytic lymphohistiocytosis (HLH). This mutation leads to significantly reduced numbers of circulatory B cells and serum immunoglobulins in patients. Therefore, they exhibit repetitive bacterial infections since infancy, and immunoglobulin (Ig) replacement therapy is the primary treatment. HLH is a life-threatening condition with manifestations of non-remitting fever, hepatosplenomegaly, cytopenias, coagulopathy, lipid disorder, and multiple organ failure. It is caused by the immune dysregulation between cytotoxic T cells, NK cells, and histiocytes. The treatment is based on HLH-2004 protocol including immunotherapy, chemotherapy, supportive therapy, and stem cell transplantation. However, as we know more about the classification and pathophysiology of HLH, the treatment is modified. T-cell-directed immunotherapy is effective in patients with primary HLH, and strong immunosuppression is contraindicated in patients with severe ongoing infections or some primary immunodeficiency diseases (PIDs). Here, we report the case of a 7-year-old boy who presented with ecthyma gangrenosum and several episodes of pyogenic infections during childhood. At the age of 5 years, he exhibited cyclic HLH every 2–3 months. The remission of HLH episodes finally achieved after he received monthly Ig replacement therapy (400 mg/kg) at the 4th HLH. However, transient elevation of IgM was incidentally discovered after 6 cycles of monthly Ig replacement therapy. IgM-secreting multiple myeloma, Waldenström's macroglobulinemia, and lymphoma were excluded. The IgM levels then declined and returned to the normal range within a year. The patient and his parents received whole-genome sequencing analysis. It revealed a novel hemizygous c.1632-1G>A mutation in the BTK gene and XLA was diagnosed. XLA exhibits a spectrum of clinical and immunological presentations in patients. The identification of the mutation in the BTK gene contribute to an accurate diagnosis. Ig replacement therapy is the primary treatment for HLH in patients with XLA.

Novel BTK mutation in X-linked agammaglobulinemia: Report of a 17-year-old male

“…The IVIG therapy is an effective method to decrease the risk of infection in XLA patients. 6,14 As a matter of fact, our case did not experience the pre-mentioned infection episodes yet after receiving the IVIG therapy.…”

“…Some studies suggest that the severity of XLA disease can be influenced by specific mutations, while several others have concluded that the correlation between genotype and phenotype in XLA is not significant. 6,14,15 The main treatment for this disease is the lifelong immunoglobulin replacement therapy for every three to four weeks, in addition to the use of prophylactic or intensive antibiotic treatment in case of more infections. The IVIG therapy is an effective method to decrease the risk of infection in XLA patients.…”

Clinical, immunological and genetic characterization of patients with X‐linked agammaglobulinemia in Costa Rica

“…Patient 9 has changed an isoleucine for a phenylalanine in exon 17. This specific site was not previously described but in this exon, patients with atypical presentations such as HLH 44 and Pseudomonas infections 6 have been published. This could potentially affect the structure of the protein through the introduction of a benzene derivate, with differential physical–chemical properties.…”

Familial Hemophagocytic Lymphohistiocytosis secondary to UNC13D mutation: a report of two cases

“…Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening disease that can be fatal [ 1 ]. It is characterized by some clinical signs (e.g., non-remitting fever, hepatosplenomegaly) and laboratory findings (e.g., cytopenia, increased ferritin level, hypofibrinogenemia, lipid disorders, such as hypertriglyceridemia, coagulopathy, and multiple organ failure) [ 2 , 3 ]. Immune dysregulation in cytotoxic T cells, Natural killer (NK) cells, and histiocytes is considered the leading cause of this disease.…”

“…T-cell-directed immunotherapy could be advantageous in patients with primary HLH. In contrast, strong immunosuppression therapy is contraindicated in patients with severe proceeding infections or some primary immunodeficiency diseases other than familial HLH and X-linked lymphoproliferative syndrome [ 3 ]. In addition, more T-cell targeting therapies, such as anti-thymocyte globulin, etoposide, and alemtuzumab, can be beneficial to patients with primary HLH due to overactivated T cells [ 4 , 5 ].…”