A case of familial X-linked thrombocytopenia with a novel WAS gene mutation
A 4-year-old boy had frequently visited the outpatient clinic for the past year with refractory thrombocytopenia since birth and recurrent herpes simplex infections. He had been treated with intravenous immunoglobulin and steroid since birth; however, refractory thrombocytopenia had persisted. Bone marrow aspiration and biopsy showed slightly increased megakaryocyte counts without the presence of any abnormal cells. The atopic skin manifestations did not appear until 3 years of age. Regarding family history, his older brother who was diagnosed as chronic thrombocytopenia died due to intracranial hemorrhage at the age of 10 years, but his 14-year-old sister was healthy.\nUntil the age of 4, complete blood count showed only thrombocytopenia, hemoglobin (Hb) 11.9 g/dL, white blood cells (WBC) 6,900/µL with 65.0% segment neutrophils, and platelets 7,000/µL. After developing recurrent infection and eczema, his laboratory findings revealed neutropenia state such as Hb 8.8 g/dL, WBC 1,690/µL with 27.0% segment neutrophils, platelets 2,000/µL, and reticulocyte count 3.13%. Serum immunoglobulin levels were within normal ranges for immunoglobulin IgG, IgA, and IgM although the level of IgE was slightly increased. Lymphocyte subset analysis showed CD4+ at 21.1% and CD8+ at 44.4%, with a CD4+/CD8+ ratio of 2.1. Blood chemistry data was within normal ranges. Single donor platelet and pure red cell transfusion were performed with methylpredisolone pulse therapy for 3 days. However, the platelet counts did not recover. Based on the findings of recurrent infection, refractory thrombocytopenia, and a family history of an elder brother with chronic thrombocytopenia, we decided to perform genetic analysis for WAS after informed consent was obtained. After diagnosis, we evaluated human leukocyte antigen (HLA) typing within the family for hematopoietic stem cell transplantation and performed genetic analysis of the family with genetic counseling. The results showed that his sister was not matched, and we therefore searched for an unrelated HLA-matched donor. While awaiting the HLA-matched donor, his condition rapidly deteriorated with dehydration, petechia, and recurrent epistaxis.\nOne month later, he was readmitted with fever, subconjuntival hemorrhage, oral mucosal hemorrhage, a pale appearance, and >10 episodes of dark brown-colored vomiting. On the next day, he showed decreased mental status. Because of a strong suspicion of intracranial hemorrhage, emergency brain CT was performed. The CT findings revealed an intracranial hemorrhage in the left frontal lobe and a small intraventricular hemorrhage in the caudate nucleus. Despite aggressive medical and surgical intervention to control the intracranial hemorrhage, he died after three days.\nThe results of genetic sequence analysis revealed a novel pathogenic deletion mutation in exon 9 of the WAS gene: c.858delC (p.ser287Leufs*21) (). This novel pathogenic variant causes the early termination of protein translation. This mutation in the WAS gene was identified in his mother later while neither his father nor sister. This result suggested that his brother, who earlier died from chronic thrombocytopenia, also had an inherited WAS ().