Clinical and genetic analysis of 2 rare cases of Wiskott–Aldrich syndrome from Chinese minorities

Abstract

Rationale: Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by thrombocytopenia, small platelets, eczema, immunodeficiency, and an increased risk of autoimmunity and malignancies. X-linked thrombocytopenia (XLT), the milder phenotype of WAS, is always limited to thrombocytopenia with absent or slight infections and eczema. Here, we illustrated the clinical and molecular characteristics of 2 unrelated patients with WAS from Chinese minorities. Patient concerns: Patient 1, a 13-day-old male newborn of the Chinese Lahu minority, showed a classic WAS phenotype, including thrombocytopenia, small platelets, buttock eczema, and recurrent infections. Patient 2, an 8-year-and 8-month-old boy of the Chinese Zhuang minority, presented an XLT phenotype without eczema and repeated infections. Diagnosis: Next-generation sequencing was performed to investigate the genetic variations. Flow cytometry was used to quantify the expression of WAS protein and analyze the lymphocyte subsets. A novel frameshift WAS mutation (c.927delC, p.Q310Rfs∗135) and a known nonsense WAS mutation (c.1090C>T, p.R364X) were identified in Patient 1 and Patient 2, respectively. Both patients were confirmed to have WAS protein deficiency, which was more severe in Patient 1. Meanwhile, the analysis of lymphocyte subsets revealed an abnormality in Patient 1, but not in Patient 2. Combined with the above clinical data and genetic characteristics, Patient 1 and Patient 2 were diagnosed as classic WAS and XLT, respectively. In addition, many miliary nodules were accidentally found in abdominal cavity of Patient 2 during appendectomy. Subsequently, Patient 2 was confirmed with pulmonary and abdominal tuberculosis through further laboratory and imaging examinations. To our knowledge, there have been only a few reports about WAS/XLT with tuberculosis. Interventions: Both patients received anti-infection therapy, platelet transfusions, and intravenous immunoglobulins. Moreover, Patient 2 also received antituberculosis treatment with ethambutol and amoxicillin-clavulanate. Outcomes: The clinical symptoms and hematological parameters of these 2 patients were significantly improved. Regrettably, both patients discontinued the treatment for financial reasons. Lessons: Our report expands the pathogenic mutation spectrum of WAS gene and emphasizes the importance of molecular genetic testing in diagnosing WAS. Furthermore, researching and reporting rare cases of WAS from different populations will facilitate diagnosis and treatment of this disease.

The recurrent WASF1 nonsense variant identified in two unaffected Chinese families with neurodevelopmental disorder: case report and review of the literatures

“…Mammalian WASP, possibly a regulator of lymphocyte and platelet function. Defects in WASP are the cause of Wiskott-Aldrich syndrome (WAS), an X-linked recessive disorder characterized by immune dysregulation and micro thrombocytopenia [ 11 , 12 ]. WASP protein binds the actin nucleation protein complex Arp2/3 [ 13 ].…”

A Novel Splicing Mutation Leading to Wiskott-Aldrich Syndrome from a Family

“…Since the discovery of the WAS gene in 1994, more than four hundred mutations in WAS genes have been reported, the most common of which are missense and splice site mutations [ 4 , 8 ]. Patients typically experience a reduction in the quantity or a truncated form of WASP [ 10 ]. These mutations lead to the expression of defective WASP, frequently causing the X-linked thrombocytopenia (XLT) phenotype, sometimes with only intermittent thrombocytopenia.…”