2033/2133: Wiskott-Aldrich Syndome (WAS)

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency affecting 1 to 10 of every 1 million male newborns. It is characterized by microthrombocytopenia and defective lymphocyte function. The decreased numbers and reduced size of platelets (microthrombocytopenia) in the blood often result in bruising, bloody diarrhea, and potentially severe internal bleeding. Defective lymphocyte function can manifest with recurrent infections such as otitis media and pneumonia, autoimmune disorders, and malignancies.¹

The WAS gene encodes the WASp protein which has important roles in hematopoietic cellular function. Patients with Wiskott-Aldrich syndrome contain a WAS gene variant and altered WASp expression leading to a range of clinical presentations. A WAS scoring system was developed to categorize WAS-associated symptoms into three distinct groups (X-linked Neutropenia, X-linked Thrombocytopenia, and Classic WAS). See table below. Patients with microthrombocytopenia and only mild, transient eczema or minor infections are classified with X-linked thrombocytopenia (XLT). Those with treatment-resistant eczema and recurrent infections, or an autoimmune disease or malignancy receive the WAS classification. The spectrum of clinical manifestations underscores the complex role of WASp in cellular function.²³⁴

Table: Scoring System to Define Clinical Phenotypes Associated with WAS mutations⁵

	XLN	iXLT	XLT		Classic WAS
Score	0	<1	1	2	3	4	5
Thrombocytopenia	-	Intermittent	Present	Present	Present	Present	Present
Small Platelets	-	Present	Present	Present	Present	Present	Present
Eczema	-	-	-	Mild, transient	Persistent but therapy-responsive	Difficult to control	Any: Absent to difficult to control
Immunodeficiency	Absent or mild	-	Absent or mild	Mild	Present	Present	Absent, Mild, or Present
Infections	Absent or mild	-	-	Mild, infrequent without sequelae	Recurrent, requiring antibiotics and IVIG prophylaxis	Score 3 OR severe, life-threatening	Any: Absent to severe, life-threatening
Autoimmunity and/or Malignancy	-	-	-	-	-	-	Present
Congenital Neutropenia	Present	-	-	-	-	-	-
Myelodysplasia	Possible myelodysplasia	-	-	-	-	-	-

XLN: X-linked Neutropenia, iXLT: Intermittent X-linked Thrombocytopenia, XLT: X-linked Thrombocytopenia, WAS: Wiskott-Aldrich Syndrome

¹ Ozsahin H, Cavazzana-Calvo M, Notarangelo L, et al. Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation. Blood, 2008;111(1):439-45.

² Bosticardo M, Marangoni F, Aiuti A, et al. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood, 2009;113(25):6288-96.

³ Puck J and Candotti F. Lessons from the Wiskott-Aldrich Syndrome. New England Journal of Medicine, 2006;355(17):1759-61.

⁴ Notarangelo LD, Miao CH, Ochs HD. Wiskott-Aldrich Syndrome. Current Opinion in Hematology, 2008; 15:30-36.

⁵ Adapted from: Albert, M. H., Notarangelo, L. D., & Ochs, H. D. (2011). Clinical spectrum, pathophysiology and treatment of the Wiskott–Aldrich syndrome. Current opinion in hematology, 18(1), 42-48.

• 2033: WAS Pre-HCT
• 2133: WAS Post-HCT

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