WISKOTT-ALDRICH SYNDROME

WISKOTT-ALDRICH SYNDROME - PatriciaBorman, MD
BASICS
DESCRIPTION
• Males affected by this rare X-linked genetic disorder display combined immunodeficiency, microcytic thrombocytosis, and eczema leading to life-threatening infections and bleeding complications. Average life span is 11 years. The syndrome has variable expression. X-linked thrombocytopenia (XLT) is a related but milder form with mostly platelet defects.
• System(s) Affected: Hemic/Lymphatic/Immunologic; Skin/Exocrine
• Synonym(s): Aldrich syndrome; Immunodeficiency-2
ALERT
Geriatric Considerations
None have survived this long.
Pediatric Considerations
• Onset at birth
• 1st-year infections with encapsulated bacteria: respiratory, meningitis, sepsis
• Later infections occur with opportunistic organisms and virus.
GENERAL PREVENTION
Genetics counseling
• Identify carriers
• Prenatal diagnosis
EPIDEMIOLOGY
• Predominant age: Onset at birth, most diagnosed by 24 months of age
• Predominant sex: Male > Female
- Females rarely develop Wiskott-Aldrich syndrome (WAS). Some carriers express disease; others have different but related gene defect.
Incidence
In the US: 1 in 4 million live male births
RISK FACTORS
• Family history of WAS
• History of congenital defects
Genetics
• Family history in >60%
• X-linked recessive trait
• Wiskott-Aldrich syndrome protein (WASP) and XLT genes located at X/11.22
- Codes for cytoplasmic protein that signals cell membrane structure changes required for activation of blood cells
ETIOLOGY
• Hematopoietic cells express WASP.
- Defective WASP fails to organize membrane activation.
- Membranes do not form normal actin cytoskeletons.
- Altered motility and inability to change cell shapes inhibit normal functions.
• Platelets are intrinsically abnormal.
- Accelerated destruction, sequestered in spleen
• T cells show decreased responsiveness to antigens.
• B cells show abnormal antibody production.
ASSOCIATED CONDITIONS
Lymphomas, brain is primary site in 50%; nephropathy, other lymphoreticular tumors


DIAGNOSIS
SIGNS AND SYMPTOMS
Physical Exam
• Neonatal
- Excessive bleeding from circumcision
- Bloody diarrhea
- Petechiae and purpura
• Childhood
- Eczema with secondary skin infections
- Recurrent bacterial infections
- Viral infections
- Hepatosplenomegaly
- Autoimmune vasculitis and hemolytic anemia
TESTS
Lab
• Platelets abnormal at birth
- 30,000 mean platelet volume, 2/3 normal
• B-cell and T-cell changes over time
- White blood cell count fall by age 6 years
- Low IgM, normal IgG, high IgA and IgE
- Decreased response to capsular antigens
- Low CD 8 counts in 61%
- Decreased delayed hypersensitivity responses
- Decreased mitogenic responses
• Special tests
- Genetic testing for WASP
- Carrier identification
• Drugs that may alter lab results: Antibiotics
• Disorders that may alter lab results: Infections
Imaging
Not helpful
Diagnostic Procedures/Surgery
• Bone marrow aspiration to exclude leukemia and aplastic conditions and to HLA type for bone marrow transplantation
• Gene mapping of mutation in affected or female carriers
• Chorionic villus sampling for in utero diagnosis
Pathological Findings
• Hyperplasia of lymphoreticular system
• Vasculitic changes with multiple thromboses of small arterioles of kidney, lung, pancreas, brain
DIFFERENTIAL DIAGNOSIS
• May be difficult in infancy, before immune changes present
• Idiopathic thrombocytopenic purpura; other causes of thrombocytopenia
• Severe atopic disease
• Acute lymphoblastic anemia
• Other causes of immunodeficiency: Severe combined immunodeficiency, HIV
• Leukemias or marrow aplasias
TREATMENT
STABILIZATION
• Inpatient for acute infections
• No live virus vaccination
GENERAL MEASURES
• Cross-matched platelets
• Irradiated, cytomegalovirus-negative blood products
• Aggressive antibiotic therapy for infections
• Prophylactic antibiotics
Diet
No special diet
Activity
• Plan activities to help normal development.
• Avoid contact sports and prevent head injuries.
• Avoid crowds.
MEDICATION (DRUGS) (1)[B]
• Immunoglobulin infusions
• Prophylactic penicillin after splenectomy
• Antibiotics as indicated by culture
• Topical steroids for eczema
• Parenteral steroids, vincristine, or plasmapheresis for autoimmune complications
• Interleukin-2 can increase platelet counts while awaiting stem cell transplantation.
• Contraindications: Refer to the manufacturer's literature for each drug.
• Precautions: Corticosteroids in immunosuppressed patients. Refer to the manufacturer's literature for each drug.
• Significant possible interactions: Refer to the manufacturer's literature for each drug.
First Line
HLA-typed bone marrow or umbilical cord blood stem cell transplant restores all abnormalities with an 85% cure rate. (2)[B]
SURGERY
Splenectomy can transiently improve thrombocytopenia but increases the risk of infection.
FOLLOW-UP
PROGNOSIS
• Usual course is acute and chronic infections with progressive decrease in immune status.
• Average life expectancy is 11 years, with more living past 20 with stem cell transplant. Transplant therapy can restore all abnormalities. Causes of death have been infection (50%), bleeding (27%), and malignancies (12%).
COMPLICATIONS
• Severe infections, especially after splenectomy
• Hemorrhage, cerebral common
• Malignancies (lymphoreticular, leukemia, Kaposi)
• Nephropathy
• Autoimmune disease in 40%, can be aggressive
• Malabsorption syndrome
PATIENT MONITORING
As needed for therapy; monitor for infections, for progression of disease, complications
REFERENCES
1. Ochs HD. The Wiskott-Aldrich syndrome. Isr Med Assoc J. 2002;4(5):379-384.
2. Tsuji Y, et al. Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant. 2006;1-9.
3. Klein C, et al. Gene therapy for Wiskott-Aldrich syndrome: Rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice. Blood. 2003;101(6):2159-2166.
4. Braithwaite K, Abu-Ghosh A, Anderson L, Cairo MS. Treatment of severe thrombocytopenia with IL-11 in children with Wiskott-Aldrich syndrome. J Pediatr Hematol Oncol. 2002;24(4):323-326.
5. Ming JE. Syndromic immunodeficiencies with humoral defects. Immunol Allergy Clin North Am. 2001;21(1):91-111.
MISCELLANEOUS
See also: Idiopathic Thrombocytopenic Purpura (ITP); Immunodeficiency Diseases; Leukemia