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Wiskott-Aldrich Syndrome

- Typical presentation is a boy with early-onset thrombocytopenia, small platelet size, atopic dermatitis, and frequent infections. - Triad of mucosal bleeding/petechiae, eczema, and recurrent otitis media is present in a minority of patients. - Average age at diagnosis is 21 months. - Definitive diagnosis: male patient with microthrombocytopenia and one of the following: - WAS mutation - Northern blot demonstration of absence of WAS messenger RNA in lymphocytes - WASp absent from lymphocytes - Maternal male relatives with microthrombocytopenia

- Family history of WAS in >60% of patients (women with WAS typically have no family history) - Neonatal - Excessive bleeding from circumcision - Intermittent mucosal bleeding - Bloody diarrhea during infancy

- Childhood - Eczema with secondary skin infections - Hepatosplenomegaly

- Platelets abnormal at birth (count <50,000); mean platelet volume, 3.8 to 5 fL (normal, 7.1 to 10.5 fL) - B and T cell changes over time: - WBC count falls by age 6 years. - Low IgM, normal IgG (low IgG2), high IgA and IgE - Normal CD19 B cells and high CD4 to CD8 ratio - Low CD8 counts in 61% - Decreased delayed-type hypersensitivity responses - Decreased mitogenic responses - Decreased natural killer function - Absent isohemagglutinin titers

- Enhance immune function: - Intravenous immunoglobulin (IVIG) infusions for antibody deficiency - Immunosuppressive treatments (i.e., steroids, vincristine, plasmapheresis) for autoimmune manifestations. - Granulocyte colony-stimulating factor (GCSF) for neutropenia

- Severe infections, especially after splenectomy, are as follows: - Antibiotic prophylaxis, IVIG replacement - Pneumocystis jirovecii prophylaxis with trimethoprim " “sulfamethoxazole or pentamidine

para>Onset at birth

Commonly presents with prolonged bleeding following circumcision

In the first year of life, patients may be afflicted with pneumonia or meningitis from susceptibility to encapsulated bacteria.

Later in life, opportunistic organisms and viruses are more likely to cause infections.

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EPIDEMIOLOGY

Incidence

  • Male predominant (X-linked): >90%
  • 1/250,000 live male births in the United States
  • Mild thrombocytopenia is occasionally seen in female carriers.
  • Onset is at birth and most diagnoses are made by 24 months of age.

Prevalence

  • There are approximately 500 WAS patients in the United States.
  • All races are affected, but WAS is less prevalent in blacks and Asians.

ETIOLOGY AND PATHOPHYSIOLOGY

  • Defects in Wiskott-Aldrich syndrome protein (WASp) result in abnormal actin polymerization.
  • WASp is expressed exclusively in hematopoietic cells and results in pleomorphic effects in many cell lines.
  • T-cell lymphopenia is multifactorial and these cells display abnormal interactions with antigen presenting cells, immune regulation, migration, and polarization of cytotoxic granules.
  • Regulatory T cells fail to suppress T and B cells, which may lead to autoimmunity.
  • B-cell lymphopenia, abnormal B cells migration, and autoantibody production results in abnormal immune homeostasis.
  • Platelets are intrinsically abnormal, resulting in accelerated destruction and splenic sequestration.
  • Natural killer cells, macrophages, monocytes, and neutrophils are also abnormal.

Genetics

  • X-linked recessive trait; gene located at Xp11.22 " “23. The specific mutation impacts the phenotype. WAS gene encodes the WASp, a 502-amZino-acid, proline-rich cytoplasmic protein.
  • Complete penetrance and variable expressivity in males.
  • The small number of cases in women may be explained by nonrandom X inactivation, or phenocopy, owing to mutation in gene-encoding binding partner of WASp. Human Genome Organisation (HUGO) gene symbol WAS (Online Mendelian Inheritance in Man [OMIM] 301000).

RISK FACTORS

Family history in >60% ‚

GENERAL PREVENTION

  • Prenatal genetic counseling is important for patients with a family history of WAS (maternal cousins, uncles, and nephews) to identify carriers.X chromosome analysis can be performed if the familial mutation is unknown.
  • Perinatal diagnosis by DNA analysis of fetal blood or chorionic villus sampling (CVS) can be performed if mutation is known.

COMMONLY ASSOCIATED CONDITIONS

  • Autoimmune disorders: hemolytic anemia, small and large vessel vasculitis, nephritis, rheumatoid arthritis, immune thrombocytopenia, and inflammatory bowel disease. Risk increases with age; up to 40% who survive early complications will develop ≥1 autoimmune conditions.
  • Increased susceptibility to herpes virus infection
  • LymphomasEspecially in those exposed to Epstein-Barr virusIncreased risk in those with autoimmune conditions and with ageMay occur in usual extranodal locations; brain is primary site in 50% but also lung and GI tract
  • Lymphoreticular tumors
  • Atopic dermatitis

DIAGNOSIS

  • Typical presentation is a boy with early-onset thrombocytopenia, small platelet size, atopic dermatitis, and frequent infections.
  • Triad of mucosal bleeding/petechiae, eczema, and recurrent otitis media is present in a minority of patients.
  • Average age at diagnosis is 21 months.
  • Definitive diagnosis: male patient with microthrombocytopenia and one of the following:WAS mutationNorthern blot demonstration of absence of WAS messenger RNA in lymphocytesWASp absent from lymphocytesMaternal male relatives with microthrombocytopenia
  • Probable diagnosis: male patient with microthrombocytopenia and one of the following:EczemaRecurrent bacterial or viral infectionsAutoimmune diseaseAbnormal antibody response to polysaccharide antigensLymphoma, leukemia, or brain tumor

HISTORY

  • Family history of WAS in >60% of patients (women with WAS typically have no family history)
  • NeonatalExcessive bleeding from circumcisionIntermittent mucosal bleedingBloody diarrhea during infancy
  • ChildhoodEczema with secondary skin infectionsRecurrent bacterial infectionsViral infectionsAutoimmune vasculitis and hemolytic anemia

PHYSICAL EXAM

  • NeonatalPetechiae and purpuraPurulent otitis media, pneumoniaEczema
  • ChildhoodEczema with secondary skin infectionsHepatosplenomegaly

DIFFERENTIAL DIAGNOSIS

  • May be difficult to diagnose during infancy, since immune changes may develop later
  • X-linked thrombocytopenia (XLT) is an attenuated phenotype allelic to WAS with thrombocytopenia but mild or absent eczema and immune dysfunction.
  • X-linked congenital neutropenia (XLN) is a distinct entity resulting from a constitutively activating mutation in the WAS gene, causing severe neutropenia.
  • 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
  • DiGeorge syndrome
  • X-linked hyperimmunoglobulin (Ig) M
  • Bruton agammaglobulinemia

DIAGNOSTIC TESTS & INTERPRETATION

  • Platelets abnormal at birth (count <50,000); mean platelet volume, 3.8 to 5 fL (normal, 7.1 to 10.5 fL)
  • B and T cell changes over time:WBC count falls by age 6 years.Low IgM, normal IgG (low IgG2), high IgA and IgENormal CD19 B cells and high CD4 to CD8 ratioLow CD8 counts in 61%Decreased delayed-type hypersensitivity responsesDecreased mitogenic responsesDecreased natural killer functionAbsent isohemagglutinin titers
  • Molecular genetic testingGenetic testing for WAS; sequence analysis of WAS mutations in ~99% of affected malesCarrier identification
  • Chest x-ray part of infectious workup
  • MRI and CT in workup of complications after transplant

Diagnostic Procedures/Other

  • Bone marrow aspiration to exclude leukemia and aplastic conditions and HLA type for BMT
  • Identification of mutation in affected patients or female carriers
  • CVS for in utero diagnosis of those at risk

Test Interpretation

  • Hyperplasia of lymphoreticular system
  • Vasculitic changes, with multiple thromboses of small arterioles of kidney, lung, pancreas, and brain

TREATMENT

GENERAL MEASURES

  • Treatment approaches are variable for this pleomorphic, rare disease (1).
  • HSCT, from bone marrow or cord blood, achieved a 75% 7-year disease-free survival in a retrospective multicenter study (2)[B].
  • HSCT is currently the only curative treatment.
  • HSCT is recommended for any WAS patient with an HLA-matched sibling donor, especially if the patient is <5 years of age.
  • Preferred donor is an HLA-matched sibling. For patients without an HLA-matched sibling:HSCT with an unrelated HLA-matched donor is recommended if the patient is <5 years of age and has severe disease. HSCT may be less successful if patient is >5 years of age.For patients without HLA matched donors, gene therapy has been used in a limited number of patients, with some success (3)[B].

MEDICATION

  • Enhance immune function:Intravenous immunoglobulin (IVIG) infusions for antibody deficiencyImmunosuppressive treatments (i.e., steroids, vincristine, plasmapheresis) for autoimmune manifestations.Granulocyte colony-stimulating factor (GCSF) for neutropenia
  • Antimicrobial prophylaxis:Antibiotics (e.g., penicillin) after splenectomyPneumocystis jirovecii (carinii) (PJP/PCP) prophylaxis in infants and children <3 to 4 years of age.Herpes simplex virus (HSV) prophylaxis for recurrent herpes infections
  • Manage bleeding complicationsPlatelet transfusionsConsider splenectomy.Interleukin-2 can increase platelet counts while awaiting HSCT.
  • Supportive care are as follows:Update immunizationsTreat eczema.Treat infections thrombocytopenia.

ISSUES FOR REFERRAL

  • Hematology/oncology: HSCT and treatment of malignancies
  • Genetics: molecular genetic testing of affected individuals; prenatal diagnosis
  • Surgery: splenectomy, if necessary

ADDITIONAL THERAPIES

  • Blood products should be cross-matched, irradiated, and verified cytomegalovirus-negative.
  • Prophylactic antibiotics

COMPLEMENTARY & ALTERNATIVE MEDICINE

  • Gene therapy is an investigational therapy that can induce partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis but carries the risk of inducing leukemia (4)[B].
  • Advances in methods using lentiviral transduction may result in less genotoxicity (5)[B].

SURGERY/OTHER PROCEDURES

Splenectomy can transiently improve thrombocytopenia but increases the risk of infection. ‚

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

  • Avoid contact sports and prevent head injuries.
  • Avoid crowds.
  • No live-virus vaccinations

Patient Monitoring

As needed for therapy; monitor for infections, disease progression, and complications. ‚

DIET

No special diet is required. ‚

PATIENT EDUCATION

  • Patient/parent counseling to cope with disease and outcome
  • Genetic testing and counseling for family

PROGNOSIS

  • Usual course is acute and chronic infections with progressive decrease in immune status.
  • Survival to adulthood, formerly rare, is now increasing owing to advances in medical treatment. HSCT is potentially curative; it can restore platelets and immune function.
  • Median survival is 15 years, with some living past 20 years with HSCT.
  • Causes of death include infection, bleeding, and malignancy.

COMPLICATIONS

  • Severe infections, especially after splenectomy, are as follows:Antibiotic prophylaxis, IVIG replacementPneumocystis jirovecii prophylaxis with trimethoprim " “sulfamethoxazole or pentamidine
  • Hemorrhage, including intracerebral (common)Avoid circumcision of at-risk newborns who have thrombocytopenia.Avoid medications that interfere with platelet function.
  • Malignancies (lymphoreticular, lymphoma): 13% develop lymphoma at an average age of 9.5 years.
  • Autoimmune disease in 40% of those who survive infancy; can be aggressiveHemolytic anemiaImmune thrombocytopenic purpuraImmune-mediated arthritisVasculitis

REFERENCES

11 Conley ‚ ME, Saragoussi ‚ D, Notarangelo ‚ L, et al. An international study examining therapeutic options used in treatment of Wiskott-Aldrich syndrome. Clin Immunol. 2003;109(3):272 " “277.22 Boztug ‚ K, Schmidt ‚ M, Schwarzer ‚ A, et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med. 2010;363(20):1918 " “1927.33 Hacein-Bey Abina ‚ S, Gaspar ‚ HB, Blondeau ‚ J, et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 2015;313(15):1550 " “1563.44 Braun ‚ CJ, Boztug ‚ K, Paruzynski ‚ A, et al. Gene therapy for Wiskott-Aldrich syndrome " “long-term efficacy and genotoxicity. Sci Transl Med. 2014;6(227):227ra33.55 Aiuti ‚ A, Biasco ‚ L, Scaramuzza ‚ S, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341(6148):1233151.

ADDITIONAL READING

  • Aldrich ‚ RA, Steinberg ‚ AG, Campbell ‚ DC. Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. Pediatrics. 1954;13(2):133 " “139.
  • Braithwaite ‚ K, Abu-Ghosh ‚ A, Anderson ‚ L, et al. Treatment of severe thrombocytopenia with IL-11 in children with Wiskott-Aldrich syndrome. J Pediatr Hematol Oncol. 2002;24(4):323 " “326.
  • Dupuis-Girod ‚ S, Medioni ‚ J, Haddad ‚ E, et al. Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics. 2003;111(5, Pt 1):e622 " “e627.
  • Frecha ‚ C, Toscano ‚ MG, Costa ‚ C, et al. Improved lentiviral vectors for Wiskott-Aldrich syndrome gene therapy mimic endogenous expression profiles throughout haematopoiesis. Gene Ther. 2008;15(12):930 " “941.
  • Massaad ‚ MJ, Ramesh ‚ N, Geha ‚ RS. Wiskott-Aldrich syndrome: a comprehensive review. Ann N Y Acad Sci. 2013;1285:26 " “43.
  • Ochs ‚ HD. The Wiskott-Aldrich syndrome. Isr Med Assoc J. 2002;4(5):379 " “384.
  • Ozsahin ‚ H, Cavazzana-Calvo ‚ M, Notarangelo ‚ LD, 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 " “445.
  • Pai ‚ SY, DeMartiis ‚ D, Forino ‚ C, et al. Stem cell transplantation for the Wiskott-Aldrich syndrome: a single-center experience confirms efficacy of matched unrelated donor transplantation. Bone Marrow Transplant. 2006;38(10):671 " “679.
  • Qasim ‚ W, Gaspar ‚ HB, Thrasher ‚ AJ. Progress and prospects: gene therapy for inherited immunodeficiencies. Gene Ther. 2009;16(11):1285 " “1291.
  • Schurman ‚ SH, Candotti ‚ F. Autoimmunity in Wiskott-Aldrich syndrome. Curr Opin Rheumatol. 2003;15(4):446 " “453.

SEE ALSO

Idiopathic Thrombocytopenic Purpura; Immunodeficiency Diseases ‚

CODES

ICD10

D82.0 Wiskott-Aldrich syndrome ‚

ICD9

279.12 Wiskott-aldrich syndrome ‚

SNOMED

Wiskott-Aldrich syndrome (disorder) ‚

CLINICAL PEARLS

  • Rare; consider WAS if prolonged bleeding following circumcision and in children with recurrent infections, eczema, and low platelet counts.
  • Without HSCT, death usually occurs between the ages of 8 and 14 years; the most common causes of death include infection, malignancy, and bleeding.
  • Mnemonic (TIME):ThrombocytopeniaImmune DeficiencyMale SexEczema