Wiskott-Aldrich syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chandrakala Yannam, MD [2]; Syed Hassan A. Kazmi BSc, MD [3]; Cafer Zorkun, M.D., Ph.D. [4]

Synonyms and keywords: Aldrich syndrome

Overview

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet counts), immune deficiency, and bloody diarrhea (due to the low platelet counts). It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954.[1] The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similar but less severe symptoms and are caused by mutations of the same gene.

Historical Perspective

The syndrome is named after Dr Robert Anderson Aldrich, an American pediatrician who described the disease in a family of Dutch-Americans in 1954, and Dr Alfred Wiskott, a German pediatrician who first noticed the syndrome in 1937.[2] Wiskott described three brothers with a similar disease, whose sisters were unaffected. In 2006 a German research group analysed family members of Wiskott's three cases, and surmised that they probably shared a novel frameshift mutation of the first exon of the WAS gene.[3]

Classification

Jin et al (2004) employ a numerical grading of severity:[4]

Pathophysiology

In the Wiskott–Aldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen, which leads to low platelet counts.

Wiskott–Aldrich syndrome was linked in 1994 to mutations in a gene on the short arm of the X chromosome, which was termed Wiskott-Aldrich syndrome protein (WASp). It was later discovered that the disease X-linked thrombocytopenia (XLT) was also due to WASp mutations, but different ones from those that cause full-blown Wiskott–Aldrich syndrome. Furthermore, the rare disorder X-linked neutropenia has been linked to particular mutations of the WASp gene.

The WASp gene codes for the protein by the same name, which is 502 amino acids long and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by binding to the Arp2/3 complex. In T-cell, WASp is important because it is known to be activated via T-cell receptor (TCR) signaling pathways to induce cortical actin cytoskeleton rearrangements that are responsible for forming the immunological synapse.

The immune deficiency is caused by decreased antibody production, and an inability for T cells to become polarized [5] (making it a combined immunodeficiency). This leads to increased susceptibility to infections, particularly of the ears and sinuses. T cells are unable to reorganize their actin cytoskeleton. The type of mutation to the WASp gene correlates significantly with the degree of severity: those that led to the production of a truncated protein caused significantly more symptoms than those with a missense mutation but a normal-length WASp. Although autoimmune disease and malignancy occur in both types of mutation, those patients with truncated WASp carry a higher risk.

A defect in CD43 molecule has been found to be associated in patients with Wiskott–Aldrich syndrome.[6]

Causes

In Wiskott–Aldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen, which leads to low platelet counts.

Wiskott–Aldrich syndrome was linked in 1994 to mutations in a gene on the short arm of the X chromosome, which was termed Wiskott-Aldrich syndrome protein (WASp). It was later discovered that the disease X-linked thrombocytopenia (XLT) was also due to WASp mutations, but different ones from those that cause full-blown Wiskott–Aldrich syndrome. Furthermore, the rare disorder X-linked neutropenia has been linked to particular mutations of the WASp gene.

The WASp gene codes for the protein by the same name, which is 502 amino acids long and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). The main function of WASp is to activate actin polymerization by binding to the Arp2/3 complex. In T-cell, WASp is important because it is known to be activated via T-cell receptor (TCR) signaling pathways to induce cortical actin cytoskeleton rearrangements that are responsible for forming the immunological synapse.

The immune deficiency is caused by decreased antibody production, and an inability for T cells to become polarized [5] (making it a combined immunodeficiency). This leads to increased susceptibility to infections, particularly of the ears and sinuses. T-cells are unable to reorganize their actin cytoskeleton. The type of mutation to the WASp gene correlates significantly with the degree of severity: those that led to the production of a truncated protein caused significantly more symptoms than those with a missense mutation but a normal-length WASp. Although autoimmune disease and malignancy occur in both types of mutation, those patients with truncated WASp carry a higher risk.

A defect in CD43 molecule has been found to be associated in patients with Wiskott–Aldrich syndrome.[6]

Differentiating Wiskott-Aldrich Syndrome From Other Disorders of Humoral Imuunodeficiency

Wiskott-Aldrich Syndrome should be differentiated from other disorders leading to hypogammaglobulinemia and defects of humoral immunity. The following conditions may be considered as differentials:[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][30][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]

Disorder Mechanism Characteristic Features Clinical Presentation Laboratory Findings
Wiskott-Aldrich Syndrome
X-Linked (Bruton) Agammaglobulinemia
Selective IgA Deficiency
  • Serum IgA < 7 mg/dl
  • Normal IgG and IgM levels
Common Variable Immunodeficiency
  • Defective B cell differentiation
  • May be acquired in 20-30 years of age
Autosomal dominant hype IgE syndrome (Job's Syndrome)
  • Distinctive coarse facies
  • Cold (non-inflammatory) Staphylococcal abscesses
  • Retained primary teeth
  • Eczema
Severe combined immunodeficiency (SCID)
Ataxia Telangiectasia
Hyper IgM Syndrome
  • Malignancy: can cause the reduction in the immunoglobulin production.
  • Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
  • Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.
  • Other causes of primary humoral immunodeficiencies.
  • Smoking: may cause IgG2 subclass deficiency.
  • Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

Differentiating Wiskott-Aldrich Syndrome From Other Bleeding Diseases

  • Wiskott-Aldrich syndrome must be differentiated from other bleeding disorders. Different causes of bleeding disorders can be differentiated based on their clinical manifestation and laboratory findings. These features have discussed in the below table:
Category Subcategory Disease History Clinical manifestation Laboratory testing Comments
Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT
Platelet disorders Qualitative Disorders of Platelet Function Inherited Disorders of Platelet Function Wiskott-Aldrich syndrome
  • Positive family history
+ + + + Nl or ↓ Nl Nl Nl
  • Anti-WASP antibody can be used to detect presence or absence of WAS protein
  • In Wiskott–Aldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen, which leads to low platelet counts.
Glanzmann’s thrombasthenia
  • Positive family history
+ + + + Rare Nl or ↓ Nl Nl Nl
  • AR inheritance
  • Absence of the platelet Gp IIb/IIIa receptor
  • Diminished for GP 2B-3A on flow cytometry
Bernard-Soulier syndrome
  • Positive family history
+ + + + Nl or ↓ Nl Nl Nl
  • AR inheritance
  • Absence of the platelet Gp Ib-IX-V receptor
  • On PBS: giant platelets
  • Ristocetin - no aggregation
Platelet storage pool disorder: + + + + Nl or ↓ Nl Nl Nl
  • AD inheritance
  • AbNlities of platelet granule formation
Acquired Disorders of Platelet Function + + + + ± ± Nl or ↓ Nl Nl Nl
Von Willebrand Disease + + + + ± ± Nl Nl See the table below for the details about different types.
Subcategory Disease History Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT Comments
Thrombocytopenia Infection-Induced thrombocytopenia
  • History of prior infection
+ + + + + + Nl Nl Nl
Medication-Induced Thrombocytopenia + + + + + + Nl Nl Nl Most important part of treatment is discontinuing of the medication.
Heparin-Induced thrombocytopenia + + + + + + Nl Nl For more information click here: Heparin-induced thrombocytopenia.
Immune Thrombocytopenic Purpura + + + + + + Nl Nl Nl
Inherited Thrombocytopenia
  • Positive family history
+ + + + + + Nl Nl Nl
Thrombotic Thrombocytopenic Purpura History of: + + + + + + Nl Nl Nl
Hemolytic Uremic Syndrome History of: + + + + + + Nl Nl Nl
Subcategory Disease History Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT Comments
Vessel wall disorders Metabolic and Inflammatory Disorders
  • History of the underlying disease
+ + ± Nl Nl or ↑ Nl Nl Nl
Inherited Disorders of the Vessel Wall
  • Positive family history
+ + ± Nl Nl or ↑ Nl Nl Nl
Coagulation factor disorders

[57]

Fibrinogen deficiency

Different types of the fibrinogen disorders:

+ + ± + Nl
  • Impaired fibrin cross-linking or clot dissolution
  • Mild or severe bleeding idepend on levels of functional fibrinogen
  • Variable age of onset
Subcategory Disease History Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT Comments
Prothrombin deficiency + + + + + Nl Nl
Factor V deficiency + + + + Nl Nl
  • The severity of bleeding related to the degree of factor V deficiency
Factor VII deficiency + + + Nl Nl Nl
  • Thrombosis in inherited factor VII deficiency
  • Treatment with the administration of factor VII replacement therapy
Factor X deficiency
  • Prolonged bleeding following circumcision
  • Easy bruising
  • Hematuria
  • Menorrhagia
  • Abortion
  • Postpartum hemorrhage
  • Epistaxis
  • Pseudotumors
  • Intracranial bleeding
  • Hemarthroses
+ + + + + Nl Nl Nl
Factor XII deficiency
  • Asymptomatic
  • Recurrent miscarriages
  • Painful leg ulcers
Nl Nl Nl Nl
Subcategory Disease History Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT Comments
High molecular weight kininogen (HMWK) deficiency
  • Positive family history of bleeding
Nl Nl Nl Nl
Prekallikrein deficiency
  • Positive family history of bleeding
Nl Nl Nl Nl
Factor XIII deficiency
  • Sub unit A mutation disease (more common)
  • Sub unit B mutation disease
  • Positive family history of bleeding
± ± ± ± ± ± Nl Nl Nl or ↑ Nl Nl
  • Impaired fibrin cross-linking or clot dissolution
  • The severity of factor XIII deficiency bleeds can be different in different patients
Hemophilia Type A deficiency + + + Nl Nl Nl Nl
Type B deficiency + + + Nl Nl Nl Nl
Type C deficiency
  • Positive family history
  • Bleeding after surgery or injury
+ Rare Rare Nl Nl Nl Nl
Subcategory Disease History Mucosal bleeding Petechia Ecchymoses Menorrhagia Hematoma Hemarthrosis Plt BT PT PTT TT Comments
Rare diseases Disseminated Intravascular Coagulation + + + + + + Nl
Vitamin K Deficiency + + + + + Nl Nl or mildly prolonged Nl

Risk Factors

  • Positive family history of Wiskott-Aldrich syndrome, can be considered as a risk factor.

Screening

  • Flow cytometry:
    • Anti-WASp antibody can be used to detect presence or absence of WAS protein. However, flow cytometry may not detect expression of mutated, reduced or poor WASp.[58]
  • Identification of carriers: Known female carriers can be identified by using DNA mutation analysis of WAS gene.
  • Prenatal diagnosis: DNA analysis from chorionic villus sampling can be performed.[59]

Natural History, Complications, and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

  • Patients with Wiskott-Aldrich syndrome have

Physical Examination

Laboratory Findings

Electrocardiogram

  • There are no specific electrocardiogram findings associated with Wiskott-Aldrich syndrome.

X-ray

  • There are no specific x-ray findings associated with Wiskott-Aldrich syndrome. However, a chest x-ray may be helpful in the diagnosis of complications, which include pneumonia.

Echocardiography or Ultrasound

CT scan

MRI

  • There are no specific MRI findings associated with Wiskott-Aldrich syndrome.

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

References

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