Wiskott-Aldrich syndrome
| Wiskott-Aldrich syndrome | |
| ICD-10 | D82.0 |
|---|---|
| ICD-9 | 279.12 |
| OMIM | 301000 |
| DiseasesDB | 14176 |
| MeSH | D014923 |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chandrakala Yannam, MD [2]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [3]
Synonyms and keywords: Aldrich syndrome
Patient Informtion
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]
- 0.5: intermittent thrombopenia
- 1.0: thrombopenia and small platelets
- 2.0: thrombopenia and normally responsive eczema or occasional upper respiratory tract infections.
- 2.5: thrombopenia and therapy-responsive but severe eczema or airway infections requiring antibiotics
- 3.0: both eczema and airway infections requiring antibiotics
- 4.0: eczema continuously requiring therapy and/or severe or life threatening infections
- 5.0: autoimmune disease or malignancy in an XLT/WAS patient.
Pathophysiology
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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]
Causes
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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 ((Page name)) from Other Diseases
Epidemiology and Demographics
The combined incidence of WAS and XLT is about 4-10 in 1 million live births. There is no geographical factor.
Risk Factors
Screening
Natural History, Complications, and Prognosis
If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
OR
- Common complications of Wiscott-Aldrich syndrome include:
- Severe and recurrent infections with bacterial, viral, fungal and opportunistic infections.. Most common clinical manifestations include otitis media, sinusitis, pneumonia, meningitis, skin infections, and sepsis.[7][8][9]
- Bleeding diathesis (eg, epistaxis, ecchymoses,intracranial and gastric hemorrhages)[10][11]
- Autoimmune manifestations may occur in the form of autoimmune hemolytic anemia, immune thrombocytopenic purpura and neutropenia, vasculitis involving small and large vessels, inflammatory bowel disease, and immune-mediated damage to the kidneys and joints.[10][12][13]
- Increased risk of malignancies such as lymphoma, leukaemia is a frequent occurence in Wiskott-Aldrich syndrome.[14][15]
OR
Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.
Diagnosis
Diagnostic Study of Choice
History and Symptoms
The majority of patients with [disease name] are asymptomatic.
OR
The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].
Physical Examination
Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].
OR
Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].
OR
The presence of [finding(s)] on physical examination is diagnostic of [disease name].
OR
The presence of [finding(s)] on physical examination is highly suggestive of [disease name
Laboratory Findings
An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].
OR
Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
OR
[Test] is usually normal among patients with [disease name].
OR
Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].
OR
There are no diagnostic laboratory findings associated with [disease name].
Electrocardiogram
X-ray
Echocardiography or Ultrasound
CT scan
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Treatment of Wiskott-Aldrich syndrome is based on correcting symptoms. Aspirin and other non-steroidal anti-inflammatory drugs should be avoided, since these may interfere with platelet function. A protective helmet can protect children from bleeding into the brain which could result from head injuries. For severely low platelet counts, patients may require platelet transfusions or a splenectomy. For patients with frequent infections, intravenous immunoglobulins (IVIG) can be given to boost the immune system. Anemia from bleeding may require iron supplementation or blood transfusion.
Surgery
As Wiskott-Aldrich syndrome is primarily a disorder of the blood-forming tissues, a hematopoietic stem cell transplant, accomplished through a cord blood or bone marrow transplant offers the only hope of cure. This treatment is inherently fraught with risks, but is nonetheless recommended for patients with HLA-identical donors, matched sibling donors, or even in cases of incomplete matches if the patient is age 5 or under.
Primary Prevention
Secondary Prevention
Secondary preventive measures of Wiskott-Aldrich syndrome are similar to primary prevention.
References
- ↑ Aldrich RA, Steinberg AG, Campbell DC (1954). "Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea". Pediatrics. 13 (2): 133–9. PMID 13133561.
- ↑ Wiskott, A (1937). "Familiärer, angeborener Morbus Werlhofii? ("Familial congenital Werlhof's disease?")". Montsschr Kinderheilkd. 68: 212–16.
- ↑ Binder V, Albert MH, Kabus M, Bertone M, Meindl A, Belohradsky BH (2006). "The genotype of the original Wiskott phenotype". N. Engl. J. Med. 355 (17): 1790–3. doi:10.1056/NEJMoa062520. PMID 17065640.
- ↑ Jin Y, Mazza C, Christie JR; et al. (2004). "Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation". Blood. 104 (13): 4010–9. doi:10.1182/blood-2003-05-1592. PMID 15284122.
- ↑ 5.0 5.1 "Wiskott-Aldrich Syndrome: Immunodeficiency Disorders: Merck Manual Professional". Retrieved 2008-03-01.
- ↑ 6.0 6.1 PMID 1683685 (PMID 1683685)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ WEINTRAUB HD, WILSON WJ (August 1964). "PNEUMOCYSTIS CARINII PNEUMONIA IN WISKOTT-ALDRICH SYNDROME". Am. J. Dis. Child. 108: 198–200. PMID 14159941.
- ↑ Blancas-Galicia L, Escamilla-Quiroz C, Yamazaki-Nakashimada MA (2011). "[Wiskott-Aldrich Syndrome: An updated review]". Rev Alerg Mex (in Spanish; Castilian). 58 (4): 213–8. PMID 24007832.
- ↑ Imai K, Morio T, Zhu Y, Jin Y, Itoh S, Kajiwara M, Yata J, Mizutani S, Ochs HD, Nonoyama S (January 2004). "Clinical course of patients with WASP gene mutations". Blood. 103 (2): 456–64. doi:10.1182/blood-2003-05-1480. PMID 12969986.
- ↑ 10.0 10.1 Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA (December 1994). "A multiinstitutional survey of the Wiskott-Aldrich syndrome". J. Pediatr. 125 (6 Pt 1): 876–85. PMID 7996359.
- ↑ Notarangelo LD (February 2013). "In Wiskott-Aldrich syndrome, platelet count matters". Blood. 121 (9): 1484–5. doi:10.1182/blood-2013-01-475913. PMID 23449611.
- ↑ Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F, de Saint Basile G, Delaunay J, Schwarz K, Casanova JL, Blanche S, Fischer A (May 2003). "Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients". Pediatrics. 111 (5 Pt 1): e622–7. PMID 12728121.
- ↑ Chen N, Zhang ZY, Liu DW, Liu W, Tang XM, Zhao XD (October 2015). "The clinical features of autoimmunity in 53 patients with Wiskott-Aldrich syndrome in China: a single-center study". Eur. J. Pediatr. 174 (10): 1311–8. doi:10.1007/s00431-015-2527-3. PMID 25877044.
- ↑ Cotelingam JD, Witebsky FG, Hsu SM, Blaese RM, Jaffe ES (1985). "Malignant lymphoma in patients with the Wiskott-Aldrich syndrome". Cancer Invest. 3 (6): 515–22. PMID 3910193.
- ↑ Yoshimi A, Kamachi Y, Imai K, Watanabe N, Nakadate H, Kanazawa T, Ozono S, Kobayashi R, Yoshida M, Kobayashi C, Hama A, Muramatsu H, Sasahara Y, Jakob M, Morio T, Ehl S, Manabe A, Niemeyer C, Kojima S (May 2013). "Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia". Pediatr Blood Cancer. 60 (5): 836–41. doi:10.1002/pbc.24359. PMID 23023736.