|
|
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (April 2013) |
| Wiskott-Aldrich syndrome |
| Classification and external resources |
| ICD-10 |
D82.0 |
| ICD-9 |
279.12 |
| OMIM |
301000 |
| DiseasesDB |
14176 |
| eMedicine |
med/1162 ped/2443 derm/702 |
| MeSH |
D014923 |
Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). 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.
Contents
- 1 Signs and symptoms
- 2 Diagnosis
- 3 Classification
- 4 Pathophysiology
- 5 Epidemiology
- 6 Treatment
- 7 History
- 8 References
- 9 External links
Signs and symptoms[edit source | edit]
Due to its mode of inheritance, the overwhelming majority of patients are male. The first signs of WAS are usually petechiae and bruising, resulting from thrombocytopenia (low platelet counts). Spontaneous nose bleeds and bloody diarrhea are common. Eczema develops within the first month of life. Recurrent bacterial infections develop by three months. Splenomegaly is not an uncommon finding. The majority of WAS children develop at least one autoimmune disorder, and malignancies (mainly lymphoma and leukemia) develop in up to a third of patients. [2]
IgM levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated.[3]
Diagnosis[edit source | edit]
The diagnosis is made on the basis of clinical parameters, the peripheral blood smear and low immunoglobulin levels. Typically, immunoglobulin M (IgM) levels are low, IgA levels are elevated, and IgE levels may be elevated; paraproteins are occasionally observed.[4] Skin immunologic testing (allergy testing) may reveal hyposensitivity. Not all patients will have a positive family history of the disorder, new mutations do occur. Often, leukemia may be suspected on the basis of low platelets and infections, and bone marrow biopsy may be performed. Decreased levels of Wiskott-Aldrich syndrome protein and/or confirmation of a causative mutation provides the most definitive diagnosis.
Sequence analysis can detect the WAS-related disorders of Wiskott–Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN). Sequence analysis of the WASp gene can detect about 98% of mutations in males and 97% of mutations in female carriers. Because XLT and XLN symptoms may be less severe than full WAS and because female carriers are usually asymptomatic, clinical diagnosis can be elusive. In these cases, genetic testing can be instrumental in diagnosis of WAS-related disorders.
Classification[edit source | edit]
Jin et al. (2004) employ a numerical grading of severity:[5]
- 0.5: intermittent thrombocytopenia
- 1.0: thrombocytopenia and small platelets (microthrombocytopenia)
- 2.0: microthrombocytopenia plus normally responsive eczema or occasional upper respiratory tract infections
- 2.5: microthrombocytopenia plus therapy-responsive but severe eczema or airway infections requiring antibiotics
- 3.0: microthrombocytopenia plus both eczema and airway infections requiring antibiotics
- 4.0: microthrombocytopenia plus eczema continuously requiring therapy and/or severe or life threatening infections
- 5.0: microthrombocytopenia plus autoimmune disease or malignancy
Pathophysiology[edit source | edit]
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.[citation needed]
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.[citation needed]
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-cells, 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.[citation needed]
The immune deficiency is caused by decreased antibody production, and the inability of T cells to become polarized [6] (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.[5] Although autoimmune disease and malignancy may occur in both types of mutations, those patients with truncated WASp carry a higher risk.
A defect in CD43 molecule has been found in patients with Wiskott–Aldrich syndrome.[7]
Epidemiology[edit source | edit]
The combined incidence of WAS and XLT is about 4-10 in 1 million live births.[citation needed] There is no geographical factor.
Treatment[edit source | edit]
Treatment of Wiskott–Aldrich syndrome is currently 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.
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 current hope of cure. This may be 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.
Studies of correcting Wiskott–Aldrich syndrome with gene therapy using a lentivirus have begun.[8][9] Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome.[10] Currently, many investigators continue to develop optimized gene therapy vectors.[5][8][9][11] In July 2013 the Italian San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) reported that three children with Wiskott–Aldrich syndrome showed significant improvement 20-30 months after being treated with a genetically modified lentevirus.[12]
History[edit source | edit]
The syndrome is named after Dr Robert Anderson Aldrich (1917–1998), an American pediatrician who described the disease in a family of Dutch-Americans in 1954,[1] and Dr Alfred Wiskott (1898–1978), a German pediatrician who first noticed the syndrome in 1937.[13] 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.[14]
References[edit source | edit]
- ^ a b Aldrich, R. A.; Steinberg, A. G.; Campbell, D. C. (1954). "Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea". Pediatrics 13 (2): 133–139. PMID 13133561. edit
- ^ http://emedicine.medscape.com/article/137015-overview
- ^ Sande, Merle A.; Wilson, Walter P. (2001). Current diagnosis & treatment in infectious diseases. New York: Lange Medical Books/McGraw-Hill. p. 361. ISBN 0-8385-1494-4.
- ^ Radl, J.; Dooren, L. H.; Morell, A.; Skvaril, F.; Vossen, J. M.; Uittenbogaart, C. H. (1976). "Immunoglobulins and transient paraproteins in sera of patients with the Wiskott-Aldrich syndrome: a follow-up study". Clinical and experimental immunology 25 (2): 256–263. PMC 1541349. PMID 954233. edit
- ^ a b c Jin, Y.; Mazza, C.; Christie, J.; Giliani, S.; Fiorini, M.; Mella, P.; Gandellini, F.; Stewart, D.; Zhu, Q.; Nelson, D. L.; Notarangelo, L. D.; Ochs, H. D. (2004). "Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation". Blood 104 (13): 4010–4019. doi:10.1182/blood-2003-05-1592. PMID 15284122. edit
- ^ "Wiskott-Aldrich Syndrome: Immunodeficiency Disorders: Merck Manual Professional". Retrieved 2008-03-01.
- ^ Rosenstein, Y.; Park, J. K.; Hahn, W. C.; Rosen, F. S.; Bierer, B. E.; Burakoff, S. J. (1991). "CD43, a molecule defective in Wiskott-Aldrich syndrome, binds ICAM-1". Nature 354 (6350): 233–235. Bibcode:1991Natur.354..233R. doi:10.1038/354233a0. PMID 1683685. edit
- ^ a b Galy, A.; Roncarolo, M. G.; Thrasher, A. J. (2008). "Development of lentiviral gene therapy for Wiskott Aldrich syndrome". Expert Opinion on Biological Therapy 8 (2): 181–190. doi:10.1517/14712598.8.2.181. PMC 2789278. PMID 18194074. edit
- ^ a b Frecha, C; M G Toscano , C Costa , M J Saez-Lara , F L Cosset , E Verhoeyen & F Martin (2008). "Improved lentiviral vectors for Wiskott Aldrich syndrome gene therapy mimic endogenous expression profiles throughout haematopoiesis". Gene Therapy 15 (12): 930–41. doi:10.1038/gt.2008.20. PMID 18323794.
- ^ Boztug, K.; Schmidt, M.; Schwarzer, A.; Banerjee, P. P.; Díez, I. S. A.; Dewey, R. A.; Böhm, M.; Nowrouzi, A.; Ball, C. R.; Glimm, H.; Naundorf, S.; Kühlcke, K.; Blasczyk, R.; Kondratenko, I.; Maródi, L. S.; Orange, J. S.; Von Kalle, C.; Klein, C. (2010). "Stem-Cell Gene Therapy for the Wiskott–Aldrich Syndrome". New England Journal of Medicine 363 (20): 1918–1927. doi:10.1056/NEJMoa1003548. PMC 3064520. PMID 21067383. edit
- ^ Dewey, R.; Avedillo Díez, I.; Ballmaier, M.; Filipovich, A.; Greil, J.; Güngör, T.; Happel, C.; Maschan, A.; Noyan, F.; Pannicke, U.; Schwarz, K.; Snapper, S.; Welte, K.; Klein, C. (2006). "Retroviral WASP gene transfer into human hematopoietic stem cells reconstitutes the actin cytoskeleton in myeloid progeny cells differentiated in vitro". Experimental Hematology 34 (9): 1161–1169. doi:10.1016/j.exphem.2006.04.021. PMID 16939809. edit
- ^ Aiuti, A.; Biasco, L.; Scaramuzza, S.; Ferrua, F.; Cicalese, M. P.; Baricordi, C.; Dionisio, F.; Calabria, A.; Giannelli, S.; Castiello, M. C.; Bosticardo, M.; Evangelio, C.; Assanelli, A.; Casiraghi, M.; Di Nunzio, S.; Callegaro, L.; Benati, C.; Rizzardi, P.; Pellin, D.; Di Serio, C.; Schmidt, M.; Von Kalle, C.; Gardner, J.; Mehta, N.; Neduva, V.; Dow, D. J.; Galy, A.; Miniero, R.; Finocchi, A.; Metin, A. (2013). "Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome". Science 341 (6148): 1233151. doi:10.1126/science.1233151. edit
- ^ Wiskott, A (1937). "Familiärer, angeborener Morbus Werlhofii? ("Familial congenital Werlhof's disease?")". Montsschr Kinderheilkd 68: 212–16.
- ^ Binder, V.; Albert, M. H.; Kabus, M.; Bertone, M.; Meindl, A.; Belohradsky, B. H. (2006). "The Genotype of the Original Wiskott Phenotype". New England Journal of Medicine 355 (17): 1790. doi:10.1056/NEJMoa062520. PMID 17065640. edit
External links[edit source | edit]
- GeneReviews/NIH/NCBI/UW entry on WAS-Related Disorders including Wiskott-Aldrich syndrome WAS X-linked thrombocytopenia XLT and X-linked congenital neutropenia XLN
- Immune Deficiency Foundation - Chapter VII, "The Wiskott-Aldrich Syndrome"
|
Immune disorders: Lymphoid and complement immunodeficiency (D80–D85, 279.0–4)
|
|
| Primary |
|
Antibody/humoral (B)
|
|
Hypogammaglobulinemia
|
- X-linked agammaglobulinemia
- Transient hypogammaglobulinemia of infancy
|
|
|
Dysgammaglobulinemia
|
- IgA deficiency
- IgG deficiency
- IgM deficiency
- Hyper IgM syndrome (2
- 3
- 4
- 5)
- Wiskott-Aldrich syndrome
- Hyper-IgE syndrome
|
|
|
Other
|
- Common variable immunodeficiency
- ICF syndrome
|
|
|
|
T cell deficiency (T)
|
- thymic hypoplasia: hypoparathyroid (Di George's syndrome)
- euparathyroid (Nezelof syndrome
- Ataxia telangiectasia)
peripheral: Purine nucleoside phosphorylase deficiency
|
|
|
Severe combined (B+T)
|
- x-linked: X-SCID
autosomal: Adenosine deaminase deficiency
- Omenn syndrome
- ZAP70 deficiency
- Bare lymphocyte syndrome
|
|
|
| Acquired |
|
|
Leukopenia:
Lymphocytopenia |
- Idiopathic CD4+ lymphocytopenia
|
|
| Complement deficiency |
- C1-inhibitor (Angioedema/Hereditary angioedema)
- Complement 2 deficiency/Complement 4 deficiency
- MBL deficiency
- Properdin deficiency
- Complement 3 deficiency
- Terminal complement pathway deficiency
- Paroxysmal nocturnal hemoglobinuria
- Complement receptor deficiency
|
|
|
|
cell/phys/auag/auab/comp, igrc
|
|
|
|
|
|
|
Sex linkage: X-linked disorders
|
|
|
X-linked recessive
|
|
| Immune |
- Chronic granulomatous disease (CYBB)
- Wiskott–Aldrich syndrome
- X-linked severe combined immunodeficiency
- X-linked agammaglobulinemia
- Hyper-IgM syndrome type 1
- IPEX
- X-linked lymphoproliferative disease
- Properdin deficiency
|
|
| Hematologic |
- Haemophilia A
- Haemophilia B
- X-linked sideroblastic anemia
|
|
| Endocrine |
- Androgen insensitivity syndrome/Kennedy disease
- KAL1 Kallmann syndrome
- X-linked adrenal hypoplasia congenita
|
|
| Metabolic |
- amino acid: Ornithine transcarbamylase deficiency
- Oculocerebrorenal syndrome
- dyslipidemia: Adrenoleukodystrophy
- carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency
- Pyruvate dehydrogenase deficiency
- Danon disease/glycogen storage disease Type IIb
- lipid storage disorder: Fabry's disease
- mucopolysaccharidosis: Hunter syndrome
- purine-pyrimidine metabolism: Lesch–Nyhan syndrome
- mineral: Menkes disease/Occipital horn syndrome
|
|
| Nervous system |
- X-linked mental retardation: Coffin–Lowry syndrome
- MASA syndrome
- X-linked alpha thalassemia mental retardation syndrome
- Siderius X-linked mental retardation syndrome
- eye disorders: Color blindness (red and green, but not blue)
- Ocular albinism (1)
- Norrie disease
- Choroideremia
- other: Charcot–Marie–Tooth disease (CMTX2-3)
- Pelizaeus–Merzbacher disease
- SMAX2
|
|
| Skin and related tissue |
- Dyskeratosis congenita
- Hypohidrotic ectodermal dysplasia (EDA)
- X-linked ichthyosis
- X-linked endothelial corneal dystrophy
|
|
| Neuromuscular |
- Becker's muscular dystrophy/Duchenne
- Centronuclear myopathy (MTM1)
- Conradi–Hünermann syndrome
- Emery–Dreifuss muscular dystrophy 1
|
|
| Urologic |
- Alport syndrome
- Dent's disease
- X-linked nephrogenic diabetes insipidus
|
|
| Bone/tooth |
- AMELX Amelogenesis imperfecta
|
|
| No primary system |
- Barth syndrome
- McLeod syndrome
- Smith–Fineman–Myers syndrome
- Simpson–Golabi–Behmel syndrome
- Mohr–Tranebjærg syndrome
- Nasodigitoacoustic syndrome
|
|
|
|
X-linked dominant
|
|
- X-linked hypophosphatemia
- Focal dermal hypoplasia
- Fragile X syndrome
- Aicardi syndrome
- Incontinentia pigmenti
- Rett syndrome
- CHILD syndrome
- Lujan–Fryns syndrome
- Orofaciodigital syndrome 1
- Craniofrontonasal dysplasia
|
|
|
|
Cytoskeletal defects
|
|
| Microfilaments |
| Myofilament |
| Actin |
- Hypertrophic cardiomyopathy 11
- Dilated cardiomyopathy 1AA
- DFNA20
- Nemaline myopathy 3
|
|
| Myosin |
- Elejalde syndrome
- Hypertrophic cardiomyopathy 1, 8, 10
- Usher syndrome 1B
- Freeman–Sheldon syndrome
- DFN A3, 4, 11, 17, 22; B2, 30, 37, 48
- May-Hegglin anomaly
|
|
| Troponin |
- Hypertrophic cardiomyopathy 7, 2
- Nemaline myopathy 4, 5
|
|
| Tropomyosin |
- Hypertrophic cardiomyopathy 3
- Nemaline myopathy 1
|
|
| Titin |
- Hypertrophic cardiomyopathy 9
|
|
|
| Other |
- Fibrillin
- Marfan syndrome
- Weill-Marchesani syndrome
- Filamin
- FG syndrome 2
- Boomerang dysplasia
- Larsen syndrome
- Terminal osseous dysplasia with pigmentary defects
|
|
|
| IF |
| 1/2 |
- Keratinopathy (keratosis, keratoderma, hyperkeratosis): KRT1
- Striate palmoplantar keratoderma 3
- Epidermolytic hyperkeratosis
- IHCM
- KRT2E (Ichthyosis bullosa of Siemens)
- KRT3 (Meesmann juvenile epithelial corneal dystrophy)
- KRT4 (White sponge nevus)
- KRT5 (Epidermolysis bullosa simplex)
- KRT8 (Familial cirrhosis)
- KRT10 (Epidermolytic hyperkeratosis)
- KRT12 (Meesmann juvenile epithelial corneal dystrophy)
- KRT13 (White sponge nevus)
- KRT14 (Epidermolysis bullosa simplex)
- KRT17 (Steatocystoma multiplex)
- KRT18 (Familial cirrhosis)
- KRT81/KRT83/KRT86 (Monilethrix)
- Naegeli–Franceschetti–Jadassohn syndrome
- Reticular pigmented anomaly of the flexures
|
|
| 3 |
- Desmin: Desmin-related myofibrillar myopathy
- Dilated cardiomyopathy 1I
- Peripherin: Amyotrophic lateral sclerosis
|
|
| 4 |
- Neurofilament: Parkinson's disease
- Charcot–Marie–Tooth disease 1F, 2E
- Amyotrophic lateral sclerosis
|
|
| 5 |
- Laminopathy: LMNA
- Mandibuloacral dysplasia
- Dunnigan Familial partial lipodystrophy
- Emery-Dreifuss muscular dystrophy 2
- Limb-girdle muscular dystrophy 1B
- Charcot–Marie–Tooth disease 2B1
- LMNB
- Barraquer–Simons syndrome
- LEMD3
- Buschke–Ollendorff syndrome
- Osteopoikilosis
- LBR
- Pelger-Huet anomaly
- Hydrops-ectopic calcification-moth-eaten skeletal dysplasia
|
|
|
| Microtubules |
| Kinesin |
- Charcot–Marie–Tooth disease 2A
- Hereditary spastic paraplegia 10
|
|
| Dynein |
- Primary ciliary dyskinesia
- Short rib-polydactyly syndrome 3
- Asphyxiating thoracic dysplasia 3
|
|
| Other |
- Tauopathy
- Cavernous venous malformation
|
|
|
| Membrane |
- Spectrin: Spinocerebellar ataxia 5
- Hereditary spherocytosis 2, 3
- Hereditary elliptocytosis 2, 3
Ankyrin: Long QT syndrome 4
- Hereditary spherocytosis 1
|
|
| Catenin |
- APC
- Gardner's syndrome
- Familial adenomatous polyposis
- plakoglobin (Naxos syndrome)
- GAN (Giant axonal neuropathy)
|
|
| Other |
- desmoplakin: Striate palmoplantar keratoderma 2
- Carvajal syndrome
- Arrhythmogenic right ventricular dysplasia 8
- plectin: Epidermolysis bullosa simplex with muscular dystrophy
- Epidermolysis bullosa simplex of Ogna
- plakophilin: Skin fragility syndrome
- Arrhythmogenic right ventricular dysplasia 9
- centrosome: PCNT (Microcephalic osteodysplastic primordial dwarfism type II)
|
|
See also: cytoskeletal proteins
- B structural
- perx
- skel
- cili
- mito
- nucl
- sclr
- DNA/RNA/protein synthesis
- membrane
- transduction
- trfk
|
|
