Wiskott-Aldrich syndrome
Encyclopedia
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. 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.
(low platelet
counts). Spontaneous nose bleeds and bloody diarrhea are common. Eczema
develops within the first month of life. Recurrent bacterial infection
s develop by three months. Splenomegaly
is not an uncommon finding. The majority of WAS children develop at least one autoimmune disorders, and malignancies (mainly lymphoma
and leukemia
) develop in up to a third of patients.
IgM
levels are reduced, IgA
and IgE
are elevated, and IgG levels can be reduced or elevated.
and low immunoglobulin levels. Typically, immunoglobulin M
(IgM) levels are low, IgA
levels are elevated, and IgE
levels may be elevated; paraprotein
s are occasionally observed. Skin immunologic testing (allergy testing) may reveal hyposensitivity. It must be remembered that not all patients will have a family history, since they may be the first to harbor the gene mutation. Often, leukemia
may initially be suspected on the basis of the low platelets and the 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.
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 acid
s long and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). Its exact function is being investigated, but signal transduction
and cytoskeleton
maintenance have been suggested.
The immune deficiency is caused by decreased antibody
production, although T cell
s are also affected (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.
and other non-steroidal anti-inflammatory drug
s 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.
Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome.
Currently, many investigators continue to develop optimized gene therapy vectors.
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
, thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
(low platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
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. 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.
Signs and symptoms
Due to its mode of inheritance, the overwhelming majority are male. The first signs of WAS are usually petechiae and bruising, resulting from thrombocytopeniaThrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
(low platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
counts). Spontaneous nose bleeds and bloody diarrhea are common. Eczema
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
develops within the first month of life. Recurrent bacterial infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s develop by three months. Splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
is not an uncommon finding. The majority of WAS children develop at least one autoimmune disorders, and malignancies (mainly lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
and leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
) develop in up to a third of patients.
IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
levels are reduced, IgA
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
and IgE
IGE
IGE was one of the largest services company buying and selling virtual currencies and accounts for MMORPG. During its peak time, it had offices in Los Angeles, China , and headquarters & customer service centre in Hong Kong. IGE was one of the main monopoly in virtual economy services, also known...
are elevated, and IgG levels can be reduced or elevated.
Diagnosis
The diagnosis is made on the basis of clinical parameters, the blood filmBlood film
A blood film or peripheral blood smear is a thin layer of blood smeared on a microscope slide and then stained in such a way to allow the various blood cells to be examined microscopically...
and low immunoglobulin levels. Typically, immunoglobulin M
Immunoglobulin M
Immunoglobulin M, or IgM for short, is a basic antibody that is produced by B cells. It is the primary antibody against A and B antigens on red blood cells. IgM is by far the physically largest antibody in the human circulatory system...
(IgM) levels are low, IgA
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
levels are elevated, and IgE
IGE
IGE was one of the largest services company buying and selling virtual currencies and accounts for MMORPG. During its peak time, it had offices in Los Angeles, China , and headquarters & customer service centre in Hong Kong. IGE was one of the main monopoly in virtual economy services, also known...
levels may be elevated; paraprotein
Paraprotein
A paraprotein is an immunoglobulin or immunoglobulin light-chain that is produced in excess by the clonal proliferation of plasma cells. Detection of paraproteins in the urine or blood is most often associated with benign MGUS , where they remain "silent", and multiple myeloma. An excess in the...
s are occasionally observed. Skin immunologic testing (allergy testing) may reveal hyposensitivity. It must be remembered that not all patients will have a family history, since they may be the first to harbor the gene mutation. Often, leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
may initially be suspected on the basis of the low platelets and the infections, and bone marrow biopsy
Bone marrow biopsy
Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, lymphoma, anemia, and pancytopenia...
may be performed. Decreased levels of Wiskott-Aldrich syndrome protein
Wiskott-Aldrich syndrome protein
The Wiskott–Aldrich Syndrome Protein is a 502-amino acid protein that is expressed in cells of the hematopoietic system. In the inactive state, WASp exists in an auto-inhibited conformation with sequences near its C-terminus binding to a region near its N-terminus...
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
Jin et al. (2004) employ a numerical grading of severity:- 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
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In Wiskott–Aldrich syndrome, the platelets are small and do not function properly. They are removed by the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, which leads to low platelet counts.
Wiskott–Aldrich syndrome was linked in 1994 to mutations in a gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
on the short arm of the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
, which was termed Wiskott-Aldrich syndrome protein
Wiskott-Aldrich syndrome protein
The Wiskott–Aldrich Syndrome Protein is a 502-amino acid protein that is expressed in cells of the hematopoietic system. In the inactive state, WASp exists in an auto-inhibited conformation with sequences near its C-terminus binding to a region near its N-terminus...
(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 acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s long and is mainly expressed in hematopoietic cells (the cells in the bone marrow that develop into blood cells). Its exact function is being investigated, but signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
and cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
maintenance have been suggested.
The immune deficiency is caused by decreased antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
production, although T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s are also affected (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
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
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
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
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
CD43
Leukosialin also known as sialophorin or CD43 is a transmembrane cell surface protein that in humans is encoded by the SPN gene.- Function :...
molecule has been found to be associated in patients with Wiskott–Aldrich syndrome.
Epidemiology
The combined incidence of WAS and XLT is about 4-10 in 1 million live births. There is no geographical factor.Treatment
Treatment of Wiskott–Aldrich syndrome is currently based on correcting symptoms. AspirinAspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
and other non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
s should be avoided, since these may interfere with platelet function. A protective helmet can protect children from bleeding into the brain
Intra-axial hematoma
A cerebral hemorrhage or hemorrhage is a subtype of intracranial hemorrhage that occurs within the brain tissue itself. Intracerebral hemorrhage can be caused by brain trauma, or it can occur spontaneously in hemorrhagic stroke...
which could result from head injuries. For severely low platelet counts, patients may require platelet transfusions or a splenectomy
Splenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
. For patients with frequent infections, intravenous immunoglobulins (IVIG) can be given to boost the immune system. Anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
from bleeding may require iron supplementation or blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
.
As Wiskott–Aldrich syndrome is primarily a disorder of the blood-forming tissues, a hematopoietic
Haematopoiesis
Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells...
stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
transplant, accomplished through a cord blood
Cord blood
Umbilical cord blood is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells which can be used to treat hematopoietic and genetic disorders.-Collection:...
or bone marrow transplant
Bone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
offers the only current hope of cure. This may be recommended for patients with HLA
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
-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
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
using a lentivirus
Lentivirus
Lentivirus is a genus of slow viruses of the Retroviridae family, characterized by a long incubation period...
have begun.
Proof-of-principle for successful hematopoietic stem cell gene therapy has been provided for patients with Wiskott–Aldrich syndrome.
Currently, many investigators continue to develop optimized gene therapy vectors.