Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome is a rare genetic condition that disrupts the immune system, causes dangerous bleeding problems, and leads to persistent eczema. Without proper treatment, this inherited disorder can become life-threatening, but modern medical advances offer hope through stem cell transplantation and gene therapy.

Table of contents

• What is Wiskott-Aldrich syndrome?
• How common is this condition?
• Symptoms and clinical features
• What causes Wiskott-Aldrich syndrome?
• Inheritance pattern
• Related forms of the disease
• Diagnosis
• Treatment options
• Outlook and prognosis

What is Wiskott-Aldrich syndrome?

Wiskott-Aldrich syndrome is a rare genetic disorder that prevents the immune system from working properly. The condition also makes it difficult for the bone marrow to produce platelets, which are the blood cells responsible for stopping bleeding^[1]. This disorder occurs almost exclusively in males^[3].

The human immune system constantly protects the body from enemies like bacteria, viruses, and parasites. The blood and immune system arise from bone marrow, where stem cells mature into different types of blood cells. These include platelets that control bleeding, T cells (white blood cells that identify and attack invaders), and B cells (white blood cells that produce antibodies against infection)^[1].

When a child has Wiskott-Aldrich syndrome, the T cells and B cells are present but don’t work properly. The white blood cells do not properly reach the sites of infections. Additionally, the body does not produce enough platelets, and the platelets that are produced are abnormally small^[1].

How common is this condition?

Wiskott-Aldrich syndrome is extremely rare. According to the National Institutes of Health, only 1 to 10 out of every 1 million boys have this condition^[1]. Other sources estimate the incidence at approximately 1 in 100,000 male live births^[4]. In the United States, this equals less than 5,000 people^[3]. The condition is rare but extremely unlikely among females^[3].

There is no ethnic or geographical predominance for this disorder^[5]. The condition may be under-reported because milder cases are sometimes misdiagnosed as idiopathic thrombocytopenia purpura^[5].

Symptoms and clinical features

Wiskott-Aldrich syndrome is characterized by three main symptoms that form the classic triad of this condition^[4]:

Problems with bleeding and bruising: The condition causes microthrombocytopenia, which means a reduced number and size of platelets in the blood^[2]. This leads to easy bruising, bloody diarrhea, nosebleeds, and prolonged bleeding following minor trauma. Small areas of bleeding just under the skin’s surface create purplish spots called purpura, or tiny red spots called petechiae^[2]. Bleeding can occur under the skin, from the nose, from the gums and mouth, in bowel movements, and in the brain^[1]. In some cases, particularly if bleeding occurs within the brain, it can be life-threatening^[2].

Immune system problems: Without normal immune cells, children with Wiskott-Aldrich syndrome are at constant risk for recurrent bacterial, viral, and fungal infections^[4]. Common infections include pneumonia, ear and sinus infections, and viral infections like herpes, cytomegalovirus (CMV), and Epstein-Barr virus (EBV)^[1].

Eczema: This skin condition causes itchy, dry patches of red, irritated skin affecting various regions of the body^[3]. The eczema in Wiskott-Aldrich syndrome is essentially indistinguishable from that of atopic dermatitis except for the presence of purpura and petechiae^[6].

Most children with Wiskott-Aldrich syndrome begin to display symptoms within the first year of life^[8]. Infants may present with severe thrush or pneumonia^[3].

Beyond the classic triad, children with Wiskott-Aldrich syndrome are also at elevated risk for developing several serious complications. These include autoimmune diseases where the immune system attacks the body’s own tissues, such as autoimmune anemia, neutropenia, thrombocytopenia, rheumatoid arthritis, vasculitis (inflammation of the blood vessels), inflammatory bowel disease, and nephritis (kidney inflammation)^[1]. Autoimmune disease is common and occurs in up to 40 to 70 percent of patients^[6].

There is also a significantly increased risk of developing cancer, particularly lymphoma, leukemia, and myelodysplasia^[6]. The chance of developing these cancers is estimated at 10 to 20 percent^[6].

What causes Wiskott-Aldrich syndrome?

A genetic change (mutation) in the WAS gene causes Wiskott-Aldrich syndrome. The WAS gene is located on the short arm of the X chromosome at position Xp11.22-23^[5]. This gene is responsible for producing the Wiskott-Aldrich syndrome protein, which is present in all blood cells except red blood cells^[3].

The Wiskott-Aldrich syndrome protein plays a crucial role in relaying signals from the surface of blood cells to the actin cytoskeleton, which is a network of fibers that makes up the cell’s structural framework^[2]. This protein is involved in cellular processes including cell movement, attachment to other cells and tissues (a process called adhesion), and the formation of connections between immune cells and foreign invaders they target^[2].

When the WAS gene is mutated, blood cells aren’t able to attach to other cells and tissues properly. This affects how the immune system defends itself, which results in the symptoms of Wiskott-Aldrich syndrome^[3]. White blood cells that lack functional protein have a decreased ability to respond to their environment. As a result, they are less able to respond to foreign invaders, causing many of the immune problems related to the condition^[2].

Similarly, the lack of functional protein in platelets impairs their development, leading to reduced size and early cell death. The normal process of removing platelets from circulation and taking them to the spleen for destruction also likely contributes to the low platelet count^[2].

More than 300 unique mutations in the WAS gene have been identified^[6]. The most common mutations are missense mutations, followed by nonsense, splice-site, and short deletion mutations^[6]. The specific type of mutation affects the severity of the disease^[5].

Inheritance pattern

Wiskott-Aldrich syndrome is inherited in an X-linked recessive pattern. This condition is considered X-linked because the mutated gene that causes the disorder is located on the X chromosome^[2].

Every person inherits one sex chromosome from each of their biological parents. Males have one X chromosome and one Y chromosome, while females have two X chromosomes. Because males have only one X chromosome, a single mutated copy of the WAS gene is sufficient to cause the condition in males. This is why Wiskott-Aldrich syndrome primarily affects males^[2].

Females who have one mutated copy of the WAS gene are typically carriers of the condition. They usually do not experience symptoms because they have a second, normal copy of the gene on their other X chromosome^[8]. However, female carriers can pass the mutation to their children.

The condition was clearly demonstrated to have an X-linked mode of inheritance in 1954 when Dr. Robert Aldrich, an American pediatrician, reported a Dutch family with affected boys across multiple generations^[6]. Notably, the sisters in the original family described by Dr. Alfred Wiskott in 1937 did not have symptoms^[4].

Related forms of the disease

Wiskott-Aldrich syndrome exists on a disease spectrum with variable presentation ranging from severe to milder forms^[5]. Healthcare providers may refer to these conditions collectively as WAS-related disorders^[3].

The majority of boys have what is known as the “classic” form of Wiskott-Aldrich syndrome, which includes the full triad of symptoms^[1]. However, in one study of 154 patients, only 30 percent had the classic presentation with all features^[6].

Some children experience a milder form of the disease known as X-linked thrombocytopenia (XLT). This is caused by a defect in the same gene involved in classic Wiskott-Aldrich syndrome, but the symptoms are much milder^[1]. Usually, children with X-linked thrombocytopenia have platelets that are overly small in both size and number. As a result, they have trouble with easy bleeding and bruising, but do not experience the other more serious complications like severe infections, autoimmune diseases, or cancer^[10].

Another related condition is X-linked neutropenia, also called congenital neutropenia. In this form, the genetic mutation causes neutrophils (a type of white blood cell) and monocytes (another type of white blood cell) to stall in their movement, so the immune system doesn’t release them to fight infection^[3]. This condition may present with severe bacterial infections^[3].

The severity of disease depends on the type of mutation in the WAS gene. In general, mutations that cause absent protein expression result in classic Wiskott-Aldrich syndrome. Reduced protein expression results in X-linked thrombocytopenia. Activating gain-of-function mutations result in X-linked neutropenia^[6].

Diagnosis

Recognition of Wiskott-Aldrich syndrome is important because curative therapies are available, without which median survival is reduced to 10 to 15 years of age^[10]. Milder forms of the disease that have some, but not all, of the usual symptoms can sometimes cause delays in making a correct diagnosis^[4].

The diagnosis typically begins when doctors notice the characteristic combination of symptoms, particularly small platelets and low platelet counts detected through blood testing. The platelet abnormality is typically present from birth^[2].

Genetic testing is used to confirm the diagnosis by identifying mutations in the WAS gene. In 1994, the gene that doesn’t work in individuals with Wiskott-Aldrich syndrome was identified, which led to better understanding of the disease spectrum^[4].

Additional laboratory studies may be performed to assess immune function and check for complications of the disease.

Treatment options

Patients with Wiskott-Aldrich syndrome require vigilant medical care and should be referred to a center with expertise in pediatric immunodeficiencies^[12]. Treatment approaches can be divided into supportive care and definitive curative therapies.

Supportive and preventive care: General treatment strategies include prophylactic antibiotics, immunoglobulin replacement therapy, and management of specific complications^[12].

Patients may receive immunoglobulin replacement therapy through intravenous infusions (IVIG) every 3 to 4 weeks or subcutaneous immunoglobulin (SQIG) every week. This helps protect against infections^[12]. Additional prophylactic antibiotics such as trimethoprim-sulfamethoxazole may be given to prevent specific infections like Pneumocystis jirovecii pneumonia^[12].

Eczema may be severe and requires aggressive management with careful attention to skin care, use of emollients, and appropriate topical steroid therapy^[12]. Infections must be treated promptly and aggressively^[12].

Patients with severe low platelet counts may require high-dose intravenous immunoglobulin and corticosteroids. Those with severe bleeding may require platelet or red blood cell transfusions. All blood products should be irradiated to prevent graft-versus-host disease^[12].

Autoimmune complications can be difficult to treat but may respond to medications like rituximab combined with corticosteroids^[12]. Surveillance for malignancy is an important aspect of care^[12].

Definitive curative therapies: The standard of care for infants with classic Wiskott-Aldrich syndrome is early hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplant, prior to the development of complications from infection, bleeding, and autoimmune disease^[12]. This is currently the only treatment that can permanently cure the disease when a compatible donor is available^[7].

For patients without a compatible donor, gene therapy based on correction of autologous hematopoietic stem cells brings considerable hope^[7]. Treatment involves taking samples of the patient’s hematopoietic stem cells that carry the genetic abnormality, then correcting them in the laboratory by introducing the healthy WAS gene using a lentiviral vector. The corrected cells are then re-injected into the patient after chemotherapy treatment^[7].

International clinical trials of gene therapy have been conducted in France, the United Kingdom, and the United States^[7]. Results from these trials showed overall improvement in the clinical condition of patients, including reduction of severe eczema, serious infections and bleeding, and improved platelet levels in the blood^[7]. Long-term follow-up studies spanning up to nine years have demonstrated that gene-corrected cells engraft stably, with no severe adverse effects related to the treatment, and patients experienced significant and stable reduction in their symptoms^[13].

In some specific cases, particularly for patients with isolated severe bleeding problems, splenectomy (surgical removal of the spleen) may be considered, though this decision requires careful evaluation^[12].

Patients with Wiskott-Aldrich syndrome should not receive live attenuated vaccines because of their compromised immune system. Killed vaccines may be given, though responses may be insufficient due to the underlying immune dysfunction^[12].

Outlook and prognosis

Without treatment, Wiskott-Aldrich syndrome can lead to life-threatening complications and a reduced life expectancy. In the original family described by Dr. Wiskott, all three affected brothers died at an early age from complications of bleeding or infection^[4]. Without curative therapy, median survival is reduced to 10 to 15 years of age^[10].

However, treatment options help prevent life-threatening risks^[3]. With modern stem cell transplantation and gene therapy, the outlook for patients with Wiskott-Aldrich syndrome has improved significantly. Early recognition and treatment are critical for the best outcomes.

The milder form of the disease, X-linked thrombocytopenia, shares similar bleeding risk from low platelet counts but is not associated with other significant clinical features and is generally managed conservatively without requiring definitive curative therapy^[10].

Following definitive treatment, patients require long-term monitoring. Those who undergo gene therapy are typically monitored for 10 years: 2 years in the main trial, then 8 years in a safety follow-up study^[7].