Introduction
WHIM syndrome is an extremely rare congenital and autosomal dominant immune deficiency disorder. Most people with WHIM syndrome are initially given the incorrect diagnosis of common variable immune deficiency (CVID), a more common type of immune deficiency, or a more typical type of neutropenia. The prevalence or incidence of WHIM syndrome in the general population is unknown, but it has been estimated to be around 0.2 per million live births. WHIM syndrome is an extremely rare disorder. There have been about 60 cases reported in the medical literature. It can affect equally as many boys and girls, and its onset typically happens in infancy or early childhood.
What Is WHIM Syndrome?
WHIM syndrome is an immunodeficient condition that is characterized by warts, hypogammaglobulinemia (fewer antibodies or gamma globulins are produced by the body), infections, and myelokathexis (a congenital condition that results in severe chronic neutropenia and leukopenia). The features of this disease also form its acronym, WHIM. People with WHIM syndrome are more prone to bacterial infections that could be fatal. They are also susceptible to viral infection, up to some extent. They are most susceptible to human papillomavirus (HPV) infection. HPV causes skin and genital warts, which can eventually lead to cancer. WHIM syndrome patients also have incredibly low levels of neutrophils, a type of white blood cell that aids in the body's defense against infection, particularly bacterial and fungal infections.
What Are the Causes of Whim Syndrome?
The mutation in WHIM syndrome is inherited as an autosomal dominant trait, which means that only one abnormal copy of the gene is required for the disease to showcase its clinical manifestations. The abnormal gene may be due to a recent mutation in the gene of the affected person, or it may have been inherited from one of the parents. Regardless of the sex of the offspring, there is a 50 percent chance that the abnormal gene will be passed from the affected parent to the offspring during each pregnancy.
WHIM syndrome is usually brought on by mutations in the gene that codes for the CXCR4 chemokine receptor. The mutation in the CXCR4 gene is also called a "gain-in-function mutation," as it causes an increase in activity by failing to bring down the activities of the CXCR4 gene. The movement of leukocytes, or white blood cells, is regulated by the protein coded by the CXCR4 gene. The CXCR4 chemokine receptor is more active in the WHIM syndrome, which prevents mature neutrophils from being released from the bone marrow. Some people who manifest the clinical symptoms of WHIM syndrome may not have a mutation in the CXCR4 gene, and instead, their cases may be related to some other genetic causes.
What Are the Clinical Manifestations of Whim Syndrome?
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The clinical characteristics that present in a specific patient and the age of the initial diagnosis can differ.
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All the patients experience recurrent infections beginning in early childhood. Numerous skin and soft tissue infections (cellulitis, impetigo, folliculitis, and abscesses), bacterial pneumonia, sinusitis, painful joint infections (septic arthritis), dental cavities, and gum infections are among the more typical infections (periodontitis). There have also been reports of infections of the membranes surrounding the brain (meningitis), urinary tract infections, and infections of the bones (osteomyelitis).
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Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, Staphylococcus aureus, and Proteus mirabilis are just a few examples of common pathogens that cause infection in patients with WHIM syndrome.
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Constant infections may result in additional symptoms. For instance, some people who frequently get ear infections might end up losing their hearing. The widening of the lungs' airways, or bronchiectasis, may develop as a result of recurrent pneumonia episodes. Repeated lung infections and potentially life-threatening complications can result from bronchiectasis.
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Patients with WHIM syndrome frequently have neutropenia (less amount of neutrophils circulating in the blood). However, they have a normal amount of neutrophils in their bone marrow.
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Individuals with WHIM syndrome also have low levels of B-lymphocytes that produce antibodies in response to bacterial or viral infection.
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Hypogammaglobulinemia, a condition characterized by low levels of specific antibodies, affects individuals with WHIM syndrome. People who do not have enough antibodies are more vulnerable to contracting certain viral and bacterial infections. Some patients may also have less value of T cells, natural killer cells, or all white blood cells. This condition is known as pancytopenia or panleukopenia. However, these features are not present in all patients who are suffering from WHIM syndrome.
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Warts are commonly seen in patients with WHIM syndrome due to human papilloma virus. Warts can be seen as early as childhood but typically appear in adolescence. The hands, feet, face, trunk, and other areas may be affected, and warts frequently return despite treatment. Warts that grow on the mucosa, the mouth, or the genitalia can increase the risk of cancer. After surgery or other conventional therapy, HPV-related warts generally come back. It is advised to perform regular monitoring to quickly identify and surgically remove any HPV lesions that seem malignant or premalignant.
How Is WHIM Syndrome Diagnosed?
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A complete blood count will reveal normal to low levels of hemoglobin and platelets, as well as low neutrophil counts, neutropenia, varying degrees of lymphopenia, and neutrophil and lymphopenia. Hypogammaglobulinemia can also be found during initial workups.
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Bone marrow biopsy is suggested if the initial test shows indications of WHIM syndrome. If the biopsy shows the presence of myelokathexis, it is highly suggestive of WHIM syndrome.
What Is the Treatment for WHIM Syndrome?
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Immunoglobulin replacement therapy, granulocyte colony-stimulating factor (G-CSF), or granulocyte-macrophage colony-stimulating factor (GM-CSF) may be used to treat WHIM syndrome in order to increase neutrophil production and maturation and lower the risk of infection.
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To lessen the incidence of chronic bacterial infections, prompt diagnosis, and aggressive early treatment are crucial. Not every patient needs ongoing treatment.
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Immunoglobulin replacement therapy has been effective in lowering infections in WHIM syndrome patients. Immunoglobulin therapy can treat hypogammaglobulinemia and help lessen the frequency of recurrent bacterial infections, whether it is given intravenously (IVIG) or subcutaneously (SCIG).
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Given the known safety of the vaccine and the severity of HPV infections in patients with WHIM syndrome, vaccination against HPV should be seriously considered in these patients. Since the underlying immune defects linked to the disorder may reduce the effectiveness of such protection, periodic revaccination may be required.
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Another effective measure to treat WHIM syndrome can be bone marrow transplants however no studies (due to the smaller number of cases) have been conducted to prove the effectiveness of the treatment.
Conclusion
WHIM syndrome is a primary immunodeficiency. It is a condition in which the immune system struggles to effectively fight infections, particularly respiratory, ear, and skin infections. It can be challenging to make the proper diagnosis because people with WHIM syndrome do not always experience the same symptoms. Healthcare providers are unable to create a precise picture of the associated symptoms and prognosis due to the small number of identified cases, the lack of significant clinical studies, and the possibility that other genes may affect the disease outcome. A proper diagnosis can alter a patient's course of treatment and outcome.
