SummaryWHIM syndrome is a rare primary immunodeficiency disorder, which are disorders in which the body’s immune system does not function properly. WHIM is an acronym for some of the characteristic symptoms of the disorder - (w)arts, (h)ypogammaglobulinemia, (i)nfections, and (m)yelokathexis. Individuals with WHIM syndrome are more susceptible to potentially life-threatening bacterial infections. To a lesser extent, they are also predisposed to viral infections. Affected individuals are particularly susceptible to human papillomavirus (HPV), which can cause skin and genital warts and potentially lead to cancer. Affected individuals have extremely low levels of certain white bloods (neutrophils) in the blood (neutropenia). In most cases, WHIM syndrome is caused by mutations of the CXCR4 gene. This mutation is inherited as an autosomal dominant trait.
IntroductionWHIM syndrome is a primary immunodeficiency disorder, one of a group of disorders characterized by irregularities in the cell development and/or cell maturation process of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against infectious agents. The T cell system (cell-mediated immune response) contributes to fighting several viruses, some bacteria and yeast and fungi. The B cell system (humoral immune response) fights infection caused by other viruses and bacteria. It does so by secreting immune factors called antibodies (also known as immunoglobulins) into the fluid portion of the blood (serum) and body secretions (e.g. saliva). There are five classes of immunoglobulins (Ig) known as IgA, IgD, IgE, IgG, and IgM. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells.
The symptoms of WHIM syndrome can vary greatly from one individual to another. Some individuals may have mild expression of the disorder; others may develop potentially life-threatening complications. Additionally, several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disease outcome prevent physicians from developing a perfectly accurate picture of associated symptoms and prognosis.
Generally, symptoms first appear in early childhood when most children experience repeated bacterial infections that can be mild or severe, but usually respond promptly to antibiotic therapy. The number and frequency of infections can vary greatly from one individual to another. Common infections in children with WHIM syndrome include recurrent middle ear infections (otitis media), infection of the skin and underlying tissue (cellulitis, impetigo, folliculitis, and abscess), bacterial pneumonia, sinusitis, painful infections of the joints (septic arthritis), dental cavities, and infection of the gums (periodontitis). Bone infection (osteomyelitis), urinary tract infections, and infection of the membranes covering the brain (meningitis) have also been reported.
Chronic infections can potentially cause additional symptoms. For example, some individuals who experience repeated ear infections may experience hearing loss. Dental infections can lead to tooth loss. Some individuals who experience repeated episodes of pneumonia may eventually develop destruction and widening of the airway tubes that carry air in and out of the lungs (bronchiectasis). Bronchiecstasis can further lead to repeated lung infections and potentially serious complications including respiratory failure, lung collapse (atelectasis), and heart failure. Some affected individuals have developed colonization of their respiratory tract with bacterial organisms such as Pseudomonas and Stenotrophomonas common in another genetic disorder called cystic fibrosis.
Upon exposure, affected individuals may develop warts due to infection with human papillomavirus (HPV), a virus that only infects humans and has more than 150 related types. Warts usually develop in the late teens, but can be seen in early childhood in some cases. Warts may be widespread affecting the hands, feet, face, and trunk and are often highly resistant to treatment (recalcitrant). Mucosal and genital warts may also develop and these warts are associated with an increased risk of progressing into a form of cancer known as carcinoma. HPV infection has been linked to cervical carcinoma in WHIM syndrome. Two siblings with WHIM syndrome developed carcinoma of the oral cavity.
Myelokathexis is a medical term for characteristic bone marrow pathology findings which include having too many white blood cells present in the bone marrow (hypercellularity). Bone marrow is the spongy substance found in the center of the long bones of the body. The bone marrow produces specialized cells that grow and develop into red blood cells, white blood cells and platelets. These cells are released into the bloodstream to perform their normal functions within the body. However, although neutrophil production occurs normally in individuals with WHIM syndrome, mature neutrophils are retained and eventually die within the bone marrow without being released into the bloodstream. Consequently, affected individuals have low levels of circulating neutrophils (neutropenia) in the blood; however this can be overcome during periods of severe infection or stress. Neutrophils play a role in the helping the body fight off infection, especially bacterial and fungal infections.
In addition to neutropenia, most individuals with WHIM syndrome also have low levels of another type of white blood cell known as a B-lymphocyte. B-lymphocytes create antibodies (immunoglobulins) in response to bacterial or viral infection. Consequently, affected individuals have low levels of certain antibodies, a condition known as hypogammaglobulinemia. The lack of sufficient B-lymphocyte antibodies leaves individuals susceptible to infection with specific types of bacteria or, to a lesser extent, certain viruses. Some affected individuals may also have low levels of other white blood cells such as T cells or natural killer cells. Some individuals have low levels of all white blood cells (panleukopenia). Although the white blood cell counts of affected individuals can be profoundly altered, it appears that the spectrum of infections that occurs in individuals with WHIM syndrome is limited.
Additional findings have been reported in specific cases. Two individuals with WHIM syndrome have developed Epstein Barr associated B cell lymphoma. Three affected individuals had a severe congenital heart malformation known as tetralogy of Fallot.
WHIM syndrome is caused by several different mutations in the chemokine receptor (CXCR4) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In the case of the known mutations that cause WHIM syndrome the mutations make the protein hyperfunctional and are thus called gain-of-function mutations.
The mutation that causes WHIM syndrome is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
Some mutations occur as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent.
Investigators have determined that the CXCR4 gene is located on the long arm (q) of chromosome 2 (2q22.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 2q22.1” refers to band 22.1 on the long arm of chromosome 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The CXCR4 gene creates (encodes) a chemokine receptor known as CXCR4. Chemokines are a special class of protein that are involved in cell trafficking. Cell trafficking is a normal process in which certain cells receive instructions telling them where in the body they should travel (migrate) to and when to stop. Mutations in the CXCR4 gene lead to increased activity of the CXCR4 protein product. It is not fully understood how increased activity of this chemokine receptor affects B cell number and function or leads to HPV susceptibility. Some studies have suggested that increased CXCR4 activity acts on mature neutrophils preventing their release from the bone marrow. More research is necessary to determine the complex, underling mechanisms that cause WHIM syndrome.
Some individuals with the characteristic symptoms of WHIM syndrome do not have a detectable mutation in the CXCR4 gene suggesting that the disorder may have other genetic causes.
WHIM syndrome is an extremely rare disorder and its exact prevalence or incidence in the general population is unknown although it has been estimated at about 0.2 / million live births. Approximately 60 cases have been reported in the medical literature. Onset is usually in infancy or early childhood. Males and females are affected in equal numbers.
A diagnosis of WHIM syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including genetic tests. Individuals with a history of recurrent bacterial infections, neutropenia, and recalcitrant warts should be tested for WHIM syndrome.
Clinical Testing and Workup
A complete blood count (CBC) will show low levels of neutrophils (neutropenia) in uninfected patients, a variable degree of lymphopenia, and normal to low hemoglobulin and platelet levels. Initial workups can also reveal hypogammaglobulinemia (low IgG) or poor response to vaccinations.
If WHIM syndrome is suspected based on initial tests, the surgical removal and microscopic examination of bone marrow tissue (bone marrow biopsy) may be performed. A bone marrow biopsy can reveal myelokathexis, which along with characteristic findings, is strongly suggestive of WHIM syndrome.
In most cases, molecular genetic testing can confirm a diagnosis of WHIM syndrome. Molecular genetic testing can detect mutations in the CXCR4 gene known to cause the disorder and is available at the National Institutes of Health at no charge if clinically indicated and informed consent is given.
The treatment of WHIM syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, immunologists, hematologists, dermatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Prompt diagnosis and early aggressive treatment of infections is important to reduce the frequency of chronic bacterial infections. Treatment may include injection of granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF), which can help to normalize neutrophil counts. These drugs stimulate the production and maturation of neutrophils.
Another therapy used to treat individuals with WHIM syndrome is monthly infusions with purified antibodies (immunoglobulins) obtained from human plasma, the fluid portion of the blood. This therapy is known as intravenous immunoglobulin or IVIG. IVIG therapy can treat hypogammaglobulinemia and can help reduce the frequency of the recurrent infections characteristic of WHIM syndrome. Immunoglobulin therapy can also be given subcutaneously on a weekly basis.
The preventative (prophylactic) use of antibiotics has not been studied in WHIM syndrome, but has proven effective in other primary immunodeficiency disorders.
HPV-associated warts often prove highly resistant to conventional treatment and frequently recur after surgery. Affected individuals should be regularly monitored to promptly detect and surgically remove within the early stages any HPV lesions that appear pre-malignant or malignant.
Because WHIM syndrome is associated with hyperfunction of the chemokine receptor CXCR4, researchers have proposed treating affected individuals with medications that inhibit CXCR4 activity. Such agents include plerixafor, a drug that is currently approved by the Food and Drug Administration (FDA) for individuals who are preparing to undergo a hematopoietic stem cell transplant. Initial studies of plerixafor in individuals with WHIM syndrome have been promising and have helped neutrophils and other white blood cells move from the bone marrow into the bloodstream. More research is necessary to determine the long-term safety and effectiveness of plerixafor for the treatment of individuals with WHIM syndrome.
Preventative (prophylactic) treatment with the HPV vaccine has been tested in some individuals with WHIM syndrome. Early vaccination may be able to prevent certain HPV infections and reduce HPV related cancer potentially associated with WHIM syndrome. However, the underlying immune defects associated with the disorder may lessen the effectiveness of such protection, thereby requiring periodic re-vaccination. More research is necessary to determine what role preventative HPV vaccination has in the treatment of individuals with WHIM syndrome.
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