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Last updated: 7/22/2024
Years published: 2013, 2016, 2020, 2024
NORD gratefully acknowledges David H. McDermott, MD, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, for assistance in the preparation of this report.
Summary
WHIM syndrome is a rare primary immunodeficiency disorder, which is a disorder 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 blood cells (neutrophils) leading to a condition called neutropenia. In most patients, WHIM syndrome is caused by changes (variants) in the CXCR4 gene and inherited in an autosomal dominant pattern.
Introduction
The symptoms of WHIM syndrome can vary greatly from one individual to another. Some individuals may have mild expression of the disorder and others may develop potentially life-threatening complications. Several factors including the small number of identified patients, 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 with WHIM syndrome 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 develop 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). Bronchiectasis 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 teens but can be seen in early childhood. Warts may be widespread affecting the hands, feet, face and trunk and are often recurrent despite treatment (recalcitrant). Mucosal, oral 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 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 make 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 patients. 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 multiple different variants 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 variant in a gene occurs, the protein product may be faulty, inefficient or absent or have increased function. A single protein can affect many organ systems of the body. In the case of the known variants that cause WHIM syndrome, the variants make the protein hyperfunctional and are thus called gain-of-function variants.
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. Variants 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, underlying mechanisms that cause WHIM syndrome.
Some very rare individuals with the characteristic symptoms of WHIM syndrome do not have a detectable variant in the CXCR4 gene suggesting that the disorder may have other genetic causes.
WHIM syndrome is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
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 livebirths. Approximately 180 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 with differential (CBC + Diff) 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, 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 patients, molecular genetic testing can confirm a diagnosis of WHIM syndrome. Molecular genetic testing can detect variants 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.
Treatment
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 plan an affected child’s treatment systematically and comprehensively.
Prompt diagnosis and early aggressive treatment of infections is important to reduce long term damage. Treatment may include injection of granulocyte colony stimulating factor (G-CSF) which can help to normalize neutrophil counts. This drug stimulates 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 frequently recur after surgery or other conventional therapy. Affected individuals should be regularly monitored to promptly detect and surgically remove any HPV lesions that appear pre-malignant or malignant within the early stages.
In 2024, mavorixafor (Xolremdi) was approved by the U.S. Food and Drug Administration (FDA) to treat patients 12 years of age and older with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
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 FDA for some individuals who are preparing to undergo a hematopoietic stem cell transplant and mavorixafor, which was FDA approved for WHIM treatment in 2024. Initial published studies of both agents 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 both agents.
Bone marrow transplant (BMT) where blood stem cells from another person (allogenic donor) are used may be able to cure many aspects of the disease. However, current practices for BMT typically require pre-transplant chemotherapy or radiation therapy of the recipient. These treatments can severely diminish the patient’s immune function for a period of time after the BMT and the white blood cells from the donor can attack the recipient’s normal tissues causing graft versus host disease (GvHD). Using stem cells from the patient (autologous) and genetically correcting them outside the body and giving them back (gene therapy) might avoid these issues but is still under investigation for 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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Kawai T, Malech HL. WHIM syndrome: congenital immune deficiency disease.
BOOK CHAPTERS McDermott DH. Warts Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome in Steihm’s Immune Deficiencies. 2014;709-717.
McDermott DH and Murphy PM. WHIM Syndrome (WHIMS) in Genetic Syndromes. Nima Rezaei, editor. Springer Reference Medicine. https://doi.org/10.1007/978-3-319-66816-1. 2023.
JOURNAL ARTICLES Badolato R, Alsina L, Azar A, et al. Phase 3 randomized trial of mavorixfor, CXCR4 antagonist, in WHIM syndrome. Blood. 2024 PMID 38643510
McDermott DH, Velez D, Cho E, et al. A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome. J. Clin Invest. 2023 (133(19):e164918 PMC11007684
Heusinkveld LE, Majumdar S, Gao JL, et al. WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure. J Clin Immunol. 2019; 39(6):532-556. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698215/
McDermott DH, Pastrana DV, Calvo KR, et al. Plerixafor for the Treatment of WHIM Syndrome. N Engl J Med. 2019; 380(2): 163-170. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425947/
McDermott DH, Pastrana DV, Calvo KR, et al. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor. Blood 2014;123:2308-16. http://www.ncbi.nlm.nih.gov/pubmed/24523241
Badolato R, Dotta L, Tassone L, et al. Tetralogy of Fallot is an uncommon manifestation of Warts, Hypogammaglobulinemia, Infections, and Myelokathexis syndrome. J Pediatr. 2012;161:763-765. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458406/
Beaussant Cohen S, Fenneteau O, Plouvier E, et al. Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Neutropenia Registry. Orphanet J Rare Dis. 2012;7:71. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585856/
McDermott DH, Liu Q, Ulrick J, et al. The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome. Blood 2011;118:4957-4962. http://www.ncbi.nlm.nih.gov/pubmed/21890643
Diaz GA. Released on a WHIM. Blood 2011;118:4764-4765. http://www.ncbi.nlm.nih.gov/pubmed/22053172
Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011;6:26. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127744/
McDermott DH, Lopez J, Deng F, et al. AMD3100 is a potent antagonist at CXCR4R334X, a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome. J Cell Mol Med. 2011;15:2071-2081. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071896/
Dale DC, Bolyard AA, Kelley ML, et al. The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome. Blood 2011;118:4963-4966. http://www.ncbi.nlm.nih.gov/pubmed/21835955
Kawai T, Malech HL. WHIM syndrome: congenital immune deficiency disease. Curr Opin Hematol. 2009;16:20-26. https://www.ncbi.nlm.hih.gov/pmc/articles/PMC2673024/
Hagan JB, Nguyen PL. WHIM syndrome. Mayo Clin Proc. 2007;82:1031. http://www.ncbi.nlm.nih.gov/pubmed/17803866
Taniuchi S, Masuda M, Fujii Y, et al. The role of a mutation of the CXCR4 gene in WHIM syndrome. Haematologica. 2005;90:1271-1272. http://www.ncbi.nlm.nih.gov/pubmed/16154852
Gorlin RJ, Gelb B, Dian GA, et al. WHIM syndrome, an autosomal dominant disorder: clinical, hematological, and molecular studies. Am J Med Genet. 2000;91:368-376. http://www.ncbi.nlm.nih.gov/pubmed/10767001
INTERNET
Whim syndrome. Online Mendelian Inheritance in Man (OMIM). Entry No:193670; Last Update: 07/09/2021. Available at: http://omim.org/entry/193670 Accessed May 5, 2024
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