WHIM syndrome is a rare, congenital primary immunodeficiency disorder associated with severe neutropenia that affects all ages. However, due to the heterogeneous presentation of the disease, coupled with lack of awareness of the condition, the diagnosis may be delayed, sometimes even into adulthood. The acronym “WHIM” stands for (W)arts, (H)ypogammaglobulinemia, (I)nfections, and (M)yelokathexis. Myelokathexis refers to an abnormal retention of white blood cells, in the bone marrow, that causes a reduction of immune fighting white blood cells, and most notably the reduction of neutrophils and lymphocytes. Importantly, the acronym WHIM can be misleading because most patients will NOT present with all the symptoms associated with the four letters of the term (W.H.I. or M.), and therefore the diagnosis of the disease may be delayed, or misdiagnosed and, consequently, underdiagnosed. Disease understanding and awareness is improving as is the discovery and development of novel treatment approaches (see Novel Treatments on the horizon)
WHIM Syndrome Overview
Philip M. Murphy, MD, Chief, Molecular Signaling Section, Laboratory of Molecular Immunology; Chief, Laboratory of Molecular Immunology, National Institute of Allergy and Infection, provides an overview of WHIM syndrome.
PATHOPHYSIOLOGY AND EPIDEMIOLOGY
WHIM syndrome is caused by mutations of the CXCR4 gene that are inherited as an autosomal dominant trait. The CXCR4 protein is a chemokine receptor that is common to both hematopoietic and nonhematopoietic cells. There is evidence that the CXCR4 receptor is involved with B-lymphocyte trafficking throughout the body. Current theory suggests that the mutations, associated with WHIM syndrome, cause abnormal retention of neutrophils in the bone marrow, preventing them from being released in the blood, resulting in neutropenia, which can present an increased risk for recurrent or severe infections for patients.
In 2012, French researchers estimated the incidence of WHIM to be less than one in a million births. In a 2019 publication, Italian researchers stated, “The increasing number of patients diagnosed in recent years suggests that the real incidence of this primary immunodeficiency may be underestimated, as delay in its recognition remains remarkable.”
Patients with WHIM syndrome have been reported in the literature at increasing rates over the last decade. A recent publication from the National Institutes of Health (NIH) reported on 105 published cases of WHIM syndrome from 1964-2019. The great majority of cases reported were from the US and Western Europe, especially Italy and France, but cases have also been reported in South America and Asia.
Like many rare diseases, the true prevalence of WHIM syndrome remains unknown, but advances in genetic diagnostic techniques (such as Next-Generation-Sequencing) and rising awareness about the disease is expected to facilitate early recognition and diagnosis.
SIGNS AND SYMPTOMS
Most individuals with WHIM syndrome have severe neutropenia, which means that they have low levels of neutrophils in their blood. In addition, most patients may also have profound lymphopenia, which means they have low levels of lymphocytes (namely T cells and B Cells) in their blood. Because of this, WHIM syndrome can be classified as both a Severe Congenital Neutropenia (SCN) and a Combined Immune Deficiency (CID). B lymphocytes are usually particularly low, and this probably prevents the immune system of some WHIM patients from making enough antibodies called immunoglobulins (hypogammaglobulinemia). Antibodies are proteins that help your body recognize and fight off causes of infections like bacteria, viruses, and fungi.
The first clinical symptoms, that often appear in very young patients, are recurrent bacterial infections (especially respiratory infections like sinusitis, otitis media, and pneumonia) and cellulitis. More than half of the patients will report a history of treatment resistant warts, which classically appear before the age of 10 years. Warts may be extensive and involve the ano-genital area and related to human papillomavirus virus (HPV) infection (which often first manifests in early childhood between the ages of 5 and 10). These HPV-related warts are resistant to treatments such as freezing (cryotherapy), salicylic acid or even surgical removal that are typically effective in other patients with warts.
In addition to infections and warts, WHIM patients may be prone to an increased risk of cancer (carcinoma), particularly when HPV warts are located in the ano-genital region although there have been reports of cancers in other parts of the body such as oral cavity. The 2019, “Long Term outcome of WHIM syndrome in 18 patients” observed HPV-related malignancy in 17% of patients (3/18). Finally, some patients also have defects of the cardiovascular (in particular Tetralogy of Fallot), urogenital, and nervous systems.
In one review of reported cases, the clinical features of WHIM were noticeable at a mean of 2 years of age, but diagnosis was not made until the patients were 12 or 13 years old. Severe bacterial infection occurred in 78% of patients, with recurrent pneumonia in 61% of cases that was complicated with bronchiectasis in 27% of patients. Patients were a mean age of 11 years of age by the time cutaneous warts were observed (in 61% of children).
Two thirds of patients have a family history of WHIM syndrome. Therefore, a family history of WHIM syndrome can facilitate the diagnosis of the disease, however, it is estimated that 30% of cases of WHIM syndrome are identified without such a family history (sporadic), reinforcing the idea that that systematic implementation of genetic testing is important for identifying these patients earlier in the course of the disease.
While identification of the most notable signs of WHIM syndrome may be straightforward, diagnosis is challenging because of its rarity and the array of the clinical presentation. Complete blood count testing (with differential) will often yield abnormally low neutrophil counts (unless bolstered during episodes of infection), low total white blood cells and low lymphocytes, and about half of the patients have low IgG, IgM and/or IgA concentrations. A detailed patient history often reveals recurrent infections in the patient. However, one of the challenges to diagnosis is the temporary, normal levels of white blood cells during acute infections,[4,6.7] which is the moment when patients most commonly seek medical attention. Because of this, looking only at blood counts drawn during an acute infection can lead clinicians into missing the key sign of low neutrophils, and therefore may cause them to miss the diagnosis. As a result, diagnosis may be delayed until other characteristics of WHIM appear, and this delay may impact the initiation of appropriate treatment.
If WHIM syndrome is suspected, a patient’s diagnosis can be confirmed through genetic tests to identify mutations in the CXCR4 gene. Bone marrow biopsies, If performed, will reveal myelokathexis.
MANAGEMENT AND CURRENT TREATMENT
Today, WHIM syndrome is managed based on the clinical signs and or symptoms presented by patients.
Physicians may choose to use therapies that replace antibodies (immunoglobulins) or increase the number of neutrophils (granulocyte–colony stimulating factor (G-CSF)), vaccinations (e.g. HPV), and prophylacticantibiotics to reduce the risk of infections in patients with WHIM syndrome. The dose of G-CSF (e.g., filgrastim) should be individualized, based on each patient’s level of neutropenia. The effectiveness of these treatments, in patients with WHIM syndrome, has not been investigated in controlled trials, presumably because of the low number of study subjects available. However, based on drug trials in patients with other types of immune disorders, it is a recommended practice. In an international review of patient cases, roughly half of patients with WHIM syndrome were given antibiotic prophylaxis. Seventy-two percent of patients were administered granulocyte–colony stimulating factors ([G-CSF], e.g., filgrastim), and 55% were given intravenous immunoglobulin treatments.
Unfortunately, therapy with G-CSF does not help resolve either the lymphopenia or monocytopenia associated with WHIM syndrome and has no effect on HPV -induced warts. Furthermore, G-CSF use can result in severe bone pain and chronic G-CSF use can cause other hematologic conditions. A review of 24 patients with WHIM syndrome in 9 families found that although G-CSF therapy is deemed controversial, it was effective in preventing and treating infections.
Warts are classically reported to be resistant to treatment, may proliferate extensively, and affect the hands or feet, face, arms, or legs. Approximately 20 to 25% of WHIM patients report anogenital condyloma acuminata. Anogenital warts are at particularly high risk of malignant transformation. Indeed, the literature describes multiple cases of cervical and vulvar dysplasia that progressed to invasive genital cancer.
There are currently no approved treatments addressing HPV susceptibility and HPV vaccine response appears impaired with no substantial reduction in the burden of lesions. Standard treatment methods (cauterization, laser therapy) and more aggressive approaches (surgical removal, interferon, cidofovir, Imiquimod) have not proven effective against cutaneous or genital warts.
COMPLICATIONS OF WHIM SYNDROME
Overall, in WHIM patients, disease morbidity and mortality is highly dependent upon the frequency and severity of bacterial infections, the development of chronic lung disease, and the severity of HPV manifestations.
Reports underscore the importance of early diagnosis in patients with chronic neutropenia. Immediate long-term treatment strategies, careful monitoring, and timely intervention for complications may control the frequency of bacterial infections and prevent future complications.
Beyond HPV-related malignancies and the threat of recurrent infections, patients with WHIM may be subject to additional long-term complications. For example, recurrent otitis media infection can predispose these patients to hearing loss. Lung damage resulting from frequent infections can cause chronic bronchiectasis or other serious respiratory problems.
A case study from McDermott’s team from the National Institutes of Health discussed the appearance of ocular toxoplasmosis (a protozoan infection) in a 14-year-old patient. In this patient, the infection resulted in permanent blindness in the affected eye.. Additional complications can include neurologic disorders, such as fine and global motor coordination disorders, balance disturbances, or mild limb ataxia.
Importantly, WHIM patients may be at a higher risk of malignancy. A 2019 report from China described a patient with acute myeloid leukemia that developed following Hodgkin’s lymphoma. The French registry reported that five WHIM patients that developed malignancy at median age of 37 years: two HPV-induced vulvar cancers (one lethal), 2 lymphomas (one bone, one skin lymphoma) and one basal cell carcinoma of the 14 patients in the registry. The 40-years rate of malignancy was calculated to be 46% (95% CI 17-88%).
NOVEL TREATMENTS ON THE HORIZON
Since WHIM syndrome specifically results from a mutation in the CXCR4 gene which causes a gain-of-function in downstream signaling, targeted treatment with a CXCR4 antagonist directly addresses the mechanism of disease.
To date, CXCR4 antagonists (e.g., plerixafor) have shown encouraging results in National Institute of Health (NIH) sponsored clinical trials as a potential treatment for adults with WHIM syndrome. Plerixafor is a subcutaneously injectable pharmaceutical that was approved at a high dose in December 2008 for acute use in patients undergoing autologous bone marrow transplant to treat certain types of hematologic cancers. Plerixafor is not an approved therapy for the treatment of WHIM syndrome. However, the NIH has conducted clinical trials using very low-dose, twice daily subcutaneous injections to demonstrate safety and efficacy in patients with WHIM syndrome. It is unknown if the manufacturer of plerixafor will pursue an approval for use in WHIM syndrome.
Another CXCR4 antagonist, mavorixafor, is a small molecule (supplied as an oral capsule), non-competitive, allosteric antagonist of CXCR4 in a global Phase 3 clinical trial evaluating the safety and efficacy in patients who have been genetically confirmed to have WHIM syndrome. (4WHIM.com)
To date, four WHIM patients who have received allogeneic hematopoietic stem cell transplantation (HSCT) have achieved durable results, no longer receive immunosuppression, and appear to be cured. HSCT in WHIM syndrome is limited by the availability of immunologically matched donors and by the significant short and long-term risks of allotransplantation.
Since the root cause of WHIM syndrome is a mutation in a specific gene (CXCR4), gene editing techniques may provide a promising avenue for research. In one patient with WHIM syndrome, the natural deletion of one copy of the gene reportedly resulted in a cure, with spontaneous and complete remission of warts, sustained correction of neutropenia and monocytopenia, and normalization of bone marrow pathology. In this patient, one copy of the CXCR4 allele was deleted in a hematopoietic stem cell, which was then used to repopulate the patient’s bone marrow. Subsequently, researchers conducted testing in mice and proposed, based on the results of this animal study, that “WHIM allele silencing of patient [hematopoietic stem cells] is a viable gene therapy strategy.”
CLINICAL TRIAL INFORMATION
PRIMARY IMMUNE DEFICIENCY ADVOCACY GROUPS AND NONPROFIT ORGANIZATIONS
Immune Deficiency Foundation
A national non-profit patient organization dedicated to improving the diagnosis, treatment and quality of life of persons with primary immunodeficiency diseases through advocacy, education and research.
International Patient Organisation for Primary Immunodeficiencies
An association of national patient organisations dedicated to improving awareness, access to early diagnosis and optimal treatments for primary immunodeficiency patients worldwide.
Jeffrey Modell Foundation
An international, non-profit, organization dedicated to helping individuals and family members affected by primary immunodeficiency disorders.
RARE DISEASE ORGANIZATIONS
A non-governmental patient-driven alliance of patient organizations representing 724 rare disease patient organizations in 64 countries.
A nonprofit health advocacy organization that engages individuals, families, and communities to transform health. They create ways to make it easier to find or build solutions in health services and research.
A rare disease patient advocacy organization that aims to build awareness, educate the global community and provide critical connections and resources that equip advocates to become activists for their disease.
National Organization for Rare Disorders
A rare disease patient advocacy organization providing a unified voice for the 30 million people who wake up every day to fight the battle with a rare disease, including parents and caregivers.
EveryLife Foundation for Rare Diseases
A rare disease patient advocacy organization dedicated to advancing the development of treatment and diagnostic opportunities for rare disease patients through science-driven public policy.
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Importance of Advocating
Gene Testing and WHIM Syndrome
Patient Story: Living With WHIM Syndrome