Learn About WHIM Syndrome

The features listed in the acronym (W)arts, (H)ypogammaglobulinemia, (I)nfections, and (M)yelokathexis represent the key manifestations of the disorder. However, not all patients will present with the four key features of WHIM at any given time. In a recent international observational cohort of patients with WHIM syndrome, only 23% presented with all four manifestations of WHIM.[3] WHIM syndrome is classified as a combined primary immunodeficiency and congenital neutropenic disorder; and, due to the similar laboratory findings, is often characterized by and misdiagnosed as severe chronic neutropenia, lymphopenia, and monocytopenia. The concentration of B lymphocytes may be particularly low and is associated with low levels of circulating antibodies also called immunoglobulins (hypogammaglobulinemia).[3]

In fact, in an international observational cohort of 66 patients with WHIM syndrome, Geier and colleagues found that the most common signs and symptoms are the laboratory findings of neutropenia (98%) and lymphopenia (88%).[3] Warts were seen in only 42%, hypogammaglobulinemia in 65%, and recurrent infections in 92% of patients. Myelokathexis is typically present in 99-100% of WHIM patients[4], is revealed via bone marrow biopsy, and may be used to confirm a WHIM diagnosis.

The initial clinical sign of WHIM syndrome is recurrent infections. The same international cohort revealed that recurrent infections were the first recognizable symptoms in 88% of patients (most commonly bacterial respiratory infections (49%) or otitis media (23%). Skin infections were seen initially in 13%, and HPV-related infections (including warts) were the first recognized symptom in only 2% of patients. In this review, 96% of patients with WHIM syndrome presented their initial symptom by age 5 years; 70% presented by 1 year of age.[3]

Although not all patients with WHIM syndrome present with warts, increased susceptibility to HPV infections manifesting as warts is a key feature of WHIM syndrome. These warts typically appear on hands and feet and may present early in childhood; anogenital warts are more common in adults.[1] These HPV-related warts are often resistant to treatments such as freezing (cryotherapy), salicylic acid, or even surgical removal, which are typically effective in other patients with warts.[1,5] In the study reported by Geier and colleagues,[3] the lifetime presence of warts in patients with WHIM syndrome was approximately 40%. Since these are generally driven by HPV, it can raise the potential concern for HPV-related malignancy (see Complications of WHIM Syndrome).

Making an accurate diagnosis in the case of WHIM syndrome can be challenging due to the diverse clinical signs and symptoms, many of which may be consistent with other immune system disorders. Part of this challenge is how clinicians recognize the particular characteristics of the presentation and the potential of a genetic association.[4] However, a diagnosis can be made based on the clinical features alone. As with other inborn errors of immunity, a systematic approach to accurate diagnosis may be best summarized in three steps: (1) Recognition of the clinical presentation (phenotype), including clues of family history; (2) diagnostic laboratory evaluations, including immunological factors; and (3) confirmatory genetic analysis, seeking specific mutations and potential variants.[4,6]

Clinical Observations. Whereas recognition of the most notable clinical signs of WHIM syndrome may be straightforward, diagnosis is challenging because of its rarity and the heterogeneity of the clinical presentation.[3,4] Recurrent infections are the most common early clinical presentation. When information is obtained through a careful patient history, the clinician may find that the severity, duration, and frequency of the infections varies, and most infections (e.g., otitis media) may be otherwise unremarkable because they resolve with antibiotic treatment.[2] Unless the patient has another obvious sign such as warts, physical exam will not likely yield a diagnosis of WHIM syndrome. This places considerable onus on clinician (often a pediatrician) to recognize that this may be the result ultimately of a genetic causality.

Inheritance and Family History. The importance of a family history was demonstrated by Dale and colleagues,[7] who identified a total of 24 patients in nine families affected by WHIM syndrome. This emphasizes the need for obtaining a comprehensive family history in patients with recurrent infections, neutropenia, and lymphocytopenia.

As many as two-thirds of patients may have a family history of WHIM syndrome in the international cohort review by Geier and colleagues.[4,8] Yet, a positive family history of WHIM prompted diagnosis in only 20% of the patients in the survey by Geier and associates.[3] This may reflect a lack of awareness of the autosomal dominant inheritance pattern or undiagnosed family members as a result of the heterogeneity of disease (which may imply a higher percentage of patients with a positive family history). For example, it may be more likely that a pediatrician recognizes that another family member has neutropenia, recurrent infections, or lymphocytopenia than one with a clinical diagnosis of WHIM syndrome.[7]

Laboratory Work-up. Identifying trends in laboratory test results helps point to WHIM syndrome as the underlying cause of the clinical symptoms and signs. It is also useful in ruling out hematologic malignancies. Complete blood count testing will often yield neutrophil counts typically below 500 cells/μL for patients who are severely neutropenic (unless elevated during episodes of infection), and low total white blood cell counts, including monocytes and lymphocytes.[8] More than half of the patients have low IgG, IgM, and/or IgA concentrations and patients may also have inadequate responses to vaccine antigen where responses may not be durable.[3,8,9] One of the challenges to diagnosis is the temporary, normal levels of neutrophils during acute infections,[10–12] which is the moment when patients most commonly seek medical attention.[5] Therefore, blood counts drawn during an acute infection episode can lead clinicians to miss the key sign of neutropenia and may further delay diagnosis.[2]

Bone Marrow Biopsy. Myelokathexis, a strong determinant of a WHIM syndrome diagnosis, is obtained through bone marrow biopsy.[2,13] Myelokathexis is the abnormal retention of neutrophils in the bone marrow, where they “overmature.”[3] The result is a reduction in these immune cells in the blood – which normally help the body fight against pathogens – thus, increasing susceptibility to infections among these patient.

Myelokathexis can be difficult to detect, and may only be identified by an experienced pathologist when evaluating the bone marrow aspirate for its key features: myeloid hyperplasia; abnormal, mature neutrophils with hypersegmentation of the nuclei; and the presence of cytoplasmic vacuolization.[2]

Although myelokathexis is a hallmark among patients with WHIM syndrome, it is not the only way to confirm a WHIM diagnosis. Genetic testing to identify pathogenetic variants in the CXCR4 gene may also be used to further confirm the findings.[3,13]

Genetic Testing. Autosomal dominant mutations in the CXCR4 gene predominantly cause WHIM syndrome.[13] With autosomal dominant transmission, the probability of inheriting the disease is 50% for a child of an affected parent and an unaffected parent.[14] If WHIM syndrome is suspected, a patient’s diagnosis can be confirmed through genetic tests to identify pathogenetic variants in the CXCR4 gene.

However, cases of spontaneous variants also occur.[13] WHIM syndrome shows genetic heterogeneity with no established correlation between phenotype and genotype.[8] Advances in genetic diagnostic techniques (such as Next-Generation-Sequencing) and increasing awareness about the disease may facilitate early recognition and diagnosis and guide management.[15]

Genetic testing and counseling are available to aid in the molecular diagnosis of WHIM syndrome. Wider availability of genetic testing panels may offer opportunities for earlier management or participation in interventional trials.[15]

Differential Diagnosis. There may be crossover in identification of WHIM syndrome with other genetic disorders, like primary immunodeficiencies such as common variable immune deficiency (CVID). Like WHIM syndrome, patients with CVID may present with warts and hypogammaglobulinemia.[2]

In a French registry of patients with severe chronic neutropenia, genetic analyses amongst other studies revealed eight patients with WHIM syndrome.[16] Therefore, patients with chronic neutropenia of unknown origin also should be considered for further testing.[17]

Researchers are continuing to study potential treatments for WHIM syndrome.18,19]

Click here to learn about management, current treatment, and complications of WHIM syndrome.

Today, WHIM syndrome is managed based on the main clinical signs and or symptoms presented by patients. These are typically infections, neutropenia, and hypogammaglobulinemia.[8]  In April of 2024, the U.S. Food and Drug Administration approved Xolremdi (mavorixafor) capsules in patients 12 years of age and older with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes. Click here to learn more about the approval, and here for the full prescribing information.

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., for HPV), and prophylactic antibiotics to reduce the risk of infections in patients with WHIM syndrome.[1] The dose of G-CSF (e.g., filgrastim) may typically be individualized, based on each patient’s level of neutropenia.[1] The effectiveness of these treatments in patients with WHIM syndrome has not been investigated in well-controlled clinical trials.[1] In an international retrospective observational study of 54 patients, 56% of patients received G-CSF, 54% received IgG replacement therapy, and 39% received antibiotic prophylaxis to reduce susceptibility to infections.[3]

Warts among patients with WHIM syndrome are classically reported to be refractory/unresponsive to treatment, may proliferate extensively, and affect the hands or feet, face, arms, legs, or anogenital regions.[7]

In WHIM syndrome patients, there are currently no approved treatments addressing HPV susceptibility and HPV vaccine response appears impaired[1] with no substantial reduction in the burden of lesions.[8] Standard treatment methods (cauterization, laser therapy) and more aggressive approaches (surgical removal, interferon, cidofovir, Imiquimod) have not proven effective against cutaneous or genital warts.

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