WHIM Syndrome

Overview

WHIM syndrome is a rare primary immunodeficiency disorder that stands for Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. It is a congenital condition that impairs the immune system’s ability to fight infections effectively. Individuals with WHIM syndrome are prone to recurrent bacterial and viral infections, particularly of the respiratory tract and skin. A hallmark feature of the disorder is myelokathexis—a defect where mature neutrophils are abnormally retained in the bone marrow, leading to neutropenia (low neutrophil count) in peripheral blood. The condition is inherited in an autosomal dominant pattern and is extremely rare, with fewer than 100 cases reported globally.

Causes

WHIM syndrome is caused by gain-of-function mutations in the CXCR4 gene, which is located on chromosome 2. The CXCR4 gene encodes a receptor for the chemokine CXCL12 (also known as SDF-1). This receptor plays a critical role in regulating the movement and retention of white blood cells in the bone marrow.

The mutations result in enhanced signaling through the CXCR4 receptor, which leads to excessive retention of neutrophils and other immune cells within the bone marrow (myelokathexis), preventing them from entering the bloodstream and reaching sites of infection. The resulting immune deficiency makes affected individuals more susceptible to infections and other immune-related complications.

Symptoms

The clinical presentation of WHIM syndrome can vary widely but typically includes the following core features, represented by the acronym:

• Warts: Persistent and widespread human papillomavirus (HPV) infections, particularly skin and genital warts. These can be difficult to treat and may become extensive or recurrent.

• Hypogammaglobulinemia: Low levels of immunoglobulins (especially IgG and IgA) in the blood, leading to poor antibody-mediated immune responses.

• Infections: Frequent, recurrent bacterial infections, especially affecting the sinuses, ears, lungs (pneumonia), and skin. Viral infections, especially from HPV and herpes viruses, are also common.

• Myelokathexis: Retention of neutrophils in the bone marrow, leading to chronic neutropenia (low neutrophil count) despite normal or increased production.

Other possible symptoms and complications:

• Failure to thrive or growth delay in childhood

• Fatigue and malaise

• Bronchiectasis or chronic lung disease from recurrent infections

• Increased risk of HPV-associated cancers, such as cervical or anogenital cancer

Diagnosis

Diagnosis of WHIM syndrome requires a combination of clinical suspicion, laboratory findings, and genetic testing. Diagnostic steps include:

• Complete blood count (CBC): Typically shows persistent neutropenia and sometimes lymphopenia or monocytopenia.

• Bone marrow biopsy: Reveals myelokathexis—abnormal retention and apoptosis of mature neutrophils within the bone marrow.

• Serum immunoglobulin levels: Measurement shows low levels of IgG and/or IgA (hypogammaglobulinemia).

• Infection history and clinical presentation: Recurrent infections and HPV-related warts raise clinical suspicion.

• Genetic testing: Confirmatory diagnosis via identification of a pathogenic gain-of-function mutation in the CXCR4 gene.

Treatment

There is no cure for WHIM syndrome, but treatment focuses on managing symptoms, preventing infections, and supporting immune function. A multidisciplinary approach involving immunologists, infectious disease specialists, and dermatologists is often necessary.

Medical Management

• Immunoglobulin replacement therapy (IVIG or SCIG): Regular infusions help prevent infections and compensate for hypogammaglobulinemia.

• G-CSF (Granulocyte-Colony Stimulating Factor): Used to mobilize neutrophils from the bone marrow and increase peripheral neutrophil counts.

• Antibiotic prophylaxis: May be prescribed to prevent recurrent bacterial infections.

• Antiviral therapy: For management of herpes viruses or HPV-associated lesions.

Targeted Therapy

• Plerixafor (CXCR4 antagonist): An FDA-approved drug that can reverse myelokathexis by inhibiting CXCR4 signaling, allowing neutrophils to exit the bone marrow. It shows promise as a targeted treatment in WHIM syndrome and is used in some patients under special programs or clinical trials.

Other Interventions

• HPV vaccination: Strongly recommended to prevent HPV infections and associated malignancies.

• Surgical removal of warts: May be necessary in cases of extensive or refractory HPV lesions.

Prognosis

The prognosis for individuals with WHIM syndrome varies depending on the severity of immune dysfunction and success of infection control. With early diagnosis and consistent medical management, many patients can lead relatively normal lives. However, untreated or poorly managed WHIM syndrome can lead to serious complications:

• Chronic lung disease: Due to repeated respiratory infections.

• Severe HPV infections: Increasing the risk of skin or mucosal cancers.

• Reduced life expectancy: In severe, untreated cases due to complications from infections or malignancies.

With advancements in targeted therapies and supportive care, outcomes have improved significantly in recent years. Lifelong follow-up with immunology specialists is essential for optimal health and quality of life in individuals with WHIM syndrome.