WHIM Syndrome: Symptoms, Common Misdiagnoses, and Treatment Options

WHIM syndrome, an acronym for Warts, Hypogammaglobulinemia, Infections, and Myelokathexis, is a rare primary immunodeficiency disorder characterized by a compromised immune system, leading to increased susceptibility to infections and other health complications. This condition is mainly caused by variants in the CXCR4 gene, a gene that helps move immune cells from the bone marrow, where they are made, into the bloodstream, where they can fight infections. 

Common Symptoms of WHIM Syndrome

WHIM syndrome symptoms can vary widely among individuals, both in terms of which symptoms are present and the severity of those symptoms. This makes it difficult for physicians to build a reliable patient profile, which is why WHIM syndrome is believed to be underdiagnosed and misdiagnosed. In many cases, the hallmark features include: 

• Warts: Persistent and recurrent warts on the neck, hands and feet, and elsewhere, often caused by human papillomavirus (HPV) infections.
• Hypogammaglobulinemia: Reduced levels of immunoglobulins (antibodies) in the blood, leading to a weakened immune response. 
• Infections: Frequent bacterial infections, particularly of the respiratory tract, skin, and ears, due to the immune system's inability to effectively combat pathogens.
• Myelokathexis: Retention of neutrophils (a type of white blood cell) in the bone marrow, resulting in neutropenia (low neutrophil count) and increased infection risk.

Additional symptoms may include lymphopenia (low lymphocyte count, which can lead to viral infections), monocytopenia (low monocyte count, which can lead to bacterial and fungal infections), and an increased risk of certain cancers.

Diagnosing WHIM Syndrome

Diagnosing WHIM syndrome involves a combination of clinical evaluation, lab tests, and genetic analysis:

1. Clinical Evaluation: Assessment of recurrent infections, presence of warts, and other characteristic symptoms.
2. Laboratory Tests:some text
   • Complete Blood Count (CBC): To detect neutropenia, lymphopenia, and monocytopenia.
   • Immunoglobulin Levels: To identify hypogammaglobulinemia.
   • Bone Marrow Biopsy: To observe myelokathexis. This entails the use of local anesthesia to collect a sample of bone marrow, typically from the hip.
3. Genetic Testing: Identification of variants in the CXCR4 gene confirms the diagnosis.

The Importance of Genetic Testing

Even after clinical evaluation and various lab tests, there are multiple reasons to also pursue genetic testing. 

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• Definitive Diagnosis: WHIM syndrome may resemble other immunodeficiencies (e.g., CVID or idiopathic neutropenia). Genetic testing ensures an accurate diagnosis by identifying a CXCR4 variant.
• Family Planning: Testing helps assess the risk of transmission to future generations. Close relatives can be tested to determine if they are carriers or at risk, which can lead to preventative care and appropriate family planning..
• Targeted Therapies: Genetic confirmation of CXCR4 variant opens the door for precision medicine, such as CXCR4 antagonists. Recently, the U.S. Food and Drug Administration (FDA) approved mavorixafor (Xolremdi) for the treatment of WHIM syndrome in patients aged 12 and older. This marks the first therapy specifically indicated for WHIM syndrome, offering new hope for patients.
• Response to Therapy: Some variants may influence the effectiveness of specific treatments, such as plerixafor or immunoglobulin replacement therapy.

• Access to Clinical Trials: Patients with confirmed CXCR4 variants may be eligible for trials of new therapies. As an exciting example, plerixafor is a CXCR4 antagonist, used currently in stem cell recipients, and while it hasn’t yet been approved for treatment of WHIM syndrome, it is showing promise in clinical trials.These developments could mean new treatment options for patients with WHIM syndrome in the near future.  

In short, genetic testing is a relatively simple way to direct, clear answers and opportunities to try new treatments.

Common Misdiagnoses

Due to overlapping symptoms, WHIM syndrome may be misdiagnosed as:

• Common Variable Immunodeficiency (CVID): Both conditions present with hypogammaglobulinemia and recurrent infections.
• Severe Congenital Neutropenia: Characterized by low neutrophil counts and recurrent infections.
• Idiopathic Neutropenia: Unexplained low neutrophil counts without a clear underlying cause.

Accurate diagnosis is essential for appropriate management and treatment.

Treatment Options for WHIM Syndrome

While there is no definitive cure for WHIM syndrome currently, several treatment strategies have been developed to manage symptoms and prevent complications:

• Immunoglobulin Replacement Therapy: To address hypogammaglobulinemia and reduce infection frequency.
• Granulocyte-Colony Stimulating Factor (G-CSF): To increase neutrophil counts and enhance infection resistance.
• Antibiotic Prophylaxis: To prevent bacterial infections.
• Antiviral Therapies: To manage HPV-related warts and reduce cancer risk.
• CXCR4 Antagonists: More treatments like the recently approved Xolremdi are currently in clinical trials.

Support Through Probably Genetic

Understanding the genetic basis of WHIM syndrome is crucial for accurate diagnosis and personalized treatment. Probably Genetic collaborates with a network of licensed genetic counselors to provide no-cost genetic testing and counseling services to eligible patients. Our patient-initiated process was designed to empower individuals with the knowledge and resources needed to manage their condition effectively and shorten their diagnostic journeys.

If you or a loved one is experiencing symptoms consistent with WHIM syndrome, consider exploring genetic testing options through Probably Genetic to gain clarity and access to appropriate care and clinical trials. Check your eligibility to get started!

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