WHIM syndrome

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WHIM Syndrome (or Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis syndrome) is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.

Other Names

Warts, Hypogammaglobulinemia, Infections, and Myelokathexis; WHIMS

Pathophysiology

WHIM syndrome results from autosomal dominant mutations in the gene for the chemokine receptor, CXCR4

Clinical features

WHIM syndrome is an acronym for a rare immunodeficiency disorder with each letter representing a predominant feature of the condition: * (W) = warts;

• (H) = hypogammaglobulinemia;
• (I) = infections; and
• (M) = myelokathexis (retention of neutrophils in the bone marrow).

Onset

Symptoms usually begin in early childhood with recurrent bacterial infections such as respiratory infections and cellulitis. In later childhood, individuals develop widespread warts that often become persistent despite treatments that are normally effective. Warts that involve the genital area may eventually cause cancer. It is caused by mutations in the CXCR4 gene and is inherited in an autosomal dominant manner. Treatment may include medications that replace antibodies (intravenous immunoglobulin) or increase the number of neutrophils; vaccinations; and prophylactic antibiotics to reduce the risk of infections.

Symptoms

80%-99% of people have these symptoms

• Abnormality of neutrophil morphology
• Bone marrow hypercellularity
• Lymphopenia
• Myelokathexis
• Neutropenia

%-79% of people have these symptoms

• Decreased circulating antibody level
• Recurrent bacterial infections
• Recurrent pneumonia
• Recurrent upper respiratory tract infections
• Verrucae

5%-29% of people have these symptoms

• Abnormality of the small intestine
• Bronchiectasis
• Cervix cancer
• Limb ataxia
• Neurological speech impairment
• Otitis media
• Pharyngitis
• Poor fine motor coordination
• Postural instability
• Sinusitis
• Tetralogy of Fallot

1%-4% of people have these symptoms

• Atelectasis
• Cellulitis
• Cutaneous melanoma
• Lymphadenitis
• Meningitis
• Parotitis
• Seizure
• Sepsis
• Severe periodontitis
• Vitiligo

Less common symptoms

• Abnormal morphology of female internal genitalia
• Abnormality of bone marrow cell morphology
• Abnormality of female external genitalia
• Autosomal dominant inheritance
• Decreased circulating IgG level
• Infantile onset

Diagnosis

• Patients exhibit increased susceptibility to bacterial and viral infections, especially from common serotype human papilloma virus, resulting in warts on the hands and feet starting in childhood.
• Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). In addition, lymphocytes and IgG antibody levels (gammaglobulins) are often deficient.

Treatment

• Early diagnosis and aggressive medical management are very important for individuals with WHIM syndrome.
• Treatment of the condition currently includes G-CSF (a medication that stimulates the production of neutrophils); intravenous immunoglobulins (IVIG) for hypogammaglobulinemia; prophylactic antibiotics to prevent infection; and aggressive surveillance for, and treatment of, skin and mucosal HPV-related lesions. The dose of G-CSF should be determined for each individual, and adjustments may be needed periodically.
• IVIG has been shown to be effective at decreasing risk of infections, and it has also been reported that the hypogammaglobulinemia may improve following treatment with G-CSF.
• The use of prophylactic antibiotics in individuals affected with WHIM has not been specifically studied, but the benefits have been assumed based on studies on other types of immunodeficiency disorders.
• Infections should be diagnosed and treated as soon as possible.

Potential new therapies

Plerixafor which blocks the activity of CXCR4 (which is increased in affected individuals) and may become a targeted therapy for WHIM syndrome as this is currently being studied.

Latest research - Pubmed

WHIM syndrome: a defect in CXCR4 signaling.

Diaz GA, Gulino AV.Curr Allergy Asthma Rep. 2005 Sep;5(5):350-5. doi: 10.1007/s11882-005-0005-0.PMID: 16091205 Review.

The first example of a human immunologic disease caused by mutation of a chemokine receptor was provided by WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, a rare, combined immunodeficiency featuring an unusual form of neutropenia. ...

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WHIM syndrome is a rare disease.