WHIM syndrome

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Classification according to ICD-10
D81.8 Other combined immunodeficiencies
ICD-10 online (WHO version 2019)

The WHIM syndrome (short for warts - hypogammaglobulinemia - immunodeficiency - myelocathexis - syndrome ) is an inherited, rare immune deficiency disease .

history

The common occurrence of the characteristic symptoms of WHIM syndrome was first described in 1964. In 2000 the genetic cause for this syndrome was found. WHIM syndrome is the first immunodeficiency to be attributed to a cytokine receptor defect.

In early 2015, the journal Cell published a report from the Clinical Center of the National Institutes of Health in Bethesda, Maryland, on a case of spontaneous healing from chromothripsis .

Symptoms

Characteristic of the WHIM syndrome is an immune deficiency that manifests itself in recurring bacterial and viral infections. This particularly affects the airways with sinus infections , tonsillitis and pneumonia . Patients are susceptible to infections with human papillomaviruses , which manifest themselves in numerous warts, especially in the hands and feet. WHIM syndrome patients also have an increased risk of developing viral cancers, such as cervical cancer. In the blood serum of the patient decreased to IgG concentrations are measured (hypogammaglobulinaemia). Histologically , the bone marrow of WHIM patients appears full of T precursor cells . On the other hand, neutropenia can be observed, which can be attributed to impaired emigration and thus retention of neutrophilic granulocytes from the bone marrow (myelocathexis).

causes

WHIM syndrome is an autosomal dominant inherited disease. Mutations of a gene on the gene locus 2q21, which codes for the chemokine receptor CXCR4 , are considered to be the most common cause, which was found in 92% of affected patients . These mutations in the intracellular part of the membrane-bound receptor for the cytokine CXCL12 (SDF-1) lead to a shortened receptor protein which lacks the ability to internalize after activation. Thus, mechanisms of negative self-regulation are interrupted and the receptor can be permanently stimulated. A reduction in the expression of CXCR4 is also a prerequisite for T precursor cells to leave the bone marrow . Due to the mutation and the lack of internalization of CXCR4 remains on the surface of the TZ progenitor cells. These precursor cells therefore cannot leave the bone marrow and are the cause of the histological findings in the bone marrow and blood.

The WHIM syndrome can, however, also be observed in isolated cases (in 8% of patients) with a non-mutated (wild type) CXCR4. One possible cause in these patients is a malfunction of proteins involved in the internalization of CXCR4, such as G-protein-coupled receptor kinases (GRKs) .

Since the CXCR4 receptor also plays a role in other migration and homing processes, the immune defense in the periphery is also disturbed.

therapy

In the treatment of patients with a WHIM syndrome, the focus is on reducing the susceptibility to infections. A substitution with immunoglobulins should reduce the frequency of infections. To normalize the release of neutrophil granulocytes from the bone marrow, GM-CSF or, better, G-CSF can be used. The use of CXCR4 antagonists, such as plerixafor , to treat patients with WHIM syndrome is currently being investigated in clinical trials .

Web links

Individual evidence

  1. ^ CE Krill, HD Smith, AM Mauer: Chronic idiopathic granulocytopenia . In: N Engl J Med . tape 270 , May 1964, pp. 973-979 , PMID 14122792 .
  2. ↑ RJ Gorlin, B. Gelb, GA Diaz, KG Lofsness, MR Pittelkow, JR Fenyk Jr: WHIM syndrome, an autosomal dominant disorder: clinical, hematological, and molecular studies . In: Am J Med Genet . tape 91 , no. 5 , April 2000, pp. 368-376 , PMID 10767001 .
  3. ↑ a b A. V. Gulino: WHIM syndrome: a genetic disorder of leukocyte trafficking . In: Curr Opin Allergy Clin Immunol . tape 3 , no. 6 , December 2003, p. 443-450 , PMID 14612668 .
  4. ↑ Spontaneous healing of a hereditary disease caused by chromothripsis. In: Dt. Medical journal. dated February 6, 2015, accessed February 7, 2015. doi: 10.1016 / j.cell.2015.01.014
  5. ↑ PA Hernandez, RJ Gorlin, JN Lukens et al: Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease . In: Nat Genet . tape 34 , no. 1 , May 2003, p. 70-74 , doi : 10.1038 / ng1149 , PMID 12692554 .
  6. ↑ B. Lagane, KY Chow, K. Balabanian et al .: CXCR4 dimerization and beta-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome . In: Blood . tape 112 , no. 1 , July 2008, p. 34-44 , doi : 10.1182 / blood-2007-07-102103 , PMID 18436740 .
  7. ↑ K. Balabanian, A. Levoye, L. Klemm et al .: Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling . In: J. Clin. Invest. tape 118 , no. 3 , March 2008, p. 1074-1084 , doi : 10.1172 / JCI33187 , PMID 18274673 , PMC 2242619 (free full text).
  8. ↑ a b T. Kawai, HL Malech: WHIM syndrome: congenital immune deficiency disease . In: Curr Opin Hematol . tape 16 , no. 1 , 2009, p. 20-26 , PMID 19057201 .
  9. ↑ J. Bohinjec, D. Andoljsek: Neutrophil-releasing activity of recombinant human granulocyte-macrophage colony stimulating factor in myelokathexis . In: Br. J. Haematol. tape 82 , no. 1 , September 1992, pp. 169-170 , PMID 1419790 .