Hematology

Miscellaneous disorders affecting neutrophils and other immune cells or arising in the differential diagnosis of infection

Miscellaneous disorders affecting neutrophils and other immune cells or arising in the differential diagnosis of infection

What every physician needs to know:

Miscellaneous disorders affecting neutrophils and other immune cells or arising in the differential diagnosis of infection:

  • WHIM: warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (CXCR-4 [fusin] mutation

- This is a disease associated with recurrent respiratory and skin infections with warts developing in later childhood.

  • Reticular dysgenesis

- Reticular dysgenesis (AK2 [adenase kinase 2] deficiency) is associated with profound pancytopenia presenting in infancy with marrow failure.

  • Papillon-Lefevre syndrome

- Papillon-Lefevre syndrome (cathepsin C deficiency) presents with abnormal oral and palmar-plantar epithelia.

  • Autoantibodies to cytokines

- Autoantibodies to cytokines such as: GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-17 (interleukin-17), or interferon-gamma lead to functional defects in cytokine activity.

Are you sure your patient has one of these neutrophil disorders? What should you expect to find?

  • WHIM

- Neutropenia, recurrent infections of the skin and lung, hypogammaglobulinemia, warts. Peripheral blood shows decreased neutrophils and B cells, but normal T cells. Marrow aspirate and biopsy shows hypercellularity with abundant retained mature neutrophils (myelokathexis).This is an autosomal dominant disorder.

  • Reticular dysgenesis

- Reticular dysgenesis is associated with profound neutropenia in the newborn with absence of other leukocytes as well, absent granulocyte colony-stimulating factor (G-CSF) response, and associated deafness. It is autosomal recessive.

  • Papillon-Lefevre syndrome

- Papillon-Lefevre syndrome presents with severe periodontitis and palmar-plantar thickening. A minority get other bacterial infections as well. Can affect deciduous or permanent teeth leading to their loss. It is autosomal recessive.

  • Anticytokine autoantibodies

- Manifestations vary with the targeted cytokine. Anti-GM-CSF autoantibodies present as pulmonary alveolar proteinosis. Anti-G-CSF autoantibodies present as neutropenia. Anti-interferon gamma autoantibodies present as disseminated nontuberculous mycobacterial or other opportunistic infectious diseases.

Beware of other conditions that can mimic these neutrophil disorders:

  • WHIM

- Any of the causes of neutropenia, warts, or hypogammaglobulinemia may be considered in the differential. However, the constellation of low neutrophils, low IgG (immunoglobulin G), and warts is very suggestive. The bone marrow aspirate in WHIM is distinctive, in that it has hypercellularity because of impaired marrow release of neutrophils, as opposed to other causes of neutropenia, in which cellularity is often reduced or shows arrest at specific stages. The marrow of patients with G6PC3 (glucose-6-phosphatase 3) deficiency may also show myelokathexis.

  • Reticular dysgenesis

- The hallmark of a leukocytosis is not seen with many other conditions, and marrow examination often shows profound neutrophil progenitor depletion. However, severe sepsis, a common consequence of severe neutropenia, can also be associated with pancytopenia. If the global aspect of the depletion is not appreciated, severe combined immune deficiency might be considered.

  • Papillon-Lefevre syndrome

- Aggressive periodontitis from other causes should be considered. Palmar-plantar thickening is also seen in disorders of the connexins.

  • Autoantibodies to cytokines

- Mendelian defects in specific genes are phenocopies of anticytokine autoantibodies. However, in general the Mendelian defects start earlier in life and may be more severe. For instance, mutations in the interferon-gamma (IFN-g)/interteukin-12 (IL-12) pathway often present in childhood, or even in infancy following BCG vaccination.

Which individuals are most at risk for developing these disorders:

  • WHIM

- WHIM is caused by autosomal dominant truncation mutations in fusin (CXCR4); first degree relatives may be similarly affected.

  • Reticular dysgenesis

- Reticular dysgenesis is caused by autosomal recessive mutations in AK2; siblings have a 25% chance of being affected.

  • Papillon-Lefevre syndrome

- Papillon-Lefevre syndrome is caused by autosomal recessive mutations in cathepsin C; siblings have a 25% chance of being affected.

  • Autoantibodies to cytokines

- Patients with autoimmune polyendocrine syndrome, type 1 (APS1 [APECED]) develop autoantibodies to interferon alpha, interleukin 17 (IL-17) and interleukin 22 (IL-22). Patients with thymoma develop autoantibodies to interferon alpha, IL-12p40, IL-17, IL-22, erythropoietin, as well as antibodies to the acetylcholine receptor, which cause myasthesnia gravis. Autoantibodies to interferon gamma appear to be more common in those born in east Asia.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

  • WHIM

- Complete blood count shows neutropenia, flow cytometry shows low B cells, immune globulin is usually low. Bone marrow shows myelokathexis.

  • Reticular dysgenesis

- Bone marrow shows myeloid block at the promyelocyte stage with lymphopenia, but relatively intact red cell and platelet production.

  • Papillon-Lefevre syndrome

- Skin biopsy from feet or palms show hyperkeratosis.

  • Autoantibodies to cytokines

- No specific laboratory value. May have hypergammaglobulinemia.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of one of these neutrophil disorders?

  • WHIM

- None.

  • Reticular dysgenesis

- None.

  • Papillon-Lefevre syndrome

- None.

  • Autoantibodies to cytokines

- None.

If you decide the patient has one of these disorders, what therapies should you initiate immediately?

  • WHIM

- Consider immune globulin, G-CSF, antibiotics.

  • Reticular dysgenesis

- Initiate antibiotics and search for bone marrow donors.

  • Papillon-Lefevre syndrome

- None.

  • Autoantibodies to cytokines

- None.

More definitive therapies?

  • WHIM

- Immune globulin replacement, prophylactic antibiotics may be useful, depending on the degree of neutropenia, G-CSF keeps the neutrophil count elevated. Dermatology should closely follow the warts for malignant change.

  • Reticular dysgenesis

- Bone marrow examination, preparation for bone marrow transplantation.

  • Papillon Lefevre

- Teeth may need aggressive cleaning or extraction. Surprisingly, implants are tolerated well.

  • Autoantibodies to cytokines

- Treatment of the specific infection (mucocutaneous candidiasis for anti-IL-17 and anti-IL-22, mycobacteria for anti-interferon gamma). The pulmonary alveolar proteinosis of anti-GM-CSF autoantibodies can be treated with aerosolized or injected GM-CSF. Refractory cases may need rituximab to eliminate B cells.

What other therapies are helpful for reducing complications?

  • WHIM

- A new treatment with the CXCR4 antagonist plerixafor is promising.

  • Reticular dysgenesis

- Prevention of bacterial and viral infections prior to transplant.

  • Papillon Lefevre

- Retinoids have been used in some cases with apparent success. Some have reported associations with liver abscess.

What should you tell the patient and the family about prognosis?

  • WHIM

- Goals are to reduce infections.

  • Reticular dysgenesis

- The goals are to achieve bone marrow engraftment. Deafness is also caused by mutations in AK2, so those who survive bone marrow transplant may be hearing impaired.

  • Papillon Lefevre

- The goals are to preserve dentition. The hyperkeratosis of the palms and soles are not disabling, but seem to respond to retinoids in some cases.

  • Anticytokine autoantibodies

- The goals are to treat the underlying condition or infection primarily. The role for rituximab is not defined but it may help reduce the pathologic antibody levels.

What if scenarios.

  • WHIM

- None specific.

  • Reticular dysgenesis

- None specific.

  • Papillon Lefevre

- None specific.

  • Anticytokine autoantibodies

- None specific.

Pathophysiology

  • WHIM

- Dominant gain of function mutations in CXCR4 lead to excessive retention of neutrophils and other cells in the bone marrow, causing the syndrome of myelokathexis.

  • Reticular dysgenesis

- AK2 is a gene that affects mitochondrial function and prevents apoptosis. In most tissues AK2 is redundant to AK1, but not in bone marrow or the inner ear. Therefore, when AK2 is deficient, bone marrow and inner ear suffer the most, leading to aleukocytosis and deafness.

  • Papillon-Lefevre syndrome

- Cathepsin C is a lysosomal exo-cysteine protease of the peptidase C1 family. It activates serine proteases such as cathepsin G in neutrophils and regulates gingiva and other epithelial integrity .

  • Autoantibodoes to cytokines

- The immediate mechanisms of how anticytokine autoantibodies exert their effect are obvious. What is not clear is why only certain diseases are associated with some and not other autoantibodies. The driving forces for the production of these antibodies are unknown.

What other clinical manifestations may help me to diagnose these neutrophil disorders?

On history, the following may be elicited:

  • WHIM

- Recurrent infections of the skin or respiratory tract. Family history of warts and infections.

  • Reticular dysgenesis

- Previous siblings or close relatives with similar problems.

  • Papillon Lefevre

- Loose teeth, bad breath, oral pain.

  • Anticytokine autoantibodies

- Those with anti-interferon gamma autoantibodies may have also had recurrent shingles and other opportunistic infections including Cryptococcus, histoplasmosis, Penicillium marneffei, and Salmonella.

What other additional laboratory studies may be ordered?

N/A

What’s the evidence?

Dhanrajani, PJ. "Papillon-Lefevre syndrome: clinical presentation and a brief review". Oral Surg Oral Med Oral Pathol Oral Radiol Endod. vol. 108. 2009. pp. e1-7.

[A recent review of a rare disease.]

Dotta, L, Tassone, L, Badolato, R. "Clinical and genetic features of warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome". Curr Mol Med. vol. 11. 2011. pp. 317-325.

[Clinical and genetic composite.]

McDermott, DH, Liu, Q, Ulrick, J. "The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome". Blood. vol. 118. 2011. pp. 4957-4962.

[First prospective study of the CXCR4 antagonist for WHIM.]

Pannicke, U, Honig, M, Hess, I. "Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2". Nat Genet. vol. 41. 2009. pp. 101-105.

[First of two back-to-back reports that reticular dysgenesis is caused by mutations in mitochondriral adenylate kinase 2.]

Lagresle-Peyrou, C, Six, EM, Picard, C. "Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness". Nat Genet. vol. 41. 2009. pp. 106-111.

[Second simultaneous report of role of mitochondrial anenylate kinase w mutations in reticular dysgenesis.]

Browne, SK, Holland, SM. "Anticytokine autoantibodies in infectious diseases: pathogenesis and mechanisms". Lancet Infect Dis. vol. 10. 2010. pp. 875-885.

[Role of anticytokine autoantibodies in predisposition to infection.]
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