Cyclic neutropenia

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Gray Collie affected with cyclic neutropenia[1]

Canine cyclic neutropenia (Gray Collie syndrome) is an autosomal-recessive genetic disease of dogs characterized by oscillations in the the number of neutrophils between almost zero and normal values with two week frequency[2].

The disease, which primarily affects the Gray Collie, is caused by a missense mutation in the canine AP3B1 gene, resulting in decreased neutrophil elastase enzymatic activity[3]m leading to a defect in the granulocyte colony-stimulating factor signal transduction pathway at a point distal to receptor binding[4].

Heterozygous carriers are unaffected and homoxygous dogs present with variable clinical symptoms. Affected puppies have a silver gray hair coat that ranges in color from very light, to darkish pewter grey, sometimes with a slight yellowing due to a mixture of light beige and light gray hair. No matter what color variation or type, all Collies have black noses except those with gray collie syndrome.

Symptoms include fever, diarrhea, joint pain, or other signs associated with eye, respiratory, or skin infections. They are also prone to bleeding episodes. Affected puppies are smaller and weaker, with a noticeable pale gray or pinkish/gray or beige color. These puppies rarely live beyond a couple of days and when they do survive, they are susceptible to numerous bacterial infections[5]. With proper treatment they can be kept alive, but few have lived beyond 2 to 3 years of age[6].

In affected dogs, the B lymphocytes in the lymph nodes are significantly increased while the T lymphocytes, although normal in numbers in peripheral lymph nodes but reduced in ciculation, have changes in receptor fraction bindings[7]. Other blood lineages (monocytes, lymphocytes, reticulocytes and platelets) also cycle, but do so in a phase opposite to that of neutrophils[8].

Affected dogs exhibit coat color dilution and are vulnerable to periodic infections on account of their neutropenia[9].

Diagnosis may only be achieved incidentally during routine hematological analysis of a dog for routine blood tests, but some dogs may present with vague illness supported by hematological evidence of neutropenia. DNA testing is usually confirmatory.

Treatment involves repeated injections of recombinant granulocyte colony stimulating factor at 3 × 107 IU/kg body weight every 2 weeks for 6 weeks[10][11].


  1. Pennylane Collies
  2. Benson KF et al (2004) Paradoxical homozygous expression from heterozygotes and heterozygous expression from homozygotes as a consequence of transcriptional infidelity through a polyadenine tract in the AP3B1 gene responsible for canine cyclic neutropenia. Nucleic Acids Res 32(21):6327-6333
  3. Meng R et al (2010) Neutrophil elastase-processing defect in cyclic hematopoietic dogs. Exp Hematol 38(2):104-115
  4. Avalos BR et al (1994) Abnormal response to granulocyte colony-stimulating factor (G-CSF) in canine cyclic hematopoiesis is not caused by altered G-CSF receptor expression. Blood 84(3):789-794
  5. Yanay O et al (2003) Treatment of canine cyclic neutropenia by lentivirus-mediated G-CSF delivery. Blood 102(6):2046-2052
  6. Allen WM et al (1996) Cyclic neutropenia in collies. Vet Rec 138(15):371-372
  7. Trail PA & Yang TJ (1986) Canine cyclic hematopoiesis: alterations in T lymphocyte subpopulations in peripheral blood, lymph nodes, and thymus of gray collie dogs. Clin Immunol Immunopathol 41(2):216-226
  8. Katen LJ et al (2002) Cloning and sequencing of the canine neutrophil elastase cDNA. DNA Seq 13(4):221-223
  9. Benson KF et al (2003) Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastase. Nature Genet 35:90–96
  10. Yanay O et al (2012) Repeated lentivirus-mediated granulocyte colony-stimulating factor administration to treat canine cyclic neutropenia. Hum Gene Ther 23(11):1136-1143
  11. Yanay O et al (2006) An adult dog with cyclic neutropenia treated by lentivirus- mediated delivery of granulocyte colony-stimulating factor. Hum Gene Ther 17(4):464-469