Alternative titles; symbols
SNOMEDCT: 191347008; ICD10CM: D70.4; ICD9CM: 288.02; ORPHA: 2686; DO: 5339;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.3 | Neutropenia, cyclic | 162800 | Autosomal dominant | 3 | ELANE | 130130 |
A number sign (#) is used with this entry because of evidence that cyclic neutropenia is caused by heterozygous mutation in the gene encoding neutrophil elastase (ELANE; 130130) on chromosome 19p13.
Cyclic neutropenia is a rare disease characterized by regular 21-day cyclic fluctuations in the number of blood neutrophils, monocytes, eosinophils, lymphocytes, platelets, and reticulocytes. The recurrent severe neutropenia causes patients to experience periodic symptoms of fever, malaise, mucosal ulcers, and, rarely, life-threatening infections. The disease occurs both as a congenital disorder and in an acquired form, with essentially identical phenotypic presentations (summary by Migliaccio et al., 1990).
Hahneman and Alt (1958) described a 29-year-old man who from an early age had neutropenia that recurred every 21 days and was accompanied by infection. Complete remission occurred at age 18 years. The man's daughter was seen at the age of 2 years with similar periodic disease recurring every 14 days. Torrioli-Riggio (1958) also reported cases.
Morley et al. (1967) described 20 cases in 5 families. Clinical manifestations usually began in childhood and improved thereafter. The commonest were fever, oral ulcerations, and skin infections. Neutropenia occurred at intervals of 15 to 35 days. It was often accompanied by monocytosis and sometimes by anemia, eosinophilia, or thrombocytopenia. Male-to-male transmission occurred.
Peng et al. (2000) described a family in which all 4 male members, the father and 3 sons, had hereditary cyclic neutropenia starting in childhood with a cycle of approximately 21 days. Recurrent mucosa and skin infections with fever had occurred frequently, but gradually decreased in severity as they reached adulthood. Monocytosis was found during the neutrophil nadirs in all 4 patients. Decreased sperm count and motility were demonstrated in the 2 elder sons. Chromosome analysis showed a pericentric inversion of the Y chromosome in all of the men. The chromosome anomaly was inv(Y)(p11.2;q11.23).
Krance et al. (1982) reported a family in which 7 persons in 4 sibships had cyclic neutropenia. One unaffected member of the family who was in the process of bone marrow transplantation as treatment for acute lymphoblastic leukemia in relapse, acquired cyclic neutropenia from her histocompatible donor sib.
While cyclic hematopoiesis is commonly described as 'benign,' Palmer et al. (1996) found that 4 affected children in 3 of 9 families died of Clostridium or E. coli colitis, documenting the need for urgent evaluation of abdominal pain. Misdiagnosis with other neutropenias was common but can be avoided by serial blood counts in index cases.
Hammond et al. (1989) found that granulocyte-colony stimulating factor (GCSF or CSF3; 138970) is effective treatment.
Inoue et al. (1992) identified cyclic neutropenia in a 34-year-old woman, her 3 sons, and her mother. Oscillations in the blood neutrophil counts were rather regular, with a periodicity of 21 days. The GCSF level in the mother's serum was persistently high, with the peak occurring during the neutropenic phase. The patient's serum appeared to contain an inhibitory factor. To control infections, Inoue et al. (1992) administered recombinant human GCSF for 7 days around the early neutropenic phase.
In a review of cyclic neutropenia, Palmer et al. (1996) found that treatment with human CSF3 resulted in dramatic improvement of neutropenia and morbidity.
Reports of male-to-male transmission of cyclic neutropenia in several families indicate autosomal dominant inheritance (Palmer et al., 1996).
On the basis of studies in 9 families, Palmer et al. (1996) found no clinical evidence of decreased penetrance or heterogeneity. However, the pattern of expression suggested anticipation: no families appeared to display milder phenotypes in successive generations, and the most severe cases occurred in children in the youngest generations. The spectrum of severity included death from necrotizing enterocolitis in 4 subjects ranging in age from 6 to 17 years. In 3 of the 9 pedigrees, the proband appeared to represent a new mutation.
Horwitz et al. (1999) used a genomewide screen and positional cloning to map the cyclic neutropenia locus to chromosome 19p13.3.
Horwitz et al. (1999) identified 7 different single-basepair substitutions in the ELANE gene (e.g., 130130.0001-130130.0005), encoding neutrophil elastase (ELA2). In each of 13 families studied, a mutation in ELANE was found on a unique haplotype; the haplotype carrying a new mutation in a sporadic case was also unique. Neutrophil elastase is a target for protease inhibition by alpha-1-antitrypsin (AAT; 107400), and its unopposed release destroys tissue at sites of inflammation. Horwitz et al. (1999) hypothesized that a perturbed interaction between neutrophil elastase and serpins or other substrates may regulate mechanisms governing the clock-like timing of hematopoiesis.
Cyclic neutropenia in the collie dog is accompanied by gray fur, leads to early death from pyogenic infections, and is an autosomal recessive (Dale et al., 1970). Weiden et al. (1974) showed by transplantation of gray collie bone marrow into normal dogs which had been irradiated that the basic defect is in the stem cell. There are sufficient similarities between the canine and human diseases (Guerry et al., 1972) to suggest that the same may be true in man. Krance et al. (1982) confirmed this when a patient, in the process of bone marrow transplantation as treatment for acute lymphoblastic leukemia in relapse, acquired cyclic neutropenia from her histocompatible donor sib. In dogs, the disease can be transferred and cured through bone marrow transplantation (Jones et al., 1975). The disease in collie dogs differs from the human disease in the length of the cycle (12 rather than 21 days).
The autosomal recessive disorder canine cyclic hematopoiesis (Lothrop et al., 1987), also known as gray collie syndrome, is not caused by mutations in neutrophil elastase. Benson et al. (2003) showed that homozygous mutation of the gene encoding the dog adaptor protein complex-3 (AP3) beta-subunit (AP3B1; 603401), directing trans-Golgi export of transmembrane cargo proteins to lysosomes, causes canine cyclic hematopoiesis. C-terminal processing of neutrophil elastase exposes an AP3 interaction signal responsible for redirecting neutrophil elastase trafficking from membranes to granules. Disruption of either neutrophil elastase or AP3 perturbs the intracellular trafficking of neutrophil elastase.
Benson, K. F., Li, F.-Q., Person, R. E., Albani, D., Duan, Z., Wechsler, J., Meade-White, K., Williams, K., Acland, G. M., Niemeyer, G., Lothrop, C. D., Horwitz, M. Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastase. Nature Genet. 35: 90-96, 2003. [PubMed: 12897784] [Full Text: https://doi.org/10.1038/ng1224]
Dale, D. C., Alling, D. W., Wolff, S. M. Cyclic hematopoiesis: the mechanism of cyclic neutropenia in grey collie dogs. J. Clin. Invest. 51: 2197-2204, 1972. [PubMed: 5054472] [Full Text: https://doi.org/10.1172/JCI107027]
Dale, D. C., Kimball, H. R., Wolff, S. M. Studies of cyclic neutropenia in gray collie dogs. (Abstract) Clin. Res. 18: 402 only, 1970.
Dale, D. C., Ward, S. B., Kimball, H. R., Wolff, S. M. Studies of neutrophil production and turnover in grey collie dogs with cyclic neutropenia. J. Clin. Invest. 51: 2190-2196, 1972. [PubMed: 5054471] [Full Text: https://doi.org/10.1172/JCI107026]
Guerry, D. D., Dale, D. C., Omine, M., Perry, S., Wolff, S. M. Studies on the mechanism of human cyclic neutropenia. (Abstract) Brit. J. Haemat. 40: 951 only, 1972.
Hahneman, B. M., Alt, H. L. Cyclic neutropenia in a father and daughter. J. Am. Med. Assoc. 168: 270-272, 1958. [PubMed: 13575153] [Full Text: https://doi.org/10.1001/jama.1958.63000030001011]
Hammond, W. P., IV, Price, T. H., Souza, L. M., Dale, D. C. Treatment of cyclic neutropenia with granulocyte colony-stimulating factor. New Eng. J. Med. 320: 1306-1311, 1989. [PubMed: 2469956] [Full Text: https://doi.org/10.1056/NEJM198905183202003]
Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G., Dale, D. C. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nature Genet. 23: 433-436, 1999. [PubMed: 10581030] [Full Text: https://doi.org/10.1038/70544]
Inoue, T., Tani, K., Tajiri, M., Ishida, Y., Seguchi, M., Tanaka, H., Asano, S., Kaneko, T., Matsumoto, N. A case report of familial cyclic neutropenia. Tohoku J. Exp. Med. 167: 107-113, 1992. [PubMed: 1282277] [Full Text: https://doi.org/10.1620/tjem.167.107]
Jones, J. B., Yang, T. J., Dale, J. B., Lange, R. D. Canine cyclic haematopoiesis: marrow transplantation between littermates. Brit. J. Haemat. 30: 215-223, 1975. [PubMed: 127610] [Full Text: https://doi.org/10.1111/j.1365-2141.1975.tb00535.x]
Krance, R. A., Spruce, W. E., Forman, S. J., Rosen, R. B., Hecht, T., Hammond, W. P., Blume, K. G. Human cyclic neutropenia transferred by allogeneic bone marrow grafting. Blood 60: 1263-1266, 1982. [PubMed: 6753968]
Lothrop, C. D., Jr., Coulson, P. A., Jr., Nolan, H. L., Cole, B., Jones, J. B., Sanders, W. L. Cyclic hormonogenesis in gray collie dogs: interactions of hematopoietic and endocrine systems. Endocrinology 120: 1027-1032, 1987. [PubMed: 3026784] [Full Text: https://doi.org/10.1210/endo-120-3-1027]
Meuret, G., Fliedner, T. M. Zellkinetik der Granulopoiese und des Neutrophilensystems bei einem Fall von zyklischer Neutropenie. Acta Haemat. 43: 48-63, 1970. [PubMed: 4986188] [Full Text: https://doi.org/10.1159/000208713]
Migliaccio, A. R., Migliaccio, G., Dale, D. C., Hammond, W. P. Hematopoietic progenitors in cyclic neutropenia: effect of granulocyte colony-stimulating factor in vivo. Blood 75: 1951-1959, 1990. [PubMed: 1692489]
Morley, A. A., Carew, J. P., Baikie, A. G. Familial cyclical neutropenia. Brit. J. Haemat. 13: 719-738, 1967. [PubMed: 6050865] [Full Text: https://doi.org/10.1111/j.1365-2141.1967.tb08838.x]
Page, A. R., Good, R. A. Studies on cyclic neutropenia: a clinical and experimental investigation. AMA J. Dis. Child. 94: 623-661, 1957. [PubMed: 13478297] [Full Text: https://doi.org/10.1001/archpedi.1957.04030070035006]
Palmer, S. E., Stephens, K., Dale, D. C. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am. J. Med. Genet. 66: 413-422, 1996. [PubMed: 8989458] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19961230)66:4<413::AID-AJMG5>3.0.CO;2-L]
Peng, H.-W., Chou, C.-F., Liang, D.-C. Hereditary cyclic neutropenia in the male members of a Chinese family with inverted Y chromosome. Brit. J. Haemat. 110: 438-440, 2000. [PubMed: 10971405] [Full Text: https://doi.org/10.1046/j.1365-2141.2000.02173.x]
Torrioli-Riggio, G. Considerazioni su una famiglia di granulopenici. Acta Genet. Med. Gemellol. 7: 237-248, 1958. [PubMed: 13532427]
Weiden, P. L., Robinett, B., Graham, T. C., Adamson, J., Storb, R. Canine cyclic neutropenia. A stem cell defect. J. Clin. Invest. 53: 950-953, 1974. [PubMed: 4591036] [Full Text: https://doi.org/10.1172/JCI107636]
Wright, D. G., Dale, D. C., Fauci, A. S., Wolff, S. M. Human cyclic neutropenia: clinical review and long-term follow-up of patients. Medicine 60: 1-13, 1981. [PubMed: 7453561] [Full Text: https://doi.org/10.1097/00005792-198101000-00001]