Pelger-Huët Anomaly in Dogs
L. Allison Logan, DVM; Kenneth S. Latimer, DVM, PhD; Holly A. Moore, DVM
Class of 2006 (Logan) and Department of Pathology (Latimer, Moore), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388
Introduction
Pelger-Huët (P-H) anomaly is an inherited disease resulting in nuclear morphologic changes of granulocytes and monocytes.1,2,4 Characteristic P-H cells have persistently hyposegmented nuclei, with presentations that range from round to slightly lobulated in appearance.1,2,4,5 The chromatin pattern of these nuclei is mature and dense.1,4,5 Pelger-Huët anomaly has been well described in humans and dogs,4,6,8 and also has been diagnosed in domestic shorthair cats,2,7 rabbits,8 and, more recently, in mice.9 Transient nuclear hyposegmentation of leukocytes, termed pseudo-Pelger-Huët anomaly, may be caused by infection, neoplastic change, or drug-induced cellular change.10 Pelger-Huët anomaly should be distinguished from these abnormalities in order to make an accurate diagnosis.10
Signalment
Pelger-Huet anomaly has been described in several pure breeds of dogs, as well as some mixed breed dogs.6,10 Australian shepherds have a relatively high incidence of the anomaly.6 A study conducted by Latimer, Campagnoli, and Danilenko found a 9.8% incidence of P-H anomaly in 892 Australian shepherds evaluated for the anomaly over a 6-year period.6 Other breeds such as the American foxhound, basenji,10 Australian cattle dog, border collie, Boston terrier, cocker spaniel, German shepherd dog, samoyed, and various coonhounds have been diagnosed with P-H anomaly.6 Pelger-Huët anomaly is congenital, but is not associated with clinical signs in its heterozygous state. Therefore, affected dogs of any age may be diagnosed with P-H anomaly.1,6,10 In the study that investigated the anomaly in Australian shepherds, the ages of the dogs diagnosed with this defect ranged from 1 day to 14 years.6 Both male and female dogs may be affected, with no obvious sex predilection for the defect.6
Etiology
Pelger-Huët anomaly is an hereditary abnormality that affects leukocyte development.5 Parents or siblings of the affected dogs may also be affected.10 The defect is likely transmitted as an autosomal dominant trait,10 but genetic evidence of incomplete penetrance has been proven in Australian shepherds.6 Incomplete penetrance has been demonstrated in a study of Australian shepherds wherein two statistically significant findings refuted simple autosomal dominant transmission.6 First, Australian shepherd parents without P-H anomaly produced offspring with the abnormality. Statistically, this finding cannot be attributed to a point mutation.6 Second, parents with P-H anomaly produced fewer affected offspring than would be expected with complete penetrance.6
Dogs with P-H anomaly theoretically may have either heterozygous or homozygous genetic expression of the anomaly.1,6,10 While both forms of the anomaly are characterized by leukocytes with hyposegmented nuclei and a coarse chromatin pattern, each has a distinct phenotype.4,6 Heterozygotes have leukocytes with more nuclear segmentation and fewer round nuclei along with a coarse chromatin pattern.4,6 Affected neutrophils usually appear bilobed (pince-nez configuration) or resemble bands and metamyelocytes. The majority of granulocytes observed in the homozygous form have a myelocyte appearance with round to ovoid nuclei, in addition to an extremely coarse chromatin pattern.4,6 The homozygous form of P-H anomaly also has been observed rarely only in humans, cats, and rabbits.2,7,8 The homozygous form of the anomaly is believed to be lethal in utero; therefore, it is presumed that the heterozygous form of P-H anomaly usually is diagnosed on the hemogram.4,6 The homozygous form of P-H anomaly has been observed rarely in humans, cats, and rabbits and has been associated with skeletal deformities.2,7,8,10
Appearance of Pelger-Huët Cells in the Stained Blood Smear
Diagnosis of P-H anomaly involves microscopic examination of a well prepared and adequately stained blood smear. Pelger-Huët anomaly is characterized by a variable degree of nuclear hyposegmentation in granulocytes (neutrophils, basophils, and eosinophils) and monocytes. The granulocytes retain a coarse, mature, chromatin pattern.1,4,6,10 These changes can be particularly well-observed in the neutrophil, whose normal appearance of segmentation is in stark contrast to the appearance of the neutrophils in a dog affected by P-H anomaly (Figures 1 and 2).4,5
Females affected with P-H anomaly also lack Barr bodies or sex chromatin ‘drumsticks’ in circulating neutrophils and eosinophils,4 although these structures may be observed infrequently in cells following emigration from the blood into the tissues.5 These sex chromatin ‘drumsticks’ are normally expected in at least 2 to 7 percent of the neutrophils from healthy females.4 Thus, the sex of a given dog cannot be determined by blood smear examination in dogs with P-H anomaly.4
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| Figure 1. A pair of neutrophils from a healthy dog have distinct nuclear lobulation (Blood smear, Wright-Leishman stain). |
Figure 2. A pair of neutrophils from a dog with Pelger-Huët anomaly display nuclear hyposegmentation with the retention of a mature, coarse chromatin (Blood smear, Wright-Leishman stain). |
Diagnosis
The diagnosis of P-H anomaly is based on demonstration of granulocytic (especially neutrophilic) nuclear hyposegmentation with the retention of a mature, coarse chromatin pattern on the Romanowsky-stained blood smear.10 An hereditary basis for the anomaly can usually be demonstrated by examining stained blood smears from the siblings, sire, or dam. Often, there is the appearance of a degenerative left shift on the hemogram or stained blood smear is an unexpected finding.6,10 Bone marrow biopsies of dogs with P-H anomaly exhibit the same characteristic nuclear hyposegmentation of the leukocytes as observed on the stained blood smear. Blast cell counts on bone marrow aspirates remain within reference intervals.10
Differential Diagnosis
Although dogs affected with P-H anomaly have very characteristic findings on the hemogram, this defect is often misdiagnosed.10 Differential diagnoses for P-H anomaly include infection with a left shift, severe inflammation, drug-induced cellular alterations, and cellular maturation alterations, as might be noted with leukemia or other neoplastic changes.10 Pelger-Huët anomaly can be distinguished from infection with a left shift because the chromatin of P-H neutrophils is obviously mature and dense.4,6,10 In contrast, the chromatin pattern of immature, or band, neutrophils in infection has a finely granular pattern.4,10 Furthermore, toxic changes should not be noted in the neutrophils of a dog with P-H anomaly, as might be expected in a dog with bacterial infection and an intense left shift.10 The morphological differences in P-H cells are persistent. In contrast, altered cellular morphology associated with infection, severe inflammation, drug administration, and neoplasia are transient following effective therapy of the underlying condition.10 An accurate medical history, as well as knowledge of the duration of the change in leukocyte morphology, would aid in the exclusion of drug-induced pseudo-P-H appearance of granulocytes. Bone marrow biopsies and aspirates may help to distinguish P-H anomaly from cellular changes induced by neoplasia. Finally, dogs affected with P-H anomaly are often clinically healthy, which may aid in excluding severe infection or neoplasia causing physical abnormalities.10
Clinical Signs
The heterozygous expression of P-H anomaly is not associated with clinical signs of disease and abnormalities associated with the disease cannot be found on physical examination.1,10 The homozygous form of P-H anomaly is likely lethal in utero; therefore mating of affected dogs may result in small litter size due to fetal resorption or stillborn puppies.1,6,10 The skeletal abnormalities found in some rabbits and a kitten with the homozygous form of P-H anomaly have not been described in dogs. Furthermore, such abnormalities have not been definitively associated with the leukocyte development defect in the animals.2,7,8
Many varied and extensive studies have been performed in order to determine the function of the abnormal P-H cells, particularly the neutrophils. Early studies suggested that the function of the neutrophils was decreased in dogs with P-H anomaly.3,5 However, more comprehensive studies were later performed that showed that the neutrophil function of affected dogs is within normal limits.3,5 These studies demonstrated that the anomaly has no effect on either random or chemotactic movement of neutrophils.3,5 Also, eosinophils of P-H dogs were demonstrated to move normally, but in lower numbers than neutrophils, as would be expected.5 Pelger-Huët neutrophils also were shown to phagocytose and destroy bacteria as rapidly and effectively as neutrophils with normal morphology.5 Dogs affected with P-H anomaly have been studied long-term. These animals have not demonstrated a predisposition to clinical infection compared to normal control dogs.5 Finally, other humoral and cell-mediated components of the immune system of dogs with P-H anomaly have been found to be as functional as those of normal dogs.5
Summary
Pelger-Huët anomaly in dogs may be diagnosed as an incidental finding on a hemogram where a degenerative left shift is observed when it is unexpected.6,10 This leukocyte abnormality is usually due to heterozygous gene inheritance and is clinically insignificant.1,6,10 Research has shown clearly that, although leukocyte morphology is altered, the function of these cells is not affected.3,5 Dogs with P-H anomaly are at no greater risk for infection than dogs with normal cellular morphology.5 As the homozygous state of P-H anomaly is often lethal in utero, selective breeding s required to prevent the risk of homozygous inheritance and subsequent smaller litter sizes.10 Both veterinarians and owners should be aware of P-H anomaly so that the leukocyte abnormality is not misdiagnosed, leading to further unnecessary diagnostic testing and / or inappropriate treatment.10
References
1, Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, Diseases of the Dog and Cat, 5th ed. Philadelphia, W.B. Saunders Co., 2000, pp. 1849,1979, 1990.
2. Latimer KS, Rowland GN, and Mahaffey MB: Homozygous Pelger-Huët anomaly and chondrodysplasia in a stillborn kitten. Vet Pathol 2004; 25:325-328.
3. Latimer KS, Prasse KW: Neutrophilic movement of a Basenji with Pelger-Huët anomaly. Am J Vet Res 1982; 43:525-527.
4. Latimer KS, Duncan JR, Kircher IM: Nuclear segmantation, ultrastructure, and cytochemistry of blood cells from dogs with Pelger-Huët anomaly. J Comp Pathol 1987; 97:61-72.
5. Latimer KS, Kircher IM, Lindl, PA, Dawe, DL, Brown J: Leukocyte function in Pelger-Huët anomaly of dogs. J Leukocyte Biol 1989; 45:301-310.
6. Latimer KS, Campagnoli RP, Danilenko DM: Pelger-Huët anomaly in Australian shepherds: 87 cases (1991-1997). Comp Hematol Int 2000; 10:9-13.
7. Latimer KS, Rakich PM, Thompson DF: Pelger-Huët anomaly in cats. Vet Pathol 1985; 22:370-374.
8. Oosterwijk JC, Mansour S, van Noort G, Waterham HR, Hall CM, Hennekam RCM: Congenital abnormalities reported in Pelger-Huët homozygosity as compared to Greenberg/HEM dysplasia: Highly variable expression of allelic phenotytes. J Med Genetics 2003; 40:937-941.
9. Shultz LD, Lyons BL, Burzeski LM, Gott B, Samuels R, Schweitzer PA, Dreger C,, Herrman H, Kalscheur V, Olins AL, Olins DE, Sperling K, Hoffmann K: Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: A single gene model for human Pelger-Huët anomaly. Human Molecular Genetics 2003; 12:61-69.
10. Tilley LP, Smith FWK (eds): The 5 Minute Veterinary Consult, 2nd ed. Baltimore, Lippincott Williams and Wilkins, 2000, p. 1051.
Acknowledgement
Picture of Sota, an Australian Shepherd, working cattle is from the website of Rising Sun Farm and is used with permission. |