Ansar, Sameer MD; Sethi, Vishal MD; Sreedhar, Radhika MD, MS; Hines, David W. MD, FACP
Pelger-Huët anomaly is a benign anomaly of granulocytes that is characterized by hypolobulation of the nuclei of white blood cells. We present this case to stress the importance of reexamining blood smears that are interpreted as a "shift to the left." Identification of this defect avoids misdiagnosis of an infection, thus preventing unnecessary evaluation and treatment.
A 44-year-old man was admitted to the hospital for evaluation of shortness of breath and cough. The patient had a 10-year history of sarcoidosis treated with prednisone. During the year before admission, the patient had mild dyspnea on exertion. Two to 3 days before admission, he began to have dyspnea at rest accompanied by dry cough. He did not have fever, chills, nausea, vomiting, diarrhea, night sweats, joint pains, or rash. He had no orthopnea or swelling of his feet. The rest of the history was unremarkable.
Physical examination was remarkable for decreased breath sounds on the right middle and lower lung zones. The laboratory evaluation was significant for an elevated blood urea nitrogen and creatinine of 33 mg/dL and 3.0 mg/dL, respectively, and elevated white blood cell counts (Table 1). His chest radiograph demonstrated a new infiltrate in the right middle lobe.
The patient was started on azithromycin and piperacillin-tazobactam for his pulmonary infection. His prednisone was continued at the same dosage. He made a rapid recovery, with normal respiratory examination of both lungs. His leukocyte count started coming down. Despite his clinical improvement, the bands were persistently high, showing a marked "shift to the left." His blood smear was reexamined and interpreted this time as showing Pelger-Huët anomaly. Antibiotics were discontinued, and the patient made a complete recovery to the baseline. Review of the previous differentials in the computer also showed that he had an increased number of bands.
Pelger-Huët anomaly is a benign anomaly of leukocytes and is inherited as a non-sex-linked, dominant trait. In 1928, the Dutch physician Pelger described patients with a morphological abnormality of leukocytes that consisted of hypolobulation of the nuclei of the neutrophils.1 Later in 1932, a pediatrician named Huët attributed this to be a genetic trait.2
The incidence of this disorder in different studies has ranged from as high as 1:1000 persons3,4 to 1:10,000.5 There is documented clustering in the Vaserbotten country of Northern Sweden, 0.6%, and in the region of Gelenau, Germany, where 1% of the population has Pelger-Huët anomaly.6
The neutrophil is one of the most easily recognizable cells in the peripheral smear. The neutrophilic cell typically has 2 to 5 lobes with 3 lobes seen on average. Hypersegmented neutrophils are associated with vitamin deficiency states as in B12 or folate deficiency. Hypolobulated nuclei can be seen transiently in the presence of infection, myeloid leukemia, or medication, unlike Pelger-Huet anomaly, which is a constant variant.
The Pelger-Huët anomaly may be inherited as a homozygous state or heterozygous condition. The homozygous states are rare. The homozygous states are generally characterized by cells with monolobulated nuclei that appear round or oval.7 The heterozygous Pelger-Huët anomaly is characterized by a peripheral smear that consists predominantly (69%-93%) of bilobed neutrophils that have been described as having a dumbbell-, peanut-, or pince-nez-shaped nuclei with smooth, round or oval individual lobes in contrast to irregular lobes seen in normal neutrophils (Fig. 1). Few cells have 3 lobes (less than 10%), and practically none have 4 lobes.8,9 These lobes are connected by a single thin filament of chromatin. The condensed clumped chromatin in Pelger-Huët cells can help distinguish them from immature cells, such as bands, metamyelocytes, or myelocytes. The presence of similar abnormalities in the blood smear in other family members as well is helpful in establishing the diagnosis.
Pelger-Huët cells survive normally in circulation. They demonstrate normal leukocyte function and are able to phagocytose and kill microorganisms.10 Thus, Pelger-Huët anomaly represents a morphological, but not a functional, alteration of the granulocytes.
Congenital Pelger-Huët anomaly is inherited as an autosomal dominant trait, believed by most investigators to have 100% penetrance. The homozygous condition was initially found in rabbits by Undritz,11 but extensive investigation were not carried out until Nachtsheim12 mated 2 heterozygous rabbits in an attempt to produce homozygotes that lived longer, but most animals died in utero, with some survivors demonstrating skeletal abnormalities.
In 1952, Haverkemp Begemann and van Lookeren Campagne7 were the first to describe Pelger-Huët anomaly homozygosity in humans. Their patient was a 2½-year-old girl with epilepsy. In her peripheral blood smear, 94% of the neutrophils had round, unsegmented nuclei, and 6% had indented nuclei.
Thirteen other patients have subsequently been described: one each from Morocco13 and Romania,14 3 each from Gelenau, Germany,6,15,16 and Italy,17 and 2 from Spain.18,19
LAMIN B RECEPTOR IN PELGER-HUËT ANOMALY
The lamin B receptor (LBR) is an integral protein of inner nuclear membrane, and anchors lamina and heterochromatin to the inner nuclear membrane. The LBR is recognized as playing a central role in mitosis-related disassembly and reassembly of the nuclear envelope.20 Mutations in the LBR gene are responsible for most, if not all, cases of Pelger-Huët anomaly. By gene mapping, the Pelger-Huët anomaly locus was linked to the 1q41-q43.6 Cells from heterozygous individuals affected with Pelger-Huët anomaly show reduced expression of the LBR, and cells homozygous with respect to Pelger-Huët anomaly contain only trace amounts of it. Investigations in autosomal recessive Greenburg/hydrops, ectopic calcifications, moth-eaten dysplasia in humans and ichthyosis in the mouse were associated with the same LBR gene, suggesting that Pelger-Huët anomaly could be associated with a wider phenotype.21
PSEUDOPELGER-HUËT ANOMALY/ACQUIRED PELGER-HUËT ANOMALY
An acquired or pseudo-Pelger syndrome can be observed in conditions, such as myxedema,22 drug sensitivity,23 myelodysplastic syndromes,24 and in transplant patients on immunosuppressive drugs. Failure to recognize the significance of these cells as early markers of impending myelodysplasia might delay diagnosis and adversely impact on prognosis. When seen in such abnormalities, they may have round nuclei, characteristic of the homozygous state. Furthermore, in a true Pelger-Huët anomaly, most of the neutrophils (70%-90%) will be bilobed in appearance. In the acquired disorders, normally segmented neutrophils are most numerous.
Determining whether a detailed evaluation is necessary may be very difficult. In the hereditary form of Pelger-Huët anomaly, an autosomal dominant pattern should be present, and this finding in other family members is helpful and reassuring. In these conditions, no other cell line involvement should be present. In contrast, if anemia or thrombocytopenia is observed, an evaluation to rule out myelodysplasia should be carried out.
In conclusion, Pelger-Huët anomaly is a benign anomaly of neutrophils, incidence of which ranges from 1:1000 to 1:10,000. One should be suspicious of this anomaly when a patient has persistently elevated band forms that does not improve on antibiotics. The only way to diagnose this anomaly is by reviewing the peripheral blood smear, which consists predominantly of bilobed neutrophils that have been described as having a dumbbell-, peanut-, or pince-nez-shaped nuclei with smooth, round or oval individual lobes, in contrast to irregular lobes seen in normal neutrophils. This morphological picture can be misinterpreted as a "shift to the left" with increased band forms. When one does recognize this anomaly, it is important to rule out other acquired causes such as acute or chronic myelogenous leukemia, infectious mononucleosis, malaria, and other myelodysplastic syndromes. Thus, in every case of a "shift to the left," it is not always a failure of antibiotics.
1. Pelger K. Demonstratie van een paar zeldzaam voorkomende typen van bloedlichaampjes en bespreking der patienten. Ned Tijdschr Geneeskd. 1928;72:1178.
2. Huet GJ. Ueber eine bisher unbekannte familiaere Anomalie der leukocyten. Klin Wschr. 1932;11:1264-1266.
3. Begemann NH, Campagne AVL. Homozygous form of Pelger-Huët's nuclear anomaly in man. Acta Haematol (Basel). 1952;7:295.
4. Heinivaara O, Kaipainen WJ. Pelger-Huët anomaly in lymphocytic leukaemia. Acta Haematol (Basel). 1961;25:375.
5. Ludden TE, Harvey M. Pelger-Huët anomaly of leukocytes. Am J Clin Pathol. 1962;37:302.
6. Hoffmann K, Dreger CK, Olins AL, et al. Mutation in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly). Nat Genet. 2002;31:410-414.
7. Haverkamp Begemann N, van Lookeren Campagne A. Homozygous form of Pelger-Huët's nuclear anomaly in man. Acta Haematol. 1952;7:295-303.
8. Skendzel LP, Hoffman GC. The Pelger anomaly of leukocytes: forty-one cases in seven families. Am J Clin Pathol. 1962;37:294.
9. Davidson WM, Lawler SD, Ackereley AG. The Pelger-Huët anomaly: investigation of family "A". Ann Hum Genet. 1954;19:1.
10. Klein A, Hussar AE, Bornstein S. Pelger-Huët anomaly of the leukocytes. N Engl J Med. 1955;253:1057-1062.
11. Undritz E. Das Ausschliessliche Vorkommen reifer runbdkerniger Leukozyten bei der reingezuchteten Pelgar-Huëtschen Anomalie der Kaninchens und die Bedeutung der Pelgar-Leukozyten in der vergleichenden Hämatologie. Folia Haemat. 1943;67:249-291.
12. Nachtsheim H. The Pelgar anomaly in man and rabbit. J Hered. 1950;41:131-137.
13. Bernard J, Undritz E, Bru Mathë G, et al. Anomalie de Pelgar homozygote chez I'homme. Sang. 1956;27:819-824.
14. Ciplea AG, Cioapciu S. Anamalie leucocytaire Pelger-Huët homozygote humaine. Presse Med. 1958;15:554-555.
15. Stobbe H, Jorke D. Befunde an homozygoten Pelgar-Merkmalsträgern. Schweiz Med Wochenschr. 1956;95:1524-1529.
16. Von Siegert E, Beier L, Gräbner H. Ein Beitrag zur homozygoten Form der Pelgar-Huetschen Kernanomalie. Kinderartzil Praxis. 1983; 51:164-119.
17. Ciatto A, Ferretti GF. Su di un caso di anomalia di Pelgar-Huët nella sue eccezionale variante omozigotica. Minerva Med. 1978;69:697-700.
18. Aznar J, Vaya A. Homozygous form of the Pelgar-Huët leukocytes anomaly in man. Acta Haematol. 1981;66:59-62.
19. Erice JG, Perez JM, Pericas FS. Homozygous form of the Pelgar-Huet anomaly. Haematologica. 1999;84:748.
20. Grant TM, Wilson KL. Nuclear assembly. Annu Rev Cell Dev Biol. 1997;13:669-695.
21. Greenburg CR, Rimoin DL, Gruben HE, et al. A new autosomal recessive lethal chondrodystrophy with congenital hydrops. Am J Med Genet. 1988;29:623-632.
22. Shanbrom E, Tanaka KR. Acquired Pelger Huet granulocytes in severe myxedema. Acta Haematol (Basel). 1962;27:289.
23. Kaplan JM, Barrett O. Reversible pseudo-Pelger anomaly related to sulfisoxazole therapy. N Engl J Med. 1967;277:421.
24. Dorr AD, Moloney WC. Acquired pseudo-Pelger anomaly of granulocytic leukocytes. N Engl J Med. 1959;261:742.
© 2006 Lippincott Williams & Wilkins, Inc.