AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Pelger-Huët anomaly (PHA) is a benign dominantly inherited defect of terminal neutrophil differentiation secondary to mutations in the lamin B receptor (LBR) gene. Characteristics observed on blood smears include leukocytes with dumbbell-shaped bilobed nuclei; a reduced number of nuclear segments; and coarse clumping of the nuclear chromatin in neutrophils, lymphocytes, and monocytes.

Distinguishing this autosomal dominant disorder from acquired or pseudo-PHA, which can be observed in individuals with myeloid leukemia, myelodysplasia, and bi-lineage acute lymphocytic leukemia, is important.

Pathophysiology

The genetics of PHA were first explored with the crossbreeding of rabbits. In 2002, genome-wide analysis of individuals from the Gelenau region of Germany was used to identify the affected gene in humans as LBR gene, located on subband 1q42.1.¹

The LBR gene product is essential for maintaining nuclear membrane structure, and heterozygotes have neutrophils with a predominance of bilobed dumbbell-shaped nuclei, which are also described as pince-nez (ie, looking like pinched-nose spectacles).² LBR also interacts with HP-1 heterochromatin proteins; this is hypothesized to account for the excessive coarse clumping of nuclear chromatin that is observed.³

Rare homozygous individuals have neutrophils that contain a single, round, eccentric nuclei with clumped chromatin and little or no nuclear segmentation. In homozygous individuals, the basophils, eosinophils, and megakaryocytes also show dense nuclear chromatin and rounded nuclear lobes.

Pelger-Huët cells survive normally in circulation. They have normal leukocytic function and can phagocytize and kill microorganisms.

Homozygous PHA is associated with neutrophil abnormalities with a round or indented single nucleus and clumped chromatin, skeletal anomalies, developmental delay, and seizures. Hydrops, ectopic calcifications, and moth-eaten (HEM) dysplasia syndrome/Greenberg syndrome is currently considered a distinct entity, even though it also occurs secondary to LBR gene mutations. Because Greenberg syndrome is lethal, cases cannot be evaluated for the presence of PHA.⁴  

Frequency

International

In several studies, the incidence rates of heterozygous PHA were 0.01-0.1% of the population. In the Gelenau region of Germany, the incidence rate is 1%.¹

Mortality/Morbidity

Neutrophilic function is normal. Heterozygous individuals are in good health, and their natural resistance to infection is unimpaired. Skeletal anomalies, developmental delay, and seizures have been reported in homozygous individuals.

Race

PHA was originally observed in individuals from Switzerland, Germany, or Holland. The anomaly has been described in all ethnic groups, including Caucasians, African Americans, and Asians.

Sex

Male-to-female ratio is 1:1.

Age

PHA may be observed in individuals of all ages.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Heterozygotes are healthy with no excessive predisposition to infection. In homozygous individuals, Pelger-Huët anomaly (PHA) is associated with congenital anomalies (eg, skeletal dysplasia).

Physical

Unique physical findings are not observed in heterozygous individuals with PHA. Homozygous individuals inconsistently have skeletal anomalies such as postaxial polydactyly, short metacarpals, short upper limbs, short stature, or hyperkyphosis.

Causes

PHA is secondary to a mutation of the LBR gene on band 1q42. It is inherited in a highly penetrant, dominant pattern.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

The practical importance of identifying Pelger-Huët anomaly (PHA) lies in distinguishing this defect from a bandemia with a left-shifted peripheral blood smear and neutrophilic band forms and from an increase in young neutrophilic forms that can be observed in association with infection.

Acquired or pseudo-PHA often develops in the course of acute or chronic myelogenous leukemia and in myelodysplastic syndromes. In patients with these conditions, the pseudo–Pelger-Huët cells tend to appear late in the disease and often appear after considerable chemotherapy has been administered. The morphologic changes have also been described in myxedema associated with panhypopituitarism, vitamin B-12 and folate deficiency, multiple myeloma, enteroviral infections, malaria, muscular dystrophy, leukemoid reactions secondary to metastases to the bone marrow, and drug sensitivity.

The acquired neutrophil nuclear changes observed in these conditions can be differentiated from the constitutional form as follows: Fewer bilobed cells and a higher percentage of normal trilobed neutrophils are present in patients with pseudo–PHA than in patients with the constitutional form of PHA, and leukemic and immature cells may be present.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Examination of a peripheral blood smear in an individual heterozygous for Pelger-Huët anomaly (PHA) is remarkable for neutrophils with a predominance of bilobed, spectacle-shaped nuclei. This appearance is often described as pince-nez. Cells that contain twin, joined, and plump nuclei resembling dumbbells are predominant. A thin bridge, which is thinner than that observed in a normal band neutrophil, joins the 2 lobes. Although rare, homozygous individuals are described.
• • About 69-93% of the neutrophils show nuclear segmentation that is arrested at the bilobe level. A small population of neutrophils that possess a nonlobulated oblong or peanut-shaped nucleus is often present.
  • Less than 10% of cells contain 3 lobes; 4 lobes are rare.
  • Most neutrophils have excessively coarse clumping of the nuclear chromatin. The finding of similar abnormalities in the blood smear of other family members may help in establishing the diagnosis.
• The homozygous state results in neutrophils that contain a single, round, eccentric nucleus with clumped chromatin and little or no nuclear segmentation. In contrast to the less than 40% of single-lobed neutrophils typically present in heterozygous individuals, most neutrophils in homozygous individuals are round or oval. In homozygous individuals, the basophils, eosinophils, and megakaryocytes also show dense nuclear chromatin and rounded nuclear lobes.
• The bone marrow of homozygous patients reveals normal morphologic features in the myeloid precursors to the myelocyte stage.
• Electron microscopy reveals persistence of nucleoli in the mature neutrophils that contain a single oval nucleus. This finding suggests altered and retarded nuclear maturation of the myeloid precursors.
• When Pelger-Huët cells are identified, initially attempt to determine if the patient has a benign inherited anomaly, an acquired morphologic feature associated with a transient condition, or evolving myelodysplasia.
• Acquired or pseudo-PHA cells may appear morphologically similar to those observed in the hereditary form; therefore, determining whether detailed workup is necessary may be difficult.
• • In the hereditary form of PHA, an autosomal dominant pattern should be present, and this finding in other family members may be helpful and reassuring.
  • In this condition, no other cell line should be involved. In contrast, if anemia or thrombocytopenia are observed, perform an evaluation to exclude a hematologic malignancy.
  • Pseudo-PHA cells may be predicative of the clinical onset of myelodysplastic disorders and malignant conditions, such as acute myelogenous leukemia, chronic myelogenous leukemia, or myelofibrosis. Therefore, if clinical suspicion warrants it, bone-marrow aspiration and biopsy are necessary.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

No treatment is needed.

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Prognosis

• Individuals with PHA have good health, and their natural resistance to infection is unimpaired.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Acquired or pseudo–Pelger-Huët cells appear transiently in several disorders and may herald the development of acute or chronic myeloproliferative disorders and are among the most obvious markers of several preleukemic syndromes.
• These cells are commonly observed during the course of acute and chronic myelogenous leukemia and idiopathic myelofibrosis. They may indicate the clinical onset of these disorders months or years in advance.
• Failure to recognize the significance of pseudo–Pelger-Huët cells as early markers of impending myelodysplasia may delay diagnosis and negatively affect the patient's prognosis.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Neutrophils in this blood smear (original magnification X1500) have the 2 characteristics of the Pelger-Huët anomaly: the pince nez appearance of the bilobate nuclei and excessively coarse clumping of chromatin. Used with permission from Little, Brown.
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Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Hoffmann K, Dreger CK, Olins AL, et al. Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly). Nat Genet. Aug 2002;31(4):410-4. [Medline].
2. Hoffmann K, Sperling K, Olins AL, Olins DE. The granulocyte nucleus and lamin B receptor: avoiding the ovoid. Chromosoma. Jun 2007;116(3):227-35. [Medline].
3. Ye Q, Callebaut I, Pezhman A, Courvalin JC, Worman HJ. Domain-specific interactions of human HP1-type chromodomain proteins and inner nuclear membrane protein LBR. J Biol Chem. Jun 6 1997;272(23):14983-9. [Medline].
4. Oosterwijk JC, Mansour S, van Noort G, et al. Congenital abnormalities reported in Pelger-Huët homozygosity as compared to Greenberg/HEM dysplasia: highly variable expression of allelic phenotypes. J Med Genet. Dec 2003;40(12):937-41. [Medline].
5. Best S, Salvati F, Kallo J, et al. Lamin B-receptor mutations in Pelger-Huët anomaly. Br J Haematol. Nov 2003;123(3):542-4. [Medline].
6. Erice JG, Perez JM, Pericas FS. Homozygous form of the Pelger-Huët anomaly. Haematologica. Aug 1999;84(8):748. [Medline].
7. Jandl JH. Leukocyte anomalies. In: Blood: Textbook of Hematology. 2^nd ed. Boston, Mass: Little, Brown; 1996:788.
8. Kalfa TA, Zimmerman SA, Goodman BK, et al. Pelger-Huët anomaly in a child with 1q42.3-44 deletion. Pediatr Blood Cancer. May 1 2006;46(5):645-8. [Medline].
9. Klein A, Hussar AE, Bornstein S. Pelger-Huët anomaly of the leukocytes. N Engl J Med. Dec 15 1955;253(24):1057-62. [Medline].
10. Matsumoto T, Harada Y, Yamaguchi K, et al. Cytogenetic and functional studies of leukocytes with Pelger-Huët anomaly. Acta Haematol. 1984;72(4):264-73. [Medline].

Article Last Updated: Sep 17, 2007