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Pelger-Huet Anomaly

  • Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP; Chief Editor: Hassan M Yaish, MD  more...
 
Updated: May 03, 2016
 

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.[1] The characteristic neutrophil appearance was first reported in 1928 by Pelger, a Dutch hematologist, who described neutrophils with dumbbell-shaped bilobed nuclei, a reduced number of nuclear segments, and coarse clumping of the nuclear chromatin. In 1931 Huet, a Dutch pediatrician, identified it as an inherited disorder.[2]

Distinguishing this benign autosomal dominant disorder from acquired or pseudo–Pelger-Huët anomaly, which can be observed in individuals with myeloid leukemia, myelodysplasia, and bi-lineage acute lymphocytic leukemia, is important.[3]

 

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Pathophysiology

Genome-wide analysis of individuals with PHA from the Gelenau region of Germany was used to identify the affected gene in humans as LBR gene, located on subband 1q42.1.[4] The LBR gene product is essential for maintaining nuclear membrane structure, and heterozygotes have at least half of their neutrophils with bilobed dumbbell-shaped nuclei, also described as pince-nez (ie, looking like pinched-nose spectacles).[5, 6] The image below demonstrates neutrophils in a patient with PHA.

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

LBR also interacts with HP-1 heterochromatin proteins; this is hypothesized to account for the excessive coarse clumping of nuclear chromatin that is observed.[7] LBR abnormalities do not affect neutrophil function, and Pelger-Huët cells survive normally in circulation and can phagocytize and kill microorganisms.[8, 9]

Homozygous LBR mutations are rare, with only 11 individuals described; neutrophils have a single, round, nucleus with clumped chromatin, and basophils, eosinophils and megakaryocytes also show rounded nuclear lobes and dense nuclear chromatin.[10] Co-inherited LBR gene nonsense mutations can also result in lethal hydrops, ectopic calcifications, and moth-eaten (HEM) dysplasia syndrome/Greenberg syndrome, and there continues to be debate as to how PHA and HEM overlap. Some patients with HEM have neutrophils with features of PHA, and some patients with PHA have mild skeletal anomalies.[5, 11, 12]

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Epidemiology

Frequency

United States

The prevalence rate in the United States is estimated as 1 case in 5000 population.

International

The prevalence rate of heterozygous PHA is 1 case in 6000 population in the United Kingdom. The highest described incidence is in the Gelenau region of Germany (1.01%) and the Vasterbotten region of Sweden (0.6%).[4]

Mortality/Morbidity

Neutrophil function is normal. Individuals with PHA are in good health, and their natural resistance to infection is unimpaired. Individuals with the rare homozygous LBR mutations may have skeletal anomalies.

Race

Pelger-Huët anomaly was originally observed in individuals from Switzerland, Germany, or Holland. The anomaly has been described in all ethnic groups, including whites, blacks, and Asians.

Sex

Male-to-female ratio is 1:1.

Age

Pelger-Huët anomaly may be observed in individuals of all ages.

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Contributor Information and Disclosures
Author

Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP Professor of Pediatrics, Albany Medical College; Chief, Division of Pediatric Hematology-Oncology, John and Anna Landis Endowed Chair for Pediatric Hematology-Oncology, Medical Director, Melodies Center for Childhood Cancer and Blood Disorders, Albany Medical Center

Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, International Society of Pediatric Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology, American Federation for Clinical Research, Council on Medical Student Education in Pediatrics, Hemophilia and Thrombosis Research Society, American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Hassan M Yaish, MD Medical Director, Intermountain Hemophilia and Thrombophilia Treatment Center; Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology, Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center

Hassan M Yaish, MD is a member of the following medical societies: American Academy of Pediatrics, New York Academy of Sciences, American Medical Association, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Michigan State Medical Society

Disclosure: Nothing to disclose.

Additional Contributors

Sharada A Sarnaik, MBBS Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Associate Hematologist/Oncologist, Children's Hospital of Michigan

Sharada A Sarnaik, MBBS is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, Children's Oncology Group, American Academy of Pediatrics, Midwest Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Frank E Shafer, MD, to the original writing and development of this topic.

References
  1. Cohen TV, Klarmann KD, Sakchaisri K, et al. The lamin B receptor under transcriptional control of C/EBPepsilon is required for morphological but not functional maturation of neutrophils. Hum Mol Genet. 2008 Oct 1. 17(19):2921-33. [Medline].

  2. Cunningham JM, Patnaik MM, Hammerschmidt DE, Vercellotti GM. Historical perspective and clinical implications of the Pelger-Hüet cell. Am J Hematol. 2009 Feb. 84(2):116-9. [Medline].

  3. Kuriyama K, Tomonaga M, Matsuo T, Ginnai I, Ichimaru M. Diagnostic significance of detecting pseudo-Pelger-Huët anomalies and micro-megakaryocytes in myelodysplastic syndrome. Br J Haematol. 1986 Aug. 63(4):665-9. [Medline].

  4. 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. 2002 Aug. 31(4):410-4. [Medline].

  5. Hoffmann K, Sperling K, Olins AL, Olins DE. The granulocyte nucleus and lamin B receptor: avoiding the ovoid. Chromosoma. 2007 Jun. 116(3):227-35. [Medline].

  6. Best S, Salvati F, Kallo J, et al. Lamin B-receptor mutations in Pelger-Huët anomaly. Br J Haematol. 2003 Nov. 123(3):542-4. [Medline].

  7. 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. 1997 Jun 6. 272(23):14983-9. [Medline].

  8. Cohen TV, Klarmann KD, Sakchaisri K, Cooper JP, Kuhns D, Anver M, et al. The lamin B receptor under transcriptional control of C/EBPepsilon is required for morphological but not functional maturation of neutrophils. Hum Mol Genet. 2008 Oct 1. 17(19):2921-33. [Medline].

  9. 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].

  10. Erice JG, Perez JM, Pericas FS. Homozygous form of the Pelger-Huët anomaly. Haematologica. 1999 Aug. 84(8):748. [Medline].

  11. 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. 2003 Dec. 40(12):937-41. [Medline].

  12. Borovik L, Modaff P, Waterham HR, Krentz AD, Pauli RM. Pelger-huet anomaly and a mild skeletal phenotype secondary to mutations in LBR. Am J Med Genet A. 2013 Aug. 161A(8):2066-73. [Medline].

  13. Kalfa TA, Zimmerman SA, Goodman BK, et al. Pelger-Huët anomaly in a child with 1q42.3-44 deletion. Pediatr Blood Cancer. 2006 May 1. 46(5):645-8. [Medline].

  14. Christensen RD, Yaish HM. A neonate with the Pelger-Huët anomaly, cleft lip and palate, and agenesis of the corpus callosum, with a chromosomal microdeletion involving 1q41 to 1q42.12. J Perinatol. 2012 Mar. 32 (3):238-40. [Medline].

  15. Sun M, Yang S, Jiang J, Wang Q. Detection of Pelger-Huet anomaly based on augmented fast marching method and speeded up robust features. Biomed Mater Eng. 2015. 26 Suppl 1:S1241-8. [Medline].

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