Pelger-Huet Anomaly
- Author: Vikramjit S Kanwar, MD, MBA, MRCP(UK), FAAP; Chief Editor: Robert J Arceci, MD, PhD more...
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 leukocyte appearance was first reported in 1928 by Pelger, a Dutch hematologist, who described leukocytes with dumbbell-shaped bilobed nuclei, a reduced number of nuclear segments, and coarse clumping of the nuclear chromatin. In 1931 Huet, a pediatrician, identified it as an inherited disorder.[2]
Distinguishing this 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]
Pathophysiology
The genetics of Pelger-Huët anomaly were first explored with the crossbreeding of rabbits. 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.[4]
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).[5, 6] The image below demonstrates neutrophils in a patient with Pelger-Huët anomaly.
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 individuals are rare, with only 11 cases described. 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. Occasionally skeletal anomalies, developmental delay, and seizures may be associated.[10]
Lethal hydrops, ectopic calcifications, and moth-eaten (HEM) dysplasia syndrome/Greenberg syndrome also occurs secondary to LBR gene nonsense mutations, and some authors feel this syndrome overlaps with homozygous Pelger-Huët anomaly,[5] whereas others consider it a distinct autosomal recessive entity.[11]
Epidemiology
Frequency
International
In several studies, the incidence rates of heterozygous Pelger-Huët anomaly were 0.01-0.1% of the population. The highest described incidence is in the Gelenau region of Germany (1.01%) and in the Vasterbotten region of Sweden (0.6%).[4]
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
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.
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. Oct 1 2008;17(19):2921-33. [Medline].
Cunningham JM, Patnaik MM, Hammerschmidt DE, Vercellotti GM. Historical perspective and clinical implications of the Pelger-Hüet cell. Am J Hematol. Feb 2009;84(2):116-9. [Medline].
Cunningham JM, Patnaik MM, Hammerschmidt DE, Vercellotti GM. Historical perspective and clinical implications of the Pelger-Huet cell. Am J Hematol. Feb 2009;84(2):116-9. [Medline].
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].
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].
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].
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].
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. Oct 1 2008;17(19):2921-33. [Medline].
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].
Erice JG, Perez JM, Pericas FS. Homozygous form of the Pelger-Huët anomaly. Haematologica. Aug 1999;84(8):748. [Medline].
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].
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].
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