eMedicine Specialties > Pediatrics: General Medicine > Hematology
Pelger-Huet Anomaly
Updated: Mar 25, 2009
Introduction
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 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.2
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 1q42.1.3
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).4
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.
LBR also interacts with HP-1 heterochromatin proteins; this is hypothesized to account for the excessive coarse clumping of nuclear chromatin that is observed.5 LBR abnormalities do not affect neutrophil function, and Pelger-Huët cells survive normally in circulation and can phagocytize and kill microorganisms.6
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.
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, although it also occurs secondary to LBR gene nonsense mutations. Because Greenberg syndrome is lethal, cases cannot be evaluated for the presence of PHA.7
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%.3
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 whites, blacks, and Asians.
Sex
Male-to-female ratio is 1:1.
Age
PHA may be observed in individuals of all ages.
Clinical
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.
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References
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-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].
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].
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].
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].
Erice JG, Perez JM, Pericas FS. Homozygous form of the Pelger-Huët anomaly. Haematologica. Aug 1999;84(8):748. [Medline].
Jandl JH. Leukocyte anomalies. In: Blood: Textbook of Hematology. 2nd ed. Boston, Mass: Little, Brown; 1996:788.
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].
Klein A, Hussar AE, Bornstein S. Pelger-Huët anomaly of the leukocytes. N Engl J Med. Dec 15 1955;253(24):1057-62. [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].
Further Reading
Keywords
Pelger-Huet anomaly, Pelger-Huët anomaly, Pelger-Huët nuclear anomaly, Pelger-Huet nuclear anomaly, PHA, pelgerization, LBR gene, pseudo-PHA, acquired PHA, Pelger-Huët cells, Pelger-Huet cells, 1q42, myeloid leukemia, myelodysplasia, acute lymphocytic leukemia, hydrops, ectopic calcifications, moth-eaten dysplasia syndrome, Greenberg syndrome, HEM, developmental delay, seizures, skeletal anomalies, skeletal dysplasia
