Pelger-Huet Anomaly

Updated: Sep 04, 2018
  • Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP; Chief Editor: Hassan M Yaish, MD  more...
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Overview

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, Huët, 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 the LBR gene, located on subband 1q42.1. [4, 5] 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). [6, 7] 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. [8, 9]  LBR abnormalities do not affect neutrophil function, and Pelger-Huët cells survive normally in circulation and can phagocytize and kill microorganisms. [10, 11]

Research also suggests that PHA and HEM skeletal dysplasia are related to a defect in cholesterol synthesis, resulting from LBR point mutations that cause a loss of sterol C14 reductase activity associated with the LBR protein. This loss occurs when the point mutations lower LBR’s affinity for the reducing agent nicotinamide adenine dinucleotide phosphate (NADPH). [12, 13]

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. [14] Co-inherited LBR gene nonsense mutations can also result in lethal hydrops, ectopic calcification, moth-eaten (HEM) skeletal dysplasia/Greenberg skeletal dysplasia, and there continues to be debate as to how PHA and HEM skeletal dysplasia overlap. Some patients with HEM skeletal dysplasia have neutrophils with features of PHA, and some patients with PHA have mild skeletal anomalies. [6, 15, 16]

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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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