Pelger-Huet Anomaly

Updated: Aug 04, 2020
  • Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP; Chief Editor: Hassan M Yaish, MD  more...
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Overview

Practice Essentials

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]

Signs of Pelger-Huët anomaly

Unique physical findings are not observed in heterozygous individuals with PHA. Homozygous individuals are extremely rare and inconsistently have skeletal anomalies such as postaxial polydactyly, short metacarpals, short upper limbs, short stature, or hyperkyphosis. [4]

Workup in and management of Pelger-Huët anomaly

The diagnosis of PHA is based on the morphologic characteristics of the neutrophils observed on peripheral blood film examination. When a complete blood count (CBC) is requested, digital analyzers will report a shift to the left without identifying the specific anomaly of the neutrophils.

Examination of a peripheral blood smear in an individual heterozygous for PHA is remarkable for neutrophils with a predominance of bilobed, spectacle-shaped nuclei, an appearance often described as pince-nez. Neutrophils with bilobed nuclei make up 60-90% of the neutrophils seen; those with a single, nonlobulated nucleus account for 10-40%, with normal-appearing neutrophils with three-lobed nuclei sometimes accounting for as little as 10%. Most neutrophils have excessively coarse clumping of the nuclear chromatin. 

Although extremely rare, the homozygous state results in neutrophils that contain a single, round, eccentric nucleus with clumped chromatin and little or no nuclear segmentation, and 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.

No treatment is needed in individuals with PHA.

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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. [5, 6] 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). [7, 8] 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. [9, 10]  LBR abnormalities do not affect neutrophil function, and Pelger-Huët cells survive normally in circulation and can phagocytize and kill microorganisms. [11, 12]

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). [13, 14]

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. [4] 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. [7, 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%). [5]

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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