Pelger-Huet Anomaly 

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

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]

 

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]

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.

 

Presentation

History

Heterozygotes are healthy with no excessive predisposition to infection. In homozygous individuals, Pelger-Huët anomaly (PHA) may be associated with skeletal anomalies[16]

Physical

Unique physical findings are not observed in heterozygous individuals with PHA. The proportion of neutrophils with abnormal morphology is usually 50% or more. This distinguishes it from pseudo–Pelger-Huët anomaly, which may be seen in association with malignancies and other disease states, for which the proportion of abnormal appearing cells is usually around 5%.

Homozygous individuals are extremely rare and inconsistently have skeletal anomalies such as postaxial polydactyly, short metacarpals, short upper limbs, short stature, or hyperkyphosis.[14]

The practical importance of identifying PHA lies in distinguishing this defect from a bandemia with a left-shifted peripheral blood smear that can be observed in association with infection. In addition, acquired or pseudo–Pelger-Huët anomaly often develops in the course of acute or chronic myelogenous leukemia and in myelodysplastic syndromes.

In pseudo–Pelger-Huët anomaly, the percentage of abnormal neutrophils is usually less than 20% and often around 5%. Coarser clumping of nuclear matter may be seen. Pseudo–Pelger-Huët cells may be seen in large numbers following paclitaxel or docetaxel therapy, but this is usually transient and resolves after 10-14 days of chemotherapy administration. The morphologic changes have also been described in myxedema associated with panhypopituitarism, vitamin B-12 and folate deficiency, multiple myeloma, enteroviral infections, malaria, muscular dystrophy, leukemoid reactions secondary to metastases to the bone marrow, and drug sensitivity.

Because PHA is autosomal dominant, when PHA is encountered on a blood smear, family studies can often relieve anxiety about pseudo–Pelger-Huët anomaly and avoid unnecessary investigations.

Causes

Pelger-Huët anomaly is secondary to a mutation of the LBR gene on band 1q42.[17] It is inherited in a highly penetrant, dominant pattern.

 

DDx

 

Workup

Laboratory Studies

The diagnosis of Pelger-Huët anomaly (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.

Neonatologists frequently utilize the ratio of mature to immature neutrophils reported by autoanalyzers for evaluating the risk of sepsis in the neonate. In the rare newborn with PHA, this can lead to a report of large numbers of immature neutrophils and an incorrect diagnosis of sepsis. Unless a peripheral blood smear is examined, the anomaly will not be identified and the report will be deceiving to the neonatologist.[18]

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.

When Pelger-Huët cells are identified, initially attempt to determine if the patient has a benign inherited anomaly or an acquired morphologic feature (ie, pseudo–Pelger-Huët anomaly). In pseudo–Pelger-Huët anomaly, cells may appear morphologically similar to PHA, but absence of these findings in other family members, a low percentage of affected cells (usually 5-20%), and involvement of other cell lines (eg, anemia or thrombocytopenia) suggest an acquired anomaly. Pseudo-PHA may be predictive of the clinical onset of myelodysplastic disorders, myeloid leukemias, or myelofibrosis, and bone-marrow aspiration and biopsy may be warranted. A molecular technique that extracts and analyzes the nuclear skeleton can also be used to differentiate PHA from pseudo-PHA with a sensitivity and specificity of over 80% but is not in routine use.[19]

A study by Sasada et al found that on hematopoietic cell images from peripheral blood smears belonging to patients with myelodysplastic syndrome, observers often missed signs of pseudo–Pelger-Huët anomaly (pseudo-PHA) unless nuclei had the characteristic pince-nez appearance. Cytoplasmic hypogranularity was also often not recognized on the images. The investigators suggested that in order to increase the likelihood that myelodysplastic syndrome will be accurately diagnosed, morphologic cell classification must be further standardized and automatic cell classification–supporting devices need to be developed.[20]

 

Treatment

Medical Care

No treatment is needed in individuals with Pelger-Huët anomaly (PHA).

 

Follow-up

Prognosis

Individuals with Pelger-Huët anomaly (PHA) have good health, and their natural resistance to infection is unimpaired.