Pelger-Huet Anomaly

A number sign (#) is used with this entry because of evidence that Pelger-Huet anomaly (PHA) can be caused by heterozygous mutation in the gene encoding the lamin B receptor (LBR; 600024) on chromosome 1q42.

Homozygous mutation in the LBR gene can cause PHA with mild skeletal anomalies (PHASK; 618019) or Greenberg dysplasia (GRBGD; 215140).

Clinical Features

Pelger-Huet anomaly is an autosomal dominant disorder characterized by hypolobulated neutrophil nuclei with coarse chromatin (Hoffmann et al., 2002). The nucleus of the granulocytes has been described as hyposegmented, being rodlike, dumbbell- or peanut-shaped, or spectaclelike.

Rioux et al. (1968) reported an extensively affected French-Canadian kindred with PHA. The nuclei of leukocytes had a pince-nez appearance.

Oneson et al. (1987) described a child with familial Pelger-Huet anomaly who developed acute lymphoblastic leukemia. The disorder is effectively detected by the average lobe index (ALI) of the neutrophils. The ALI is the total number of nuclear lobes in 100 neutrophils divided by 100. The normal range for ALI is 2.5 to 3.1 (mean, 2.8). ALI in the affected nonleukemic members of this family varied from 1.12 to 1.60, with the lowest values in children and the highest values in adults. That folate deficiency increases segmentation was indicated by the fact that the ALI of the proband increased during 6-mercaptopurine and methotrexate therapy. Elevation of temperature to 42 degrees C resulted in an increase in the ALI of both normal cells and cells with the Pelger-Huet anomaly.

Population Genetics

In Spokane, Washington, Ludden and Harvey (1962) found 4 cases of PHA among 43,000 persons. Affected persons were of German or Dutch descent. In Cleveland, Skendzel and Hoffman (1962) found a frequency of 1 in 4,785 routine smears. All figures in this country and also that of Davidson in England (1 in 6,000) are lower than that of Nachtsheim (1 in 1,020).

The frequency of PHA is estimated to be 0.01-0.1% (Skendzel and Hoffman, 1962), but the frequency is much higher in Vasterbotten County in northern Sweden (0.6%) and in the mountain village of Gelenau in southeastern Germany (1.01%), according to Hoffmann et al. (2002), who did positional cloning studies in families from the latter region.

Mapping

By genomewide linkage scan, Hoffmann et al. (2002) mapped the PHA locus to 1q41-q43, the region that contains the lamin B receptor gene (LBR; 600024).

Molecular Genetics

To identify the genetic cause of PHA, Hoffmann et al. (2002) studied 11 families from Gelenau with 18 unaffected and 29 affected members, including a presumed homozygous individual. In contrast to the neutrophils of healthy subjects, all neutrophils of individuals of PHA had bilobed or rod-like nuclei. The presumed homozygous individual had neutrophils with round, nonsegmented nuclei and presented with mental retardation, disproportionate body habitus, macrocephalus with prominent forehead, ventricular septal defect, and short metacarpals in several fingers. Hoffmann et al. (2002) identified a founder haplotype in 10 of the 11 families. The affected members of these 10 families carried the same mutation, a 6-bp deletion in the 3-prime splice site region of intron 12 of the LBR gene (600024.0001). In the affected individual in the eleventh family, a different splice acceptor site mutation was found, in intron 2 of LBR (600024.0002). Six further mutations in LBR were found in individuals from Spain, the United States, and Mexico. Only splice site, frameshift, and nonsense mutations were found.

Biochemical Features

Hoffmann et al. (2002) found that the expression of the lamin B receptor affected neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Hoffmann et al. (2002) stated that their findings have implications for understanding the interactions between the nuclear envelope and heterochromatin, the pathogenesis of Pelger-like conditions in leukemia (Sainty et al., 2000), infection (Shenkenberg et al., 1982), and toxic drug reactions (Juneja et al., 1996), as well as the evolution of neutrophil nuclear shape.

Animal Model

Hoffmann et al. (2002) stated that Pelger-Huet anomaly was first described in rabbits. Homozygous rabbits show severe chondrodystrophy (Nachtsheim, 1950).

In 2 independent mouse strains with the blood phenotype associated with homozygosity for Pelger-Huet anomaly (Green et al., 1975), Hoffmann et al. (2002) found 1 frameshift and 1 nonsense mutation in Lbr.

Mice with the 'ichthyosis' (ic) phenotype display marked abnormalities in nuclear heterochromatin, similar to those observed in PHA. Shultz et al. (2003) observed that mice homozygous for deleterious mutations at the ic locus present with a blood phenotype similar to PHA and develop other phenotypic abnormalities, including alopecia, variable expression of syndactyly, and hydrocephalus. The ic locus on mouse chromosome 1 shares conserved synteny with the chromosomal location of the human LBR locus on human chromosome 1. Shultz et al. (2003) identified 1 nonsense and 2 frameshift mutations within the Lbr gene of mice homozygous for 1 of 3 independent mutations (ic, icJ, or ic4J, respectively) at the ichthyosis locus. These allelic mutations resulted in a truncated or severely impaired protein. Tissues from mice homozygous for the icJ mutation revealed a complete loss of Lbr protein, as shown by immunofluorescence microscopy and immunoblotting.