SNOMEDCT: 85559002; DO: 9631;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q42.12 | Pelger-Huet anomaly | 169400 | Autosomal dominant | 3 | LBR | 600024 |
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).
Pelger-Huet anomaly (PHA) 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.
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. Hoffmann et al. (2007) noted that a plausible historical connection between these two communities may be a founder Swedish soldier from the Thirty Years' War (1618-1648).
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).
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.
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.
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.
Green, M. C., Shultz, L. D., Nedzi, L. A. Abnormal nuclear morphology of leukocytes in the mouse mutant ichthyosis. Transplantation 20: 172-175, 1975. [PubMed: 1101484]
Hoffmann, K., Dreger, C. K., Olins, A. L., Olins, D. E., Shultz, L. D., Lucke, B., Karl, H., Kaps, R., Muller, D., Vaya, A., Aznar, J., Ware, R. E., Cruz, N. S., Lindner, T. H., Herrmann, H., Reis, A., Sperling, K. Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huet anomaly). Nature Genet. 31: 410-414, 2002. [PubMed: 12118250] [Full Text: https://doi.org/10.1038/ng925]
Hoffmann, K., Sperling, K., Olins, A. L., Olins, D. E. The granulocyte nucleus and lamin B receptor: avoiding the ovoid. Chromosoma 116: 227-235, 2007. [PubMed: 17245605] [Full Text: https://doi.org/10.1007/s00412-007-0094-8]
Jensson, O., Arnason, K., Johannesson, G. M., Ulfarsson, J. Studies on the Pelger anomaly in Iceland. Acta Med. Scand. 201: 183-185, 1977. [PubMed: 848354] [Full Text: https://doi.org/10.1111/j.0954-6820.1977.tb15679.x]
Juneja, S. K., Matthews, J. P., Luzinat, R., Fan, Y., Michael, M., Rischin, D., Millward, M. J., Toner, G. C. Association of acquired Pelger-Huet anomaly with taxoid therapy. Brit. J. Haemat. 93: 139-141, 1996. [PubMed: 8611447] [Full Text: https://doi.org/10.1046/j.1365-2141.1996.4701020.x]
Latimer, K. S., Rakich, P. M., Thompson, D. F. Pelger-Huet anomaly in cats. Vet. Path. 22: 370-374, 1985. [PubMed: 4035941] [Full Text: https://doi.org/10.1177/030098588502200412]
Ludden, T. E., Harvey, M. Pelger-Huet anomaly of leukocytes: report of a case and survey of incidence. Am. J. Clin. Path. 37: 302-304, 1962. [PubMed: 14467172] [Full Text: https://doi.org/10.1093/ajcp/37.3.302]
Nachtsheim, H. The Pelger-anomaly in man and rabbit: mendelian character of the nuclei of the leucocytes. J. Hered. 41: 131-137, 1950. [PubMed: 15436969] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a106108]
Oneson, R., Sabio, H., Innes, D. J., Jr. Acute lymphoblastic leukaemia in a child with familial Pelger-Huet anomaly. Brit. J. Haemat. 66: 193-197, 1987. [PubMed: 3475111] [Full Text: https://doi.org/10.1111/j.1365-2141.1987.tb01298.x]
Oosterwijk, J. C., Mansour, S., van Noort, G., Waterham, H. R., Hall, C. M., Hennekam, R. C. M. Congenital abnormalities reported in Pelger-Huet homozygosity as compared to Greenberg/HEM dysplasia: highly variable expression of allelic phenotypes. J. Med. Genet. 40: 937-941, 2003. [PubMed: 14684694] [Full Text: https://doi.org/10.1136/jmg.40.12.937]
Rioux, E., St. Arneault, G., Brosseau, C. The Pelger-Huet anomaly of leukocytes: description of a Quebec kindred. Canad. Med. Assoc. J. 99: 621-624, 1968. [PubMed: 5686316]
Rosse, W. F., Gurney, C. W. The Pelger-Huet anomaly in three families and its uses in determining the disappearance of transfused neutrophils from the peripheral blood. Blood 14: 170-186, 1959. [PubMed: 13618374]
Sainty, D., Liso, V., Cantu-Rajnoldi, A., Head, D., Mozziconacci, M.-J., Arnoulet, C., Benattar, L., Fenu, S., Mancini, M., Duchayne, E., Mahon, F.-X., Gutierrez, N., Birg, F., Biondi, A., Grimwade, D., Lafage-Pochitaloff, M., Hagemeijer, A., Flandrin, G. A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements. Blood 96: 1287-1296, 2000. [PubMed: 10942370]
Shenkenberg, T. D., Rice, L., Waddell, C. C. Acquired Pelger-Huet nuclear anomaly with tuberculosis. Arch. Intern. Med. 142: 153-154, 1982. [PubMed: 7053717]
Shultz, L. D., Lyons, B. L., Burzenski, L. M., Gott, B., Samuels, R., Schweitzer, P. A., Dreger, C., Herrmann, H., Kalscheuer, V., Olins, A. L., Olins, D. E., Sperling, K., Hoffmann, K. Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huet anomaly. Hum. Molec. Genet. 12: 61-69, 2003. [PubMed: 12490533] [Full Text: https://doi.org/10.1093/hmg/ddg003]
Skendzel, L. P., Hoffman, G. C. The Pelger anomaly of leukocytes: forty-one cases in seven families. Am. J. Clin. Path. 37: 294-301, 1962. [PubMed: 13913617] [Full Text: https://doi.org/10.1093/ajcp/37.3.294]
Ware, R., Kurtzberg, J., Brazy, J., Falletta, J. M. Congenital Pelger-Huet anomaly in triplets. Am. J. Hemat. 27: 226-227, 1988. [PubMed: 3348208] [Full Text: https://doi.org/10.1002/ajh.2830270316]