Pelger-Huet Anomaly With Mild Skeletal Anomalies

A number sign (#) is used with this entry because of evidence that Pelger-Huet anomaly with mild skeletal anomalies (PHASK) is caused by homozygous or compound heterozygous mutation in the LBR gene (600024) on chromosome 1q42.

Homozygous mutation in the LBR gene can also cause Greenberg dysplasia (215140), a lethal disorder. Heterozygous mutation in LBR can cause Pelger-Huet anomaly (169400).

Description

Pelger-Huet anomaly with mild skeletal anomalies is characterized by abnormal nuclear shape and chromatin organization in blood granulocytes (PHA), short stature, and mild skeletal anomalies (Hoffmann et al., 2002; Borovik et al., 2013). Initial skeletal features may improve with age (Sobreira et al., 2014).

Clinical Features

Hoffmann et al. (2002) reported a family in which parents with PHA and heterozygosity for a founder mutation (600024.0001) in the LBR gene had a son who was presumably homozygous for the mutation. Instead of the hypolobulated neutrophil nuclei with coarse chromatin found in his parents, the son had ovoid neutrophil nuclei. He had presented at 20 months of age with developmental delay, disproportionate body habitus, macrocephaly with prominent forehead, ventricular septal defect, shortened third and fifth metacarpals in the left hand, and shortened third, fourth, and fifth metacarpals in the right hand.

Oosterwijk et al. (2003) identified 11 reported patients with Pelger-Huet anomaly and mild additional features who were presumed homozygotes, including the patients of Haverkamp Begemann and van Lookeren Campagne (1952), Aznar and Vaya (1981), and Hoffmann et al. (2002). The patient reported by Aznar and Vaya (1981) had postaxial polydactyly of all 4 limbs. Oosterwijk et al. (2003) noted that none of these patients had severe skeletal dysplasia or congenital anomalies, early lethality, or skin abnormalities. They suggested that homozygous LBR mutations result in distinct mild (PHA homozygosity) or severe (Greenberg skeletal dysplasia) phenotypes based on allelic heterogeneity.

Borovik et al. (2013) reported a 12-year-old adopted girl, thought to be of northern Chinese origin, who was first seen at age 10 years because of short stature and a possible bone dysplasia. On routine screening, she was found to have PHA with dumbbell-shaped nuclei. She had mild short stature, borderline microcephaly, mild thoracolumbar kyphosis, mild hyperlordosis, mild decreased pronation of the elbows, limited elbow extension, and bilateral shortening of the fourth and fifth metacarpals.. She had normal cognitive development. Sterol analysis on patient cultured lymphoblasts demonstrated trace amounts of cholesta-8,14-dien-3-beta-ol.

Sobreira et al. (2014) described a 15-year-old boy with PHA who was diagnosed at birth with spondylometaphyseal dysplasia. Initial radiographs showed shortened and bowed humeri and femora, with less marked shortening of all other long bones. The radii were also bowed. Metaphyses were widened and irregular, most prominently at the wrist, knees, and ankles. Ulnar metaphyses were cupped. The ribs were mildly shortened. Platyspondyly and ovoid vertebral bodies were present. The pelvis was near normal, with mildly flared ilia. There were no abnormalities of the hands, feet, or skull. Sequential radiographs showed progressive improvement of the metaphyseal changes and resolution of the spine anomalies. There was also decreasing severity of rhizomelic shortening of the long bones. At age 14, he had short stature (-3.4 SD), lumbosacral hyperlordosis, mild limitation of shoulder elevation, minor limitation of wrist extension, minimal brachydactyly, and minor camptodactyly of the intrinsic joints; he also had minor knee flexion contractures and knee valgus. Detectable amounts of cholesta-8,14-dien-3-beta-ol were identified.

Molecular Genetics

By sequence analysis of the LBR gene in an adopted 12-year-old girl with PHA and mild skeletal anomalies, Borovik et al. (2013) identified compound heterozygosity for 2 mutations (600024.0012-600024.0013). The authors noted that the patient had dumbbell-shaped neutrophil nuclei characteristic of heterozygotes, suggesting that one of the mutations does not result in complete loss of LBR protein.

Sobreira et al. (2014) identified compound heterozygous mutations (R76X, 600024.0014 and N547S, 600024.0015) in the LBR gene in a 15-year-old boy with PHA and mild skeletal anomalies. The N547S mutation was present in heterozygosity in the mother and unaffected brothers of the proband, and neither mutation was identified in the father. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing.

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.

History

Stobbe and Jorke (1965) posited that skeletal abnormality apparently does not occur in the human PHA homozygote.

Fishbein and Falletta (1991) described a newborn with Pelger-Huet anomaly associated with multiple congenital anomalies (diaphragmatic hernia, coarse facies, and distal limb anomalies) suggestive of Fryns syndrome. The parents did not have the blood anomaly. The authors stated that PHA in the newborn may be accounted for by a spontaneous mutation, the acquired form of the disease, or false paternity.