Pelger-Huët Anomaly: A Critical Review of the Literature

Abstract

Pelger-Huët anomaly (PHA), an autosomal dominant haematological trait is characterised by neutrophil nuclear hypolobulation and modified chromatin distribution. Mutations in the lamin B receptor gene, a member of the sterol reductase family have been identified as the underlying cause. Due to its asymptomatic nature or lack of observer familiarity, PHA is often overlooked. In this review, we give an overview of the main pathophysiological, clinical, morphological and functional aspects of PHA. Furthermore, we highlight the importance of a comprehensive approach to the assessment of this laminopathy.

Lamin B receptor

“…Human Pelger-Huët anomaly (PHA) is a hematological condition whose history, genetics and clinical characteristics has been recently reviewed. 79,90,91 Heterozygous PHA is a rare condition (0.01-0.1% of the population), where (on blood smears) the majority of neutrophil granulocytes exhibit a bilobed appearance, rather than the normal 3-4 lobes. The clinical significance is distinguishing heterozygous PHA from potentially more serious, but similar appearing "pseudo-Pelger" morphologies, such as seen in various infections, neoplasias and following certain medications.…”

“…The clinical significance is distinguishing heterozygous PHA from potentially more serious, but similar appearing "pseudo-Pelger" morphologies, such as seen in various infections, neoplasias and following certain medications. [90][91][92] Homozygous PHA is considerably more devastating; most such individuals do not come to "term" (birth). Blood smears and thin section electron microscopy reveal that the neutrophil nucleus is ovoid with heterochromatin redistribution.…”

Reduced Lymphocyte Longevity and Homeostatic Proliferation in Lamin B Receptor-Deficient Mice Results in Profound and Progressive Lymphopenia

“…The LBR is an inner nuclear membrane protein with dual modality (8)(9)(10)(11). It has an N-terminal region, comprising two globular domains, including a Tudor-like DNA binding domain, joined by a linker region, which protrudes into the nucleoplasm where it engages proteins of the nuclear lamina, including lamin B1/B2, heterochromatin protein 1 (HP1), heterochromatic methyl binding protein MeCP2, and histones, and directly engages heterochromatin (4,(12)(13)(14)(15).…”

“…Two rare conditions, Pelger-Huét anomaly (PHA) and Greenberg/ HEM dysplasia, independently described in the early and late 1900s, respectively, were in [2002][2003] shown to arise from mutation of the same gene, the LBR gene (9,11,(16)(17)(18). Greenberg dysplasia is a recessive in utero lethal disorder presenting as severe hydrops, short-limbed dwarfism, and disorganization of chondroosseous (bone-cartilage) calcification.…”

“…There is still dispute, however, over whether the phenotype is consistent with cholesterol deficiency or laminopathy, the later supported by redundancy with another d 14 sterol reductase, DHCR14/Tms7sf2. PHA, which occurs in individuals heterozygous for mutations of the LBR gene, was originally described as the presence of abnormal blood neutrophil morphology, visible as reduced lobularity, without any health implications (8,9). "Pseudo PHA" can also result transiently from unrelated health conditions including infections, although whether this indicates a transient reduction in LBR expression or LBR modification is unknown.…”