Congenital abnormalities reported in Pelger-Huet homozygosity as compared to Greenberg/HEM dysplasia: highly variable expression of allelic phenotypes.(Letter to JMG)(leukocytes)

In 1928 the Dutch physician Pelger described two patients with a morphological abnormality of leukocytes that consisted of hypolobulation of the nuclei: there were two lobes instead of the usual five or more and the chromatin structure was coarse and denser. (1) This was subsequently shown to be a genetic trait by paediatrician Huet. (2) In the following years many families with Pelger-Huet anomaly (PHA) from different countries were reported and autosomal dominant inheritance was firmly established. (3) Bilobulated PHA nuclei ("spectacle" or "pince-nez" cells) can also be a transient symptom in the presence of underlying disease--for example, infection, myeloid leukaemia or medication) as part of a "shift to the left" (pseudo PHA), but constitutional PHA is a constant, genetic, and harmless nucleomorphic variant. (3) The frequency of PHA ranges from 0.01-0.1%, with documented clustering in the region of Gelenau, Germany, where 1% of the population has PHA. (4)

J Med Genet 2003;40:937-941

Homozygosity for PHA was first detected in rabbits, (5-7) before it was described in man. (8-14) Ever since, PHA homozygosity has been associated with (skeletal) abnormalities and early lethality, though mainly based on animal data. In 2002, through positional cloning, mutations in the lamin B receptor gene (LBR) on 1q42 were found to cause PHA. (4) One single founder mutation was detected in 10 Gelenau families, as well as seven other mutations in 10 families from elsewhere. Homozygosity for the founder mutation was detected in one patient that was previously reported with mild congenital abnormalities and homozygous PHA on haematological investigations. (14)

At about the same time, investigations in autosomal recessive Greenberg/HEM (hydrops, ectopic calcifications, moth-eaten) dysplasia had led to the same gene from quite a different angle. (15) Greenberg/HEM dysplasia is a rare, early (in utero) lethal skeletal dysplasia, characterised by severe hydrops, short limbed dwarfism and marked disorganisation of chondro-osseous calcification (with a moth-eaten aspect). (16) Polydactyly and other malformations may be present. (15) (17) (18) An accumulation of cholesta-8, 14-dien-3[beta]-ol was detected in fibroblasts of an affected fetus, due to deficiency of 3[beta]-hydroxysterol [DELTA]14-reductase. This was caused by a homozygous 7-base pair substitution in exon 13 of LBR, leading to a stop codon. (15) In the patient's mother, more than 60% of granulocytes appeared to have PHA (the father could not be tested). Since this finding, mutations have been detected in both alleles of LBR in three additional HEM cases (H Waterham, personal communication). Moreover, the relation between PHA and Greenberg/HEM was recently confirmed in a patient of Offiah et al (19) where PHA was demonstrated in >95% of maternal granulocytes, but not in those of the father (S Mansour, personal communication).

The finding that PHA (homozygosity) and Greenberg/HEM skeletal dysplasia are allelic disorders sheds new light on the presumed congenital skeletal abnormalities in PHA homozygosity reported in the literature. We therefore critically reviewed all published cases of PHA homozygosity, to assess a possible clinical overlap which might be relevant for genetic counselling and that could help understand the phenotypic variability of homozygous LBR defects.

REVIEW OF REPORTED CASES

A Medline literature search was used to collect all articles on PHA homozygosity. Of these, all references were checked for additional reports. A total of 11 patients were found with the diagnosis PHA homozygosity. (8-14) (20) (21)

Pelger-Huet homozygosity in human beings

In 1952 Haverkamp Begeman et al were the first to describe PHA homozygosity in a Dutch girl. (8) She had convulsions (which ran in the family) and mild psychomotor delay. Apart from mild short stature there were no abnormalities and the skeletal survey was normal. Haematological examination showed round, coarse nuclei in 94% of the neutrophil granulocytes with clumped chromatin structure, strikingly similar to that in the homozygous PHA rabbit. (5) Both parents (who were first cousins) had PHA, but the girl's two siblings had normal cellular morphology. Three other siblings had died in the first years of life due to diphtheria, diarrhoea, and convulsions respectively, and the mother had had two miscarriages. It was concluded that, although the haematological picture in humans and rabbits is the same, the disorder is not necessarily lethal in humans and does not always lead to skeletal anomalies. (8)

Ten other patients have subsequently been described: one each from Morocco, (9) and Romania, (10) three each from Gelenau, Germany, (4) (11) (14) and Italy, (20) (21) and two from Spain. (12) (13) (22) The clinical …