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Congenital abnormalities reported in Pelger-Huët homozygosity as compared to Greenberg/HEM dysplasia: highly variable expression of allelic phenotypes
  1. J C Oosterwijk1,
  2. S Mansour2,
  3. G van Noort3,
  4. H R Waterham4,
  5. C M Hall5,
  6. R C M Hennekam4
  1. 1Department of Clinical Genetics, Groningen University Hospital, Groningen, Netherlands
  2. 2Department of Medical Genetics, St George’s Hospital Medical School, London, United Kingdom
  3. 3Regional Pathology Laboratory, Enschede, Netherlands
  4. 4Department of Paediatrics, Emma Children’s Hospital, Academic Medical Centre, Amsterdam, Netherlands
  5. 5Department of Radiology, Great Ormond Street Hospital for Children, London, United Kingdom
  1. Correspondence to:
 Dr J C Oosterwijk
 Department of Clinical Genetics, University Hospital Groningen, P.O. Box 30.001, NL-9700RB, Groningen, Netherlands;

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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 Huët.2 In the following years many families with Pelger-Huët 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

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 …

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