Mosaicism del(8p)/inv dup(8p) in a dysmorphic female infant: a mosaic formed by a meiotic error at the 8p OR gene and an independent terminal deletion event.

Various chromosomal rearrangements are associated with the distal 8p region. Among them are the inv dup(8p), del(8p22), and del(8)(pter). The cardinal phenotypic features of the inv dup(8p) are brain malformations, severe mental retardation with specific involvement of speech, and minor facial dysmorphisms. Deletions (8p22) are associated with congenital heart malformations, thought to be caused by haploinsufficiency of GATA4. Other features are microcephaly, intrauterine growth retardation, mental retardation, and a characteristic hyperactive impulsive behaviour. The patients with del(8p) present with variable severe malformations dependent on the size of the deletion. The largest terminal 8p deletion which has been detected in a liveborn is del(8)(pter→21.1). Molecular analysis of both 8p duplications and 8p interstitial deletions showed that all cases shared similar chromosomal break points. This finding led to the hypothesis that these rearrangements were caused by ectopic recombination at misaligned duplicons. Recently, Giglio et al showed the presence of olfactory gene clusters (OR clusters) at the sites where the interstitial 8p deletions occur. Whereas these interstitial deletions could thus be explained by misalignments of the OR clusters during meiosis, they also presented an elegant explanation for the origin of the 8p duplications. An inversion polymorphism between these OR clusters, present in 20% of the population, abrogates correct pairing between the OR clusters which causes susceptibility for an intrachromosomal crossover between the OR repeats. Ectopic recombination at these sites can lead to a dicentric intermediate which on breakage can lead to a duplicated chromosome 8p, the inv dup(8p). The complement of this breakage event was speculated to be a terminal deleted chromosome del(8p). In this paper we describe a girl with a mosaic del(8p)/inv dup(8p) in blood lymphocytes. Mosaics with two cell lines carrying two different rearranged chromosomes are extremely rare. Two reports describe the presence of a mosaic with the same chromosome deleted in one cell line and the same chromosome duplicated in another cell line. 10 The most straightforward explanation for the finding of two cell lines in the blood of this patient carrying either a chromosome 8p+ or a chromosome 8p− would be the following postzygotic series of events. A sister chromatid exchange formed an aberrant U type chromosome 8, which at anaphase yielded an unstable dicentric chromosome 8 in one of the daughter cells. The unstable dicentric chromosome was pulled towards two different poles during a subsequent metaphase causing a break in 8p, thus resulting in a cell line with 8p+ and a cell line with an 8p− chromosome. 10 In contrast to this simple model, we show here that the 8p+ chromosome originated during maternal meiosis by ectopic recombination at the OR gene clusters by the mechanism described by Floridia et al and that the 8p− chromosome originated by an independent terminal deletion event. CASE REPORT The patient, a girl, was the first and only child of young, healthy parents of Turkish origin. Their family histories were normal without consanguinity. Pregnancy, and delivery at 39 weeks, were normal. Birth weight was 2470 (3rd centile), length 45.5 cm (3rd centile), and head circumference 33.5 cm (10th centile). Feeding problems with gastro-oesophageal reflux were present from the beginning. Psychomotor development was retarded and at the age of 13.5 months motor and cognitive development were moderately retarded (developmental level of 8 months on the Bayley developmental scale). At the age of 15 months she was referred to the genetic clinic for further diagnostic evaluation. Weight was 7.2 kg (3rd centile 7.8 kg), length 70 cm (3rd centile 72.5 cm), and head circumference 46.5 cm (50th centile). Facial appearance was mildly dysmorphic with upward slanting palpebral fissures, synophrys, and left preauricular tag. Both thumbs were low set with hypotrophic thenars, and there was bilateral clinodactyly of the fifth fingers. Except for manifest axial hypotonia, neurological findings were normal (fig 1). The most striking finding was the presence of linear areas of depigmentation with bordering areas of hyperpigmentation on the lumbar and presacral region and on both legs, most evident on the medial sides of both thighs without signs of body asymmetry. Now, at the age of 2 years,