Recombinant Chromosome 4 from a Familial Pericentric Inversion: Prenatal and Adulthood Wolf-Hirschhorn Phenotypes

Pericentric inversion of chromosome 4 can give rise to recombinant chromosomes by duplication or deletion of 4p. We report on a familial case of Wolf-Hirschhorn Syndrome characterized by GTG-banding karyotypes, FISH, and array CGH analysis, caused by a recombinant chromosome 4 with terminal 4p16.3 deletion and terminal 4q35.2 duplication. This is an aneusomy due to a recombination which occurred during the meiosis of heterozygote carrier of cryptic pericentric inversion. We also describe the adulthood and prenatal phenotypes associated with the recombinant chromosome 4. 1. Introduction Wolf-Hirschhorn Syndrome (WHS) results from partial deletion of the distal short arm of chromosome 4 (4p16.3). The clinical features are variable, with increasing severity depending on the extent of the deletion, although the minimal diagnostic criteria should include the association of typical facial appearance, growth delay, mental retardation, and seizures [1]. Considering that small and large 4p16.3 deletions are associated with mild and severe WHS phenotype, respectively, Zollino et al. [1] have suggested a WHS classification in three categories based on the clinical presentation, all sharing the minimal diagnostic criteria: “mild” form (deletions < 3.5？Mb) refers to patients with a mild mental retardation (MR), possible fluent language, and usually independent walking by the age of 2-3 years; “classical” form (deletions 5–18？Mb) is characterized by major malformations, severe psychomotor delay (PMD), delay or absence of speech, and late walking; “severe” one (deletions > 22–25？Mb) has severe PMD and MR, facial anomalies, severe scoliosis, and psychotic behaviour. At a molecular level, two WHS critical regions (WHSCRs) have been identified: the WHSCR region, which is 165？Kb in size and it is located at about 2？Mb from the telomere between the markers D4S166 and D4S3327 [2], and the WHSCR-2 region which embraces a 300–600？Kb interval between the loci D4S3327 and D4S168 and it is mapped distal to WHSCR at about 1,9？Mb from the telomere [1]. Most of the 4p16 deletions involved in WHS occur de novo, but in 10%–15% of cases the derivative chromosome 4 originate from chromosomal rearrangements in one of the parents. Four different rearrangements are reported [1]: (1) isolated 4p deletion (70% of patients); (2) unbalanced translocation (22%); (3) inverted duplication associated with terminal 4p deletion (6%); (4) recombinant chromosome 4, rec(4), consisting of unbalanced pericentric inversion with a large 4q segment duplicated on the deleted 4p (2%). Herein we describe a