A Unique Derivative Chromosome 4 with a Predominant 4p16.3 Microduplication Phenotype and a Literature Review

Constitutional structural abnormalities affecting chromosome 4 result in variable distinct phenotypic traits including duplication 4p syndrome, deletion 4p or Wolf-Hirschhorn syndrome (WHS), deletion 4q and duplication 4q syndromes. Complex rearrangements involving both chromosome 4 arms are very rarely reported with different break points occurring within regions of 4p13-p16 and 4q32-35. They most commonly occur in familial cases due to parental pericentric inversion resulting in a recombinant chromosome 4 "rec(4)." The clinical picture is dependent on the size and type of copy number imbalance and the genes involved.

We report on a female patient with delayed developmental milestones and lower limb anomalies, who carried a de novo unique type of complex rearrangement affecting both chromosome 4 arms, diagnosed by karyotype and fluorescence in situ hybridization analysis and chromosomal microarray (CMA).

The chromosome 4 rearrangement involved three copy number alterations, consisting of a terminal 1.17 Mb 4p16.3 deletion with a contiguous proximal 1.8 Mb 4p16.3 duplication, including the Wolf-Hirschhorn critical (WHSC) region, and an inverted 27 Mb terminal 4q32-35.2 duplication attached to terminal 4p. The patient's predominant phenotype was consistent with 4p16.3 microduplication syndrome. The rearrangement occurred as a de novo abnormality, and thus it was designated as a derivative chromosome 4. To the best of our knowledge, this complex type of chromosome 4 rearrangement has not been reported so far.

The present report adds to the scarce 4p16.3 microduplication syndrome reports and emphasizes the role of WHSC region in the syndromic phenotype. It also reveals the importance of CMA in detecting subtle copy number variations (CNVs) that could be dominantly reflected on the phenotype, which is very important in patients' management and family counselling.