We describe two siblings with the same unbalanced translocation of chromosomes 11 and 12. Although these siblings are concordant for most of the features and share a phenotype that is consistent with partial trisomy 11q syndrome, they are discordant for several anomalies including CDH (). This leads us to conclude that partial trisomy 11q syndrome has a variable phenotype and that CDH should be added to the spectrum of anomalies that can be present in this syndrome.
By means of complementary cytogenetic techniques, we mapped the breakpoints in both patients and their mother who carries the corresponding reciprocal translocation. The unbalanced chromosomal anomaly was detected by conventional G-banded chromosome analysis. The duplication of the ~19 Mb distal portion of 11q was easily detected by array-CGH and confirmed by FISH. The smaller ~0.5 Mb deletion of 12qter was not detected by array-CGH but was confirmed by FISH studies. The failure of the array to detect this deletion is most likely due to low representation of material distal to the breakpoint (). This region contains a cluster of zinc finger genes and a repeat cluster. RP11-452D11, the only BAC representing this region on the array partially overlapped this repeat cluster.
Due to the unbalanced translocation, there is a duplication of part of the long arm of chromosome 11, an abnormality that has been described several times in the literature as “partial trisomy 11q syndrome” or “duplication 11(q21/q23 → qter) syndrome” [Francke et al., 1977
; Pihko et al., 1981
]. The clinical features of this syndrome and the phenotype of Patients 1 and 2 are summarized in .
CDH has been described in several patients with partial duplication of 11q due to a t(11;22) [Biederman et al., 1980
; Kadir et al., 1997
; Borys and Taxy, 2004
]. To our knowledge, CDH has only been described once in a child with partial duplication 11q due to an unbalanced translocation with another chromosome than 22 [Park et al., 1993
]. Patient 2 represents the second case of an unbalanced translocation other than the t(11;22) resulting in partial duplication 11q associated with CDH, in this case associated with a small partial monosomy 12q. Although we cannot exclude a potential role for the genes deleted on 12q or that the CDH in Patient 2 only occurred by coincidence, we believe that it is more likely that one or more genes in the duplicated region on 11q predispose to the development of CDH. There have been two case-reports on monosomy 12q24, but in none of these CDH has been described [Sathya et al., 1999
; Plotner et al., 2003
]. Ultimately, environmental factors and the genetic background determine whether an individual eventually develops CDH. The discordance in these two siblings might be the result of epigenetic differences between the two brothers, such as different methylation status of genes in the duplicated region.
The duplicated region on 11q23-qter contains almost a hundred known genes and multiple unknown transcipts. Although none of the genes in this region have been implicated in the etiology of CDH, there are several genes that could play a role in the development of CDH based on their known functions. ROBO3
(roundabout, axon guidance receptor, homolog 3 [OMIM 607630]), located at 11q24.2, regulates axon guidance across the midline in the brain [Sabatier et al., 2004
] and might be involved in non-neuronal morphogenesis [Anselmo et al., 2003
genes encode the receptors for the Slit-family of genes in both Drosophila and vertebrates, and Slit-3
(OMIM 603745) binds to ROBO3 in vertebrates. Although it is unclear at this time whether central- and posterolateral-type CDHs are caused by related genes, it is interesting to note that Slit3
knockout mice display a septum transversum CDH associated with kidney agenesis and cardiac defects [Liu et al., 2003
]. Another member of the roundabout-gene-family, ROBO4
(roundabout, axond guidance receptor, homolog 4 [OMIM 607528]), also located on 11q24.2, is also duplicated in our patients. This gene is mainly expressed at sites of active angiogenesis, especially under hypoxic conditions [Huminiecki et al., 2002
]. A third duplicated gene is CDON
(Cell adhesion molecule-related/downregulated by oncogenes [OMIM 608707]), located at 11q24. In complex with BOC (Brother of CDON [OMIM 608708]), this gene regulates myogenic differentiation [Kang et al., 2002
]. Further delineation of breakpoints in patients with smaller partial duplications of 11q and CDH, functional studies, and transgenic animal experiments may help focus attention on one or more of these genes.
Recently, Zhao et al. 
described four patients with partial trisomy 11q and severe upper airway malformations. They attributed the upper airway malformations in these patients to duplication of the 11q21–q23.2 region. This conclusion was based on the proximal location of the breakpoints in patients with the upper airway anomalies, which started at q21, in comparison to patients without upper airway malformations, in which the breakpoints were located more distally at q23.2. The phenotype of Patient 1, who presented with severe Pierre–Robin sequence, would suggest that the 11q23.2-qter region is involved in upper airway formation and that incomplete penetrance may account for those individuals with 11q23-qter duplications who lack this phenotype.
In conclusion, the “partial trisomy 11q syndrome” has a highly variable phenotype. Our findings implicate that CDH should be added to the spectrum of abnormalities that can be present in this syndrome.