Ring chromosome 6 is a very rare finding, generally occurring as a de novo
event. Clinical features are manifesting with a great inter-individual variability. Most of the affected individuals show growth delay, mental retardation, facial dysmorphisms and congenital anomalies involving central nervous system (CNS), heart, ocular and auditory systems, without an identifiable phenotype. On the other hand, there are cases with minimal or absent physical anomalies, which can be associated to slight mental retardation or normal cognitive function. The presence of major congenital abnormalities can distinguish the severe from the moderate cases
]. Previous literature reports exhibit detailed descriptions of the phenotypic features of these patients but, unfortunately, the cytogenetic analyses remain elusive due to the lack of adequate molecular investigations. Here we provide a careful and complete characterization of a ring 6 chromosome by means of FISH and array-CGH. The breakpoints were located on 6p25 and 6q26-27 and the deletion was estimated to be 1.3
Mb on the short arm and 6.7
Mb on the long arm (Figure
Figure 2 Array-CGH results of chromosome 6. Full view of the chromosome 6 rearrangements is displayed in the middle. Vertical dotted lines represent log2 ratio (DLRS=0.16). On the left and on the right are shown the magnifications of the 6p (1.3 Mb) and (more ...)
These regions are very large and contain a great number of genes, making an appropriate genotype-phenotype correlation difficult. Nevertheless, to better understand the role of some genes included in the deleted segments, we compared our data to the two single previously reported patients with a molecular characterization of the ring chromosome 6.
The first study reported by Hökner et al.  describes a woman with short stature, normal psychomotor development and minor dysmorphisms, carrying a ring chromosome 6 with very small deletions on both arms and breakpoints at 240 kb and at 190 kb from the telomeres of 6p and 6q, respectively
]. These regions actually do not include known genes. The classic mechanism of ring formation is the breakage of both terminal chromosome arms followed by the loss of distal fragments and fusion of proximal broken ends. The severity of the phenotype seems to be related to the size of the deletion. Conversely, not all of the ring chromosomes can be associated with a loss of functional genetic material and, therefore, easily related with a clinical phenotype. These cases led to hypothesize that the ring formation produce difficulties in the sister chromatid separation at cell division, inducing the generation of secondary, lethal, aneuploid cells: this picture is called “ring syndrome”
]. Owing to the lack of known genes within the deletion, the case of Höakner et al. seems to support this hypothesis.
The second study of Zhang et al.
] is very close to our case because the deleted regions are exactly reversed and comparable in length (Figure
). After FISH analyses the authors demonstrated a segmental deletion of about 6
Mb on 6p and 1-2
Mb on 6q
]. Clinical features of both patients are summarized in Table
Zoom of the deleted regions. Schematic view of the investigated regions with evidence of the genes described.
Table 1 Clinical features of the present patient in comparison to those of the patient reported by Zhang et al. [
Zhang et al.
] provided evidences that the haploinsufficiency of the transcription factor FOXC1
, which maps at chromosome 6p25, is essential for the development of anterior chamber anomalies in the eye in different patients
]. In fact, mutations in this gene result in a range of anomalies associated with congenital glaucoma, including Axenfeld anomaly, Rieger anomaly, iris hypoplasia and Peters anomaly
]. Altogether, the haploinsufficiency of the FOXC1
gene, the consequent clinical effects observed in some cases, and the fact that this gene is not deleted in our patient, who does not show any eye anomalies, reinforce the hypothesis that FOXC1
could be the major cause of anterior chamber eye anomalies. Furthermore, Zhang et al. proposed that the loss of the forkhead gene cluster at 6p25 (FOXC1
) could be responsible for CNS malformations. On the contrary, our patient displayed two of these genes deleted (FOXF2
), and did not reveal the same alterations. This suggests that the genes related with CNS development could be located on the long, rather than the short arm of the chromosome 6.
Another clinical sign discussed in their report is the hearing loss, a symptom that is lacking in our patient. SERPINB6
, on 6p25, is expressed in the inner ear, particularly in hair cells. The protein encoded is a member of the serpin (serine proteinase inhibitor) superfamily and ovalbumin(ov)-serpin subfamily and plays an important role in the ear in the protection against leakage of lysosomal content during stress. A recent study, published in 2010, shows that a nonsense mutation (p.E245X) in SERPINB6
leads to a downregulation of the gene
]. The authors demonstrated that this mutation, introducing a premature stop-codon, destabilizes mRNA inducing its decay and reduces mRNA expression. SERPINB6
, being located within the deleted region in Zhang’s patient, and conserved in our patient, may be a significant candidate for hearing loss related to the ring chromosome 6 disease.
The two-dimensional color-Doppler echocardiography showed that our patient had atrial septal defect ostium secondum type and a large patent ductus arteriosus, which needed surgical intervention at 20 days of life. From the investigations of the 6q deleted region we have found only one gene with a possible relationship with heart defects. RPS6KA2
) belongs to a family of four highly homologous proteins encoded by distinct genes related with Coffin-Lowry syndrome. RSKs are serine/threonine kinases, acting at the distal end of the Ras-Mitogen-Activated Protein Kinase (MAPK) signaling pathway that plays an important role in cellular events such as growth and differentiation. In humans RSK3
is highly expressed in skeletal muscle, heart and pancreas, while, during mouse embryogenesis, its expression is increased to very high levels in the neural tube, dorsal root ganglia, the developing eye and the heart. Although no disorder associated with RSK3
mutations is actually known, these results suggest that this gene may have a specific function in these organs
Finally, our present patient shows some peculiarities in comparison with previously reported cases lacking of a detailed molecular characterization. In particular, auxological parameters are normal, whereas a growth delay is a frequent finding in ring chromosome syndromes. This may be related to the absence of secondary aneuploid cells that should lead to major ring stability. Both microcephaly and macrocephaly have been reported in ring chromosome 6, and cerebral ventriculomegaly is often associated with large head circumference as our case