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Ring syndrome: still true?
  1. E Rossi,
  2. J Messa,
  3. O Zuffardi
  1. Genetica Medica, Università di Pavia, Pavia, Italy
  1. Professor O Zuffardi, Genetica Medica, Università di Pavia, Pavia, Italy; zuffardi{at}unipv.it

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We thank Zollino et al for giving us the opportunity to discuss the ring syndrome and its related short stature. According to Cote et al1 and Kosztolanyi,2 ring syndrome is essentially characterised by severe growth failure that can even be the sole major physical abnormality. The common growth deficiency observed across many patients with diverse ring chromosomes suggested that this phenomenon is due to mitotic instability and tissue specific mosaicism.2

A reduction in growth is one of the most common findings in patients with autosomal imbalances with a characteristic intrauterine and growth retardation.3 This can be due both to the imbalance of dosage sensitive genes involved in stature or to a general morbidity state superimposed on the malformation syndrome. Growth hormone deficiency resulting in extremely short stature has also been reported in several chromosome imbalances such as trip(22)(pter->q11),4 del(18p),5 del(15q)(q11–q13),6 7 and it seems to be related to hypothalamic dysfunction or anatomical abnormalities of the pituitary gland. Short stature due to Xp22.33 deficiency involving SHOX represents a common congenital form of growth failure and is involved in the aetiology of “idiopathic” short stature and the growth deficits and skeletal anomalies in Leri–Weill, Langer and Turner syndromes. Among the other genes whose deletion/duplication is associated with low/high stature there is IGF1R (insulin-like growth factor 1 receptor precursor) at 15q26.3. We studied six cases of r(15), four by array comparative genomic hybridisation (CGH) (fig 1) and two by fluorescence in situ hybridisation (FISH) (fig 2), and found that only probands with deletion of this gene in the ring had short stature as opposed to those who had a stature almost normal in which the gene was not deleted. In all cases, blood cytogenetic analysis revealed a preponderance of cells with the ring next to a minority of cells without the ring or with the double ring (table 1).

Figure 1 Array comparative genomic hybridisation (CGH) profiles of four out of six ring chromosomes 15: (A) case 1; (B) case 5; (C) case 6; (D) case 3. Array CGH experiments have been performed with the CGH Microarray Kit 44B (Agilent Technologies, Santa Clara, California, USA).
Figure 2 Fluorescence in situ hybridisation (FISH) analysis in case 2: (A) Bacterial artificial chromosome (BAC) RP11-90E5 already present on the ring chromosome (arrowhead); (B) BAC RP11-118O18 deleted on the ring chromosome (arrowhead).
Table 1 Genotype–phenotype correlations in six cases of unstable ring chromosome 15

Our findings indeed suggest that the final stature has little or nothing to do with the instability of the ring but clearly correlates with the haploinsufficiency or the presence of the two copies of a gene involved in stature.

The case we reported of an r(4) in a patient with extreme short stature8 might thus indicate that among the genes lost at 4p, one is involved in the pronounced growth retardation with failure to thrive characteristic of the Wolf–Hirschhorn syndrome. Indeed, up to now, few genes responsible for short stature have been identified. Three recent studies used the genome wide array approach to study, in ∼63 000 individuals, adult height variation—that is, that one contributing to “normal” variation in the population.911 They report a total of 95 single nucleotide polymorphisms (SNPs), of which 54 survived stringent significance testing, influencing this trait. Although they do not identify those genes whose rare mutations can cause extreme short or tall stature, these preliminary studies will soon be able to identify the candidate genes and possibly the pathways, directly or indirectly, related to skeletal development.

In conclusion we think that the ring chromosomes phenotype must be at least partly reconsidered. Indeed, FISH analysis at first, and more recently whole genome array screenings, have demonstrated that in most of the cases a cryptic deletion is at the basis of the phenotypic abnormalities in apparently intact rings. Stankiewicz et al,12 analysing seven ring chromosomes 18 with proven deletion, concluded that, although the effect of “ring instability syndrome” could not be excluded, the phenotypes of their patients correlated with the features characteristic of 18q- and 18p- syndromes as expected by their genotypes. Similarly, Battini et al13 reported a patient with an unstable ring chromosome 22 deleted for the last 2.5 Mb, having normal stature and clinical features largely overlapping those of distal 22q deletion. Moreover, recent papers have demonstrated that intact ring chromosomes may cause areas of hypopigmentation along the lines of Blaschko as the only sign of ring induced mosaicism,14 or specific features such as a characteristic type of epilepsy and electroencephalographic pattern as reported for several ring (20) chromosomes,15 thus weakening the hypothesis of the “ring syndrome”.

We think that present data, showing that extreme short stature in ring chromosomes 15 associates with the haploinsufficiency of IGF1R rather than ring instability, further weakens the concept of the ring chromosome syndrome phenotype. Moreover, in all the array experiments we made, the ring deletion region has a log ratio between −0.8 and −1.2, clearly indicating a non-mosaic situation. Although this is likely to be due to the low level of mosaicism that makes impossible to detect this cell line with this technology, we cannot exclude the possibility that the ring instability is not present in blood DNA and appears only in cultured cells, being an in vitro phenomenon rather than an in vivo one.

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  • Competing interests: None declared.

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