Non-mosaic monosomy of chromosome 21 is suggested to be incompatible with life as such cases have been occasionally detected in spontaneous abortions 123. To our knowledge there was only one report on full monosomy 21 diagnosed prenatally with a delivery of a male newborn with multiple congenital malformations who has not survived beyond the first day of life 4. Moreover, the only monosomy potentially viable in humans seems to be that of the X-chromosome 5. However, in the literature, a number of cytogenetic reports concerning 'full monosomy of chromosome 21' in live-born children can be found. These contradictory findings usually are explained by undetected mosaicism including a normal cell line in different tissues, or are attributed to unbalanced translocations appearing as the loss of chromosome 21 6.

Here, we describe a case of a female patient with multiple congenital malformations referred to as a non-mosaic monosomy of chromosome 21 after GTG-banding, which, after application of molecular cytogenetic techniques, turned out to be the first case with an unbalanced translocation of chromosomes 7 and 21.

Despite major developments in cytogenetic techniques made throughout last three decades, routine diagnosis using standard GTG banded karyotyping is still facing cases with unexpected findings 36. A chromosomal abnormality initially diagnosed as a 'full monosomy of chromosome 21' is one of those and the suggested fetal lethality of monosomy 21 is then the indication for further cytogenetic investigations of such cases 6.

One unique description of a comprehensively investigated live born child with presumably non-mosaic monosomy 21 had demonstrated the loss of chromosome 21 to produce exceedingly severe congenital malformations incompatible with life and defined monosomy 21 as an extremely rare chromosome abnormality in live born 4. Moreover, reviewing the literature indicated that no fewer than 9 cases of unbalanced translocation involving chromosome 21 identified by FISH or molecular genetic studies of initially diagnosed 'full monosomy 21' were reported. Among them, five cases were re-diagnosed as t(5p;21q), two cases as t(11;21)(q24;q22.2), and one case, each, as t(4q;21q), t(18q;21q), and t(X;21), respectively 8910111213141516. Additionally, a case of low-level mosaic trisomy 21 in an individual with fragile × syndrome was reported 17. Thus, up to now, no similar cases involving chromosome 7 and 21 were described.

The majority of cases reported were de novo unbalanced translocations 810111415, suggesting the formation of such chromosome abnormalities being due to a reciprocal translocation involving chromosome 21 followed by the loss of one of the derivative chromosomes, regardless having an active centromere. As the phenotypic manifestations of these cases are variable, the clinical picture is more likely to be determined by the loss of other chromosome regions except those of chromosome 21.

Unfortunately, the exact breakpoints were not detailed for almost all of the aforementioned previously reported cases with cryptic translocations involving chromosome 21. In our case, the breakpoints were determined to be in 7q34 and 21q22.13. Interestingly, a check of these breakpoint regions in the NCBI build 36.1 database revealed that clusters of the olfactory receptor gene family (ORF) are located in these two regions (Fig. 4). It is known that these ORF regions can be involved in unequal crossing over and promote translocations between different regions of the genome 18. Thus, an involvement of OFR in the formation of the rearrangement of at least the reported case and probably in other 'cryptic full monosomy 21 cases' cannot be neglected and should be clarified in further studies.

As the proximal part of chromosome 21 is known to carry less genes than chromosome 7qter, it was reasonable to suggest that main clinical features of the reported case could be similar to those described previously in cases with del(7)(q34) 6. In accordance with these considerations, actually a number of phenotypic features such as renal abnormalities, microcephaly, atrophy of prefrontal cortex, short neck, 2/3 syndactyly of toes and multiple minor anomalies including epicanthic folds, upstanding palpebral fissures, low-set ears corresponded to previous clinical data on cases with del(7)(q34). Nonetheless, the phenotypic appearance was found also surprisingly similar to a previously described case of ring chromosome 21 19. Common features of r(21) and present case were characteristic craniofacial dysmorphism (microbrachycephaly, hypotelorism, short and upslanted palpebral fissures, broad nasal tip, micrognathia, large dysmorphic ears, and long philtrum) and curly scalp hair. Thus, the contribution of 21q loss may be significant for the clinical findings, as well. However, common phenotypic features of chromosome abnormalities as mental retardation, motor development delay and intrauterine growth retardation are most likely to refer to the combined effect of simultaneous loss of both 7q and 21q.

Since the appearance of G-banded derivate chromosome may be similar to the original GTG banding as it was the case of chromosome 7 in the present case report, molecular cytogenetic techniques represent the most convenient way to prove or refute initial diagnosis. Thus, when analyzing cases that appear to be a 'full monosomy of chromosome 21' or partial monosomy of chromosome 21 due to unbalanced translocations, the application of high resolution molecular cytogenetic techniques (e.g. multi-probe FISH, MCB, or CGH) is unavoidable. Although the latter may appear evident, further cases of unbalanced translocations involving chromosome 21 seems to be required in order to improve subsequent clinical and cytogenetic diagnosis of cases suggested to be a case of monosomy involving the proximal gene-poor region of the chromosome 21 with the precision of breakpoints location.

The authors declare that they have no competing interests.

SGV participated in the design of the study, analyzed clinical and cytogenetic data, and drafted basically the manuscript, IY I participated in the design of the study, drafted basically the manuscript and evaluated the FISH-studies, VY V-U picked up the case and was involved in the clinical studies and description, A W performed, evaluated and interpreted the sophisticated molecularcytogenetic studies (MCB-studies), VV M was involved in the molecular cytogenetic studies, AD K performed, evaluated and interpreted the basic evaluated the GTG-banding, IV S contributed DNA probes for site-specific molecular cytogenetic assay, PV N picked up the case and was involved in the clinical studies and description, YB Y participated in the design of the study and drafted the manuscript, T L evaluated and interpreted the sophisticated molecularcytogenetic studies (MCB-studies) and drafted the manuscript. All authors read and approved the final manuscript.

A written consent was obtained from the parents of the patient to publish details and pictures of the child.