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Partial monosomy 7q34-qter and 21pter-q22.13 due to cryptic unbalanced translocation t(7;21) but not monosomy of the whole chromosome 21: a case report plus review of the literature
© Vorsanova et al; licensee BioMed Central Ltd. 2008
- Received: 04 December 2007
- Accepted: 19 June 2008
- Published: 19 June 2008
Autosomal monosomies in human are generally suggested to be incompatible with life; however, there is quite a number of cytogenetic reports describing full monosomy of one chromosome 21 in live born children. Here, we report a cytogenetically similar case associated with congenital malformation including mental retardation, motor development delay, craniofacial dysmorphism and skeletal abnormalities.
Initially, a full monosomy of chromosome 21 was suspected as only 45 chromosomes were present. However, molecular cytogenetics revealed a de novo unbalanced translocation with a der(7)t(7;21). It turned out that the translocated part of chromosome 21 produced GTG-banding patterns similar to original ones of chromosome 7. The final karyotype was described as 45,XX,der(7)t(7;21)(q34;q22.13),-21. As a meta analysis revealed that clusters of the olfactory receptor gene family (ORF) are located in these breakpoint regions, an involvement of OFR in the rearrangement formation is discussed here.
The described clinical phenotype is comparable to previously described cases with ring chromosome 21, and a number of cases with del(7)(q34). Thus, at least a certain percentage, if not all full monosomy of chromosome 21 in live-borns are cases of unbalanced translocations involving chromosome 21.
- Mitral Valve Prolapse
- Pectus Excavatum
- Unbalanced Translocation
- Molecular Cytogenetic Technique
- Craniofacial Dysmorphism
Non-mosaic monosomy of chromosome 21 is suggested to be incompatible with life as such cases have been occasionally detected in spontaneous abortions [1–3]. 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 . Moreover, the only monosomy potentially viable in humans seems to be that of the X-chromosome . 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 .
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.
The patient, a 2 1/2-years-old girl suffering from mental retardation, motor development delay, craniofacial dysmorphism and skeletal abnormalities, was the first child of non-consanguineous parents, born in 40th week gestation. Both in mother (24 years) and in father (35 years) had no family history of mental retardation or developmental delay. A paternal grandmother has experienced a pregnancy resulted in a male stillbirth at 28 weeks of gestation.
Summary of FISH studies using site-specific DNA probes.
13 cen and 21 cen
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 [3, 6]. 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 .
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 . 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 [8–16]. Additionally, a case of low-level mosaic trisomy 21 in an individual with fragile × syndrome was reported . Thus, up to now, no similar cases involving chromosome 7 and 21 were described.
The majority of cases reported were de novo unbalanced translocations [8, 10, 11, 14, 15], 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.
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) . 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 . 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.
Peripheral blood samples of the patient and her parents were cultivated, harvested and GTG-banded according to standard cytogenetic protocols .
FISH experiments were carried out using whole chromosome painting probes (WCP) for chromosomes 7 and 21  and multicolor banding (MCB) for chromosome 21 . Additionally, two-color-FISH experiments were done using the probes specified in Table 1, which are included in the original collection of laboratory of cytogenetics of National Research Center of Mental Health RAMS [22–24] (for details see also Table 1).
The research done here was carried out in compliance with the Helsinki Declaration – the ethical committee of the National Research Center of Mental Health (RAMS), Moscow approved the study.
A written consent was obtained from the parents of the patient to publish details and pictures of the child.
All authors were supported in parts by the INTAS 03-55-4060; SGV, IYI, ADK, IVS, and YBY by the RGNF 06-06-00639a (Russian Federation) and Philip Morris USA; AW and TL by a grant of the Friedrich-Schiller University.
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