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Down syndrome like appearance with a novel de novo translocation t(6;21)(q21;q13).


Individuals with reciprocal translocation (2-way exchange of material between 2 nonhomologous chromosomes, with no net gain or loss of genetic material) are phenotypically normal unless the break-points interrupt or modify the function of a gene or genes (1). In most cases, such individuals are identified after reproductive problems that involve infertility, multiple spontaneous abortions, or the delivery of a child with multiple congenital anomalies in whom an unbalanced karyotype is observed2. Balanced reciprocal translocations are the most common structural chromosomal abnormalities in humans, with an incidence of one per 1175 in newborns. Unbalanced structural chromosome abnormalities detectable only with moderate levels of banding are present in approximately 0.04 per cent of unselected newborns and are a significant cause of morbidity and mortality (3).

We report here an unusual case of a newborn with a unique unbalanced t(6;21)(q21.1 ;q 13) translocation between chromosomes 6 and 21 with a recombinant chromosome arisen from de novo.

The newborn was the only child of healthy third degree consanguineous parents (Fig.). When he was born, the father was 28 and the mother was 24 yr old. There was no exposure to toxins or known teratogens. The baby was delivered by normal spontaneous vaginal delivery at 36-37 wk.

The proband was referred in February 2006 from the Department of Paediatric Endocrinology to the Genetics Department of Erciyes University Medical Faculty, Kayseri, Turkey, for cytogenetic and clinical evaluation when he was 5-day old. His measurements were normal except head circumference which was bigger than 95th percentile. He had down-slanting palpebral fissures, hypertelorism, broad nasal bridge, microphthalmia, low-set ears, macrocephaly, gingival hypertrophia, simian line in both hands, pectus excavatum, sacral dimple, and foot deformity (spontaneous plantar flexion of the fourth metatars). Dermatoglyphic palm patterns were normal.

Computedtomography ofthebrain, echocardiography, and abdominal ultrasonography were normal.

Chromosomal analysis of peripheral blood lymphocytes was carried out in the proband, the mother and father. High-resolution G-banding (HRB) analysis of 20 metaphases of the proband revealed a 46, XY, t(6;21) (q22;q13). The parents' karyotypes were normal.

A reciprocal translocation does not change the amount of chromosomal material, but only the order of the genetic material. These translocations usually involve the exchange of chromosome material between arms of two heterologous chromosomes. Generally, these reciprocal translocations are without consequence for the carrier. However, these carriers can produce a significant percentage of gametes with an unbalanced combination of the parental rearrangement, there is a more or less significant risk, according to cases, of chromosomal imbalances in their offspring.


In our observation, the t(6;21)(q22;q13) was found in the proband. The proband's t(6;21)(q:q) translocation was not observed in the parents. The most probable reason for this is a de novo mutation in the proband. While the balanced chromosomal translocations usually do not show any phenotypic anomalies, the unbalanced chromosomal translocations are related to phenotype abnormalities4. Frequency of all the de novo chromosomal abnormalities, including mosaicism, balanced structural abnormalities was found in 0.19 per cent and unbalanced structural abnormalities in 0.08 per cent in a recent study (5).

Several hypotheses have been suggested to explain why these phenotypic anomalies are seen in balanced chromosome rearrangements, lt may be possible that the gene is broken and the position effects of gene or change in euchromatin structure, loss or small deletions or duplications were not seen with normal cytogenetic methods (6).

The facial appearance of the present case resembled those of Down syndrome cases. Chromosome 21 contains 225 genes (7), some of which, located at the Down syndrome critical region (DSCR), are thought to contribute to the pathogenesis of DS, although the function of most of the encoded proteins still remains unknown. As the karyotype of the present case showed translocation point near the DSCR, we assumed the mongoloid features of our patient to be related to a loss of chromosomal balance.

The family of the child was councelled. The male translocation carders have often fertility problems because of various degrees of oligoasthenoteratozoospermia. Of the 9207 infertile males reviewed (8) 6 per cent were carriers of a reciprocal translocation and 0.8 per cent of a Robertsonian translocation, which is respectively 6.5 and 9.4 times higher than in newborns series (8). Some studies have reported an increased risk of aneuploidy for chromosomes not involved in the rearrangement (interchromosomal effect) among male carriers of a translocation (9-11).

Antenatal diagnosis should be proposed to couples in whom the male partner (as well as the female) is carrying a translocation. Preimplantation genetic diagnosis (PGD) has been used for the identification of chromosome abnormalities in couples who are at risk for either aneuploidy, based on maternal age, or an unbalanced parental karyotype chromosome rearrangement (such as translocations and inversions). PGD for chromosomal abnormalities or rearrangements provides an alternative to prenatal diagnosis and termination of affected foetuses and theoretic enhancement of implantation and pregnancy rates for these couples (12).

For reciprocal translocations, the prevalence of unbalanced gametes is estimated to be between 50 and 70 per cent, thus vastly reducing the number of embryos that are available for transfer and implantation (12,13). Furthermore, an embryo with a balanced or normal translocation signal may still harbour abnormalities in unrelated chromosomes.

Based on the information available we propose that in our case the chromosomal rearrangement could have separated the promoter from a distant regulatory element, or might have juxtaposed a gene with a regulatory element from another gene, or brought a gene and its regulatory element close to another gene generating competition for the regulatory element between the two genes, and finally, the rearrangement could have given rise to a position effect variegation (PEV) (14,15). New studies may find new another gene mapping proximal or distal to the breakpoint that causes the phenotype (14,16).

Munis Dundar *, Ahmet Okay Caglayan

Cetin Saatei, Korhan Arslan & Yusuf Ozkul

Erciyes University Medical Faculty

Department of Medical Genetics

Kayseri, Turkey

* For correspondence:


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(2.) Munne S, Sandalinas M, Escudero T, Fung J, Gianaroli L, Cohen J. Outcome of preimplantation genetic diagnosis of translocations. Fertil Steril 2000; 73 : 1209-18.

(3.) Jacobs PA, Browne C, Gregson N, Joyce C. Estimates of the frequence of chromosome abnormalities detectable in unselected newborns using moderate levels of banding. J Med Genet 1992; 29 : 103-8.

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(8.) Braekeleer M, Dao TN. Cytogenetic studies in male infertility: a review. Hum Reprod 1991; 6 : 245-50.

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(10.) Gianaroli L, Magli MC, Ferraretti AP, Munne S, Balicchia B, Escudero T, et al. Possible interchromosomal effect in embryos generated by gametes from translocation carriers. Hum Reprod 2002; 17 : 3201-7.

(11.) Shi Q, Martin RH. Aneuploidy in human spermatozoa: FISH analysis in men with constitutional chromosomal abnormalities, and in infertile men. Reproduction 2001; 121: 655-66.

(12.) Braude P, Pickering S, Flinter F, Ogilvie CM. Preimplantation genetic diagnosis. Nat Rev Genet 2002; 3 : 941-53.

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(14.) Festenstein R, Tolaini M, Corbella P, Mamalaki C, Parrington J, Fox M, et al. Locus control region function and heterochromatin-induced position effect variegation. Science 1996; 271 : 1123-5.

(15.) Milot E, Strouboulis J, Trimbom T, Wijgerde M, de Boer E, Langeveld A, et al. Heterochromatin effects on the frequency and duration of LCR-mediated gene transcription. Cell 1996; 87 : 105-14.

(16.) Kleinjan DJ, van Heyningen V. Position effect in human genetic disease. Hum Mol Genet 1998; 7 : 1611-8.
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Title Annotation:Correspondence
Author:Dundar, Munis; Caglayan, Ahmet Okay; Saatci, Cetin; Arslan, Korhan; Ozkul, Yusuf
Publication:Indian Journal of Medical Research
Article Type:Letter to the editor
Date:Nov 1, 2008
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