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Tayebi N, Khodaei H.  Rare Case of Pericentric Inversion, Inv (21) (p12;q22) in Repeated Pregnancy Loss: A Case Report. Oman Med J 2011 Nov; 26(6):441-443.

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Tayebi N, Khodaei H.  Rare Case of Pericentric Inversion, Inv (21) (p12;q22) in Repeated Pregnancy Loss: A Case Report. Oman Med J 2011 Nov; 26(6):441-443. Available from http://www.omjournal.org/fultext_PDF.aspx?DetailsID=174&type=fultext

Pericentric inversions are among the most frequent chromosomal rearrangements with a frequency of 1-2%. There is no phenotypic effect in the majority of pericentric inversion heterozygote carriers, when it is a balanced rearrangement. However, miscarriages, infertility and/or chromosomally unbalanced offspring can be observed in carriers of a pericentric inversion. This is a case of pericentric inversion of one chromosome 21: inv (21) (p12; q22) in repeated pregnancy loss. A couple was referred for cytogenetic examination due to idiopathic miscarriages. The proband proved to be a carrier of chromosomal inversion and her partner’s karyotype was found to be normal. The karyotype of the proband is 46, xx, inv (21) (p12; q22). This abnormal karyotype is reported as a probable reason of miscarriage in the investigated couple. The risk of further miscarriages and the risk of a progeny with abnormal karyotype are rather high. Therefore, amniocenthesis for finding the chromosomal abnormality as a prenatal diagnosis are proposed for the patient if future pregnancy does not lead to miscarriage.

Keywords: Miscarriage; Pericentric inversion of chromosome 21.

Introduction

The frequency of pericentric inversions among the commonest chromosomal rearrangements is 1-2%.¹ Pericentric inversions result from a two-break event which occurs between the short (p) and the long arms (q) within the chromosome followed by a 180^o rotation of the intercalary segment. There is no phenotypic effect in the majority of pericentric inversion heterozygote carriers with balanced rearrangement. However, miscarriages, infertility and/or chromosomally unbalanced offspring can be observed in carriers of a pericentric inversion.² Carriers of such rearrangements are at risk. During meiosis, in order to produce a percentage of abnormal gametes with duplication of the region outside the inversion segment on one arm of the inverted chromosome and deletion of the terminal segment on the other arm, and vice versa, it will end up with duplicated/ deficient recombinant chromosomes distal to the breakpoints.² 

Here, we report a female who carries a unique pericentric inversion of one chromosome 21: inv (21) (p12; q22). This abnormal karyotype was ascertained after three miscarriages.

Case Report

A consanguineous couple with a relative of first cousin was referred to the Genetic Research Center, Yazd, Iran, due to repeated pregnancy loss. The woman had three miscarriages after 6-9 weeks of pregnancy. They have had one healthy boy with normal karyotype. The family pedigree was prepared according to Rimoin et al.³ (Fig. 1)

Figure 1: Family pedigree.

The husband was a 40-year-old man with normal sperm analysis,⁴ and normal karyotype. The 29 year-old woman had normal fertility evaluation (normal ovarian reserve and hysterosalpingography in ovulatory cycles with abnormal karyotype. Her biochemical tests were also normal. Cytogenetic examination was performed on blood lymphocytes with a resolution of ~550. Separated peripheral blood lymphocytes were suspended in a RPMI 1640 medium invitrogen supplemented with 10% foetal calf serum (FCS), 1% Gentamicin and 1% L-glutamine. The lymphocytes were stimulated by phytohemagglutinin.

The culture was synchronized by the addition of Colcemid at 72 hrs. Cells were grown and then fixed according to the standard cytogenetic procedure.⁵ The karyotypes were analyzed by the use of a conventional banding technique (GTG). Analysis of 25 metaphase cells showed a pericentric inversion of one chromosome 21, with the breakpoint in the short arm at 21p12 and in the distal region of long arm at 21q22: 46, xx, inv (21) (p12; q22) in all cells (Fig. 2) while, she was phenotypically normal. Unfortunately, her karyotypes were not available also, no cytogenetic study was performed in aborts’ material.

Figure 2: Pericentric inversion of one chromosome 21, with the breakpoint in the short arm at 21p12 and in the distal region of long arm at 21q22: 46, xx, inv (21) (p12; q22) in all cells.

Discussion

In this study, we report a woman who carries a unique pericentric inversion of one chromosome 21: inv (21) (p12; q22). This abnormal karyotype was diagnosed after three miscarriages. The first case of pericentric inversion of one chromosome 21 was reported by Gray et al.⁶ Since then, at least 15 cases of this inversion have been reported.^7-16 The low frequency of inverted chromosome 21 described in the literature is probably due to the small size of the chromosome.¹ In all cases previously reported, with the exception of two case ascertained after four miscarriages and another case was diagnosed by infertility,^12,16 while our patient was ascertained after three miscarriages, other cases were referred for Down’s syndrome in offspring resulting from miotic recombination in the inverted segment. These patients had inherited the rec(21) dup(21q), leading to a partial trisomy of chromosome 21.

In fact, pairing in meiosis constitutes the main problem in inversion heterozygosis. An odd number of crossover events (during the pachytene stage of meiosis I) within the inversion segment can lead to two monocentric recombinants with reciprocal duplications/ deficiencies in the gametes, ending up in a risk of inheriting such an imbalance when conception occurs.

Hence, the offspring of the reported patient carries such risk of imbalance in the inverted chromosome 21. It has been shown that the risk of recombination depends on the location of breakpoints and on the rearranged chromosomes. Several studies have demonstrated that the more distal the breakpoints, the higher the risk.^17,18 This is because of the fact that the imbalance is smaller, thus more compatible with life, and that the probability of crossover will be higher in the inverted segment. Moreover, the risk of a live born child with a recombinant is higher when the carrier is ascertained through the birth of an affected individual than through miscarriage or infertility. In one study, the authors estimated that the risk of recombination in patients with an inversion of one chromosome 21 is close to 10%.⁹

In our patient, the breakpoint on the long arm is more distal than those reported in the literature. Hence, the inverted segment is larger in our patient, leading to a higher risk of recombination. 

For genetic counseling, the main concerns are related to the phonotypical consequence of a child inheriting chromosomal abnormality derived from the paternal or maternal inv (21). It is known that a deletion or a duplication of the region distal to p12 in an acrocentric chromosome does not lead to any phenotypic effect. On the other hand, the presence of an abnormal phenotype (mental retardation and/or malformations) is not always present in patients with partial trisomy or monosomy of the distal region of the long arm of chromosome 21(21q22.3qter).¹⁹ In humans, the problem of genetic counseling of inversion carriers and risk estimation is very difficult to resolve. With respect to the probability of chromosomal abnormality in the future progeny of our patient therefore; amniocenthesis is proposed for the patient if the pregnancy does not lead to miscarriage in order to find chromosomal abnormality in a child as a prenatal diagnosis.

Conclusion

The abnormal karyotype is reported as a probable reason for miscarriage in the investigated couple. The risk of further miscarriages and the risk of a progeny with abnormal karyotype are rather high. Therefore, amniocenthesis for finding the chromosomal abnormality as a prenatal diagnosis are proposed for the patient if future pregnancy does not lead to miscarriage.

Acknowledgements

The authors reported no conflict of interest and no funding was received on this work.

1. Kaiser P. Pericentric inversions. Problems and significance for clinical genetics. Hum Genet 1984;68(1):1-47.

2. Gardner RJ, Sutherland G. Inversions. In chromosomal abnormalities and Genetic counseling, 3rd edn. Oxford University Press, New York, 2004.

3. Rimoin D, Connor M, Korf B, Emery A. Emery and Rimoin’s principles and practice of medical genetics. 4th edn. Churchill Livingstone. 2001.

4. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction, 4th edn. Cambridge, UK; New York, NY: Cmbridge University Press,1999.

5. Rooney DE. Human Cytogenetics: constitutional analysis. A practical approach. Oxford University press. 2001.

6. Gray JE, Mutton DE, Ashby DW. Pericentric inversion of chromosome 21. A possible further cytogenetic mechanism in mongolism. Lancet 1962 Jan;1(7219):21-23.

7. Fraisse J. Pericentric inversion of a chromosome 21. Study of 3 generations. Genetic counseling. J Genet Hum 1975 Oct;23(SUPPL):107-111.

8. Fraisse J, Philip T, Bertheas MF, Lauras B. Six cases of partial duplicationdeficiency 21 syndrome: 21(dupq22delp23) due to maternal pericentric  inversion: inv(21)(p12;q22). A family study. Ann Genet 1986;29(3):177-180.

9. Groupe de Cytogénéticiens Français. Pericentric inversions in man. A French collaborative study. Ann Genet 1986;29(3):129-168.

10. Léonard C, Gautier M, Sinet PM, Selva J, Huret JL. Two Down syndrome patients with rec(21),dupq,inv(21)(p11;q2109) from a familial pericentric inversion. Ann Genet 1986;29(3):181-183.

11. Miyazaki K, Yamanaka T, Ogasawara N. A boy with Down’s syndrome having recombinant chromosome 21 but no SOD-1 excess. Clin Genet 1987 Dec;32(6):383-387.

12. Gabriel-Robez O, Ratomponirina C, Croquette M, Couturier J, Rumpler Y. Synaptonemal complexes in a subfertile man with a pericentric inversion in chromosome 21. Heterosynapsis without previous homosynapsis. Cytogenet Cell Genet 1988;48(2):84-87.

13. Tardy EP, Tóth A, Kosztolányi G. Prenatal exclusion of segmental trisomy in familial chromosome 21 pericentric inversion by fluorescence in situ hybridization. Prenat Diagn 1997 Sep;17(9):871-873.

14. Ilgin Ruhi H, Tükün A, Karabulut H, Bayazit P, Bökesoy I. A Down syndrome case with a karyotype of 46,XY,rec(21)dup(21q)inv(21)(p11q22) derived from paternal pericentric inversion of chromosome 21. Clin Genet 2001 May;59(5):368-370.

15. Lazzaro SJ, Speevak MD, Farrell SA. Recombinant Down syndrome: a case report and literature review. Clin Genet 2001 Feb;59(2):128-130.

16. Malan V, Pipiras E, Sifer C, Kanafani S, Cedrin-Durnerin I, Martin-Pont B, et al. Chromosome segregation in an infertile man carrying a unique pericentric inversion, inv(21)(p12q22.3), analysed using fluorescence in situ hybridization on sperm nuclei: significance for clinical genetics. A case report. Hum Reprod 2006 Aug;21(8):2052-2056. Published online 3 Apr 2006.

17. Dutrillaux B, Laurent C, Robert JM, Lejeune J. Pericentric inversion, inv(10), in a mother and aneusomy by recombination, inv(10), rec(10), in her son (author’s transl). Cytogenet Cell Genet 1973;12(4):245-253.

18. Dutrillaux B, Aurias A, Viegas-Pequignote E. Modifications chromosomiques dans l’evolution en pathologie: analyse des inversions pericentriques. C R Seances Soc Biol Fil 1980;174:730-740.

19. Chen CP, Lin SP, Chern SR, Lee CC, Huang JK, Wang W, et al. De novo satellited 21q associated with corpus callosum dysgenesis, colpocephaly, a concealed penis, congenital heart defects, and developmental delay. Genet Couns 2004;15(4):437-442.