Abstract

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Down syndrome, characterized by an extra chromosome 21 is the most common genetic cause for congenital malformations and learning disability. It is well known that the extra chromosome 21 most often originates from the mother, the incidence increases with maternal age, there may be aberrant maternal chromosome 21 recombination and there is a higher recurrence in young women. In spite of intensive efforts to understand the underlying reason(s) for these characteristics, the origin still remains unknown. We have experienced a case of recurrent prengnancy of Down syndrome, or trisomy 21. We present this case with a brief review of a literature.

Case

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Parity: : 1-0-2-1

Address and current history: the patient had amernorrhea 19+4 weeks, through ultrasonography, Atypical features were found and suspected of intrauterine fetal death. For further examination and treatment the patient was admitted

Surgical history: One Cesarean section, one induced abortion due to the down syndrome pregnancies

Laboratory findings: Hemoglobin 10.4 g/dL, hematocrit 31%, white blood cells, platelet count was normal. No specific findings on liver function tests and renal function tests. Syphilis and hepatitis antigen test were negative and the patient’s blood type was Rh positive. No abnormal findings on ECG, chest X-ray examination and urinary analysis.  APTT coagulation are 20.9sec in a slightly decreased.

Cytogenetic findings: Using Long term flask culture with GTG banding analysis method to the amniocentesis after admission, 47, X( ), +21 was found, yielded cytogenetic diagnosis result was trisomy 21; Down syndrome, respectively. Two independent flasks were observed in a total of 40-50 colonies, 20 colonies of the mid-phase from an analysis, all cells were found competent trisomy 21, or Down syndrome karyotype was observed. Down syndrom is classified as tristomy 21, mosaicism, and tranlocational by karyotyping, each occurrence frequency were 93%, 2%, and 5%. The patient belonged to the trisomy 21. ETBR karyotype results were 46, XX and 46, XY which were the normal karyotype of both sex. Analysis methods were 1)PHA stimulated T-lymphocyte culture with GTG banding 2)High resolution culture using ETBR, and used peripheral blood of the patient and the spouse.

Obstetrical course: Induction was determined to enforce due to the intrauterine fetal death. Induction of labor using misoprostol caused vaginal bleeding, retained placenta was suspected, therefore curettage was performed. Stillborn height was 128mm, weight 256mg.

Clinical outcome after delivery: Two days after delivery, the patient did not have vaginal bleeding and was discharged.

 

Discussion

There are three hypotheses about parents’ age and trisomy 21. The age of the father does not affect non-separation of chromosomes and non-separation is related to the age of the mother. From here, the first hypothesis can be made: each germ cell has different period of mutation. The second hypothesis is that non-separation of chromosomes from both parents and the age and the presence of the association, which can be seen as a result of the environment factors. The third hypothesis is that maternal age is increased in non-separation of the parents, regardless of source, the chance of giving birth to children with Down syndrome increases to be, which means ability of removing fetal chromosomal abnormalities as a pregnant women takes ages. ²⁾³⁾⁴⁾  

For mechanism of chromosomal non-separation of a mother, it is a leading hypothesis that early mitosis with loss of 21^st chromosome homozygotes, or mitosis error after zygote in a normal pregnancy, which causes acquisition of 21^st chromosome.

Recurrence rate is about 1% for the couple who has an experience of down syndrome to have another child with down syndrome. In addition, if the down syndrome of the child is caused by parent who are translocational carrier. in this case, recurrence rate will be much higher and will not have relevance with age.⁶⁾ If one of the parent has trisomy 21 mosaicism in germ cells, it will be significantly associated to recurrence.⁷⁾   

There is a thesis paper, announced in 2006, about mosaicism of recurrent 21 trisomy. In the paper, it reported that down syndrome is caused by fertilization of disomic 21 ovum and monosomic 21 sperm. In this case, fetus of trisomy 21 recurrent pregnancy rate is high, therefore pre-diagnosis is required. Also, evaluation should be based on tissue of reproductive organ due to somatic non-separation of chromosome 21 during fetus mitosis. Therefore, if mother has recurrence pregnancy of trisomy, cytogenetic analysis of the parental tissue is needed.⁸⁾

Based on these, we have presumed of cause of recurrent Down syndrome in this case. First, the pregnant woman was age 39. In this case, there is a delay (especially for 40 years old and above) to meiosis and it can cause error in 1^st period of meiosis. Second, possibility recurrence due to 21 trisomy mosaicism in germline, since peripheral blood chromosome test of both pregnant women and the spouse had no abnormality. To this end, in this case in order to explore the exact cause of testicular and ovarian tissue parents additional cytogenetic are needed.¹⁰⁾ We have experienced a pregnant women with two consecutive pregnancy of fetus with 21 trisomy, through this case, we report on the rare recurrence of Down syndrome with literature review

References

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1) Morris, JK, Mutton, DE, Alberman, E. Revised estimates of the maternal age specific live birth prevalence of Down's syndrome. J Med Screen 2002; 9:2.
2) Bricarelli FD, Pierluigi M, Landucci M, Arslnian A, Covielo DA, Ferro MA, Strigini P : Parentalage and the origin of trisomy 21. Hum Genet 82:20-26, 1989
3) Stewart GD, Hassold TJ, Berg A, Watkins P,Rudolph T : Trisomy 21(Down syndrome) : Studying nondisjunction and meiotic recombination by using cytogenetic and molecular polymorphisms that span chromosome 21. Am J Hum Genet 42:227-236, 1988
4) Lorber BJ, Grantham M, Peters J, Willard HF, Hassold TJ : Nondisjunction of chromosome 21 : Comparisons of cytogenetic and molecular studies of the meiotic stage and parent of origin. Am J Hum Genet 51:1265-1276, 1992
5) Bruyere H, Rupps R, Kuchinka BD, Friedman JM, Robinson : Recurrent trisomy 21 in a couple with a child presenting trisomy 21 mosaicism and maternal uniparental disomy for chromosome 21 in the euploid cell line. Am J Med Genet. 2000 Sep 4;94(1):35-41
6) Alberman E, Mutton D, Morris JK,  Cytological and epidemiological findings in trisomies 13, 18, and 21: England and Wales 2004-2009.Am J Med Genet A. 2012 May;158A(5):1145-50. Epub 2012 Apr 11.
7) James RS, Ellis K, Pettay D, Jacobs PA.Cytogenetic and molecular study of four couples with multiple trisomy 21 pregnancies. Eur J Hum Genet 1998 May-Jun;6(3):207-12.  
8) Hultén M.A. · Jonasson J. · Iwarsson E. · Uppal P. · Vorsanova S.G. · Yurov Y.B. · Iourov I.Y., Trisomy 21 Mosaicism: We May All Have a Touch of Down Syndrome. Cytogenet Genome Res 2013;139:189-192
9) CUI Ying-xia, HAO Li-jun, WANG Yun-hua, XIA Xin-yi, SHI Yi-chao, LU Hong-yong, YAO Bing, HUANG Yu-feng :Second pregnancy of trisomy 21 in a mother with mosaicism. Chinese Medical Journal 2007, Vol. 120 No. 14.
10) Maj A Hultén, Suketu D Patel, Maira Tankimanova, Magnus Westgren, Nikos Papadogiannakis, Anna Maria Jonsson, and Erik Iwarsson : On the origin of trisomy 21 Down syndrome. Mol Cytogenet. 2008; 1: 21. 18.

Source(s) of Funding

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None

Competing Interests

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No