Reproductive failure is the inability to achieve conception or sustain a pregnancy to term. It is estimated that fetal viability is only achieved in 30.0% of all human conceptions [1]. Chromosomal abnormalities are a known contributory factor in infertility, bad obstetric history (BOH) and spermatogenetic arrest. Male infertility may be associated with chromosomal abnormalities, involving sex chromosomes (4.0-8.0%) and autosomes (1.0-2.0%) [2]. Complete spermatogenic and partial spermatogenetic arrest is mainly associated with sex chromosomal aneuploidies and autosomal structural abnormalities, respectively [3]. The frequency of autosomal reciprocal translocations is estimated to be 0.25% in the general population, 0.5% in azoospermia and 0.7% in oligozoospermia [4,5]. The incidence of these genetic abnormalities increases with decline in semen quality [6]. Kumar
The proband was a healthy male (178 cm/76 kg) with well developed secondary sexual characters. He was oligoasthenoteratozoospermic (95000 spermatozoa/mL). Endocrine evaluation showed that follicle-stimulating hormone (FSH) (6.5 mIU/mL), luteinizing hormone (LH) (4.3 mIU/mL) and testosterone (360 ng/dL) were normal. Because of the spermiogram results and the duration of infertility, ICSI was performed and failed three times. The wife of the proband was normal on gynecological examination.
The proband’s sister (II-2), aged 26 years (158 cm/56 kg), suffered three first trimester spontaneous abortions. Her husband was clinically and cytogenetically normal. Her hormonal profile (FSH 5.5 mIU/mL, LH 15.0 mIU/mL and prolactin (PRL) 11.0 ng/dL) was within the normal range.
The mother (I-2) of the proband was 66 years old (155 cm/69 kg). Her two children were conceived after 12 years of marriage; and she had a history of repeated miscarriages in the first trimester of pregnancy, but was not able to recollect her case history properly.
Ethical clearance was obtained prior to the study from the Ethics Clearance Committee of the All India Institute of Medical Sciences (AIIMS), New Dehli, India. The patients were referred from the infertility clinic of the Department of Urology, AIIMS, and the ART Centre of the Army Research and Referral Hospital, New Delhi, India. The study was explained to both patients and controls in English and Hindi (local language).
The proband was oligoasthenoteratozoospermic. His average sperm count was 0.95 million/mL after three semen analyses. The grade A, B, C and D motility was 38.0, 30.0, 20.0 and 12.0%, respectively. The abnormal morphology was found in 79.0% sperms (65.0% sperms had coiled tails, 14.0% had tapered heads and 21.0% had normal morphology). The proband was found to carry a balanced translocation between chromosomes 13;22. The breakpoint was at 13q21.2 and the terminal part was transferred to 22q13.3. The karyotype was 46;XY,t(13;22) (q21.2;q13.3). Incidentally, the same translocation was observed in the mother and sister of the proband. The karyotypes of mother and sister were 46,XX,t(13;22) (q21.2;q13.3) and 46,XX,t(13;22)(q21.2;q13.3), respectively. The sister of the proband got pregnant during the investigation and was counseled about the risk to the fetus, of inheriting the genetic abnormality. The couple opted for amniocentesis (in a private center other than AIIMS, New Delhi, India). The amniocentesis was done at the 17th week of pregnancy and the fetus was found to carry the same translocation (46;XX, t(13;22)(q21.2;q13.3) as that of the mother (shown in Figure 2). However, couple decided to continue the pregnancy. The growth of the fetus was monitored through ultrasound and mother (II-2) delivered a phenotypically normal girl.
Spontaneous abortion involves pregnancy fatalities from the start until the 24th week of pregnancy [15,16]. Many risk factors are related with early pregnancy loss, including genetic and endocrine irregularities, immune dysfunction and progressive maternal age [17]. Reciprocal translocations are the leading cause of recurrent miscarriages [18]. Translocation of 13;22 is a leading cause of partial trisomy with elevated levels of neutrophils in patients [19].
We describe here a familial case of t(13:22) in three generations of a family with a BOH. Family members were phenotypically normal because of nature of the translocation. Pedigree analysis helped in tracking the path of transmission of the translocation from mother (I-2). From the proband’s sister (II-2), the translocation transmitted to her child (III-2). We were successful in identifying the breakpoint interval on the long arm of chromosome 13q21. It has been reported to be an AT-rich repeat region and very prone to rearrangements due to the presence of fragile sites. The sequences and mechanisms responsible for the fragility at these sites remains largely unknown [20,21]. Deletions in chromosome 13q21 occur frequently in head and neck squamous cell carcinoma (HNSCC) [22]. Manjunatha
Poor fertilization and pregnancy rate has been reported in several studies on translocation carriers opting for ART [30]. Preimplantation genetic diagnosis (PGD) in such cases has shown a very high incidence of aneuploidies, and structural abnormalities [31,32]. This study is highly significant in this era of ART, where the majority of couples with BOH or infertility opt for ART/ICSI. The ART is a very expensive technique and is usually not covered by medical insurance, and if it fails recurrently, leads to severe physical and financial stress. Despite major advances in ART and professional expertise, the carry home live birth rate following ART is 25.0-35.0%. It has been reported that genetic abnormality could be a major cause for fertilization failure or poor blastocyst development following ART and may lead to pre or post implantation failure [8,33].
Thus, all couples with BOH/reproductive and recurrent ART failure should undergo genetic analysis and those results could be corerelated with PGD of the blastocysts that are expected to be transferred. On conception, the patient should be followed by prenatal diagnosis. The present study is one of the finest case report of familial BOH, recurrent ART failures and chromosomal abnormality.