Genetic abnormalities in Turkish women with premature ovarian failure

Objective

To identify the distribution of cytogenetic abnormalities among Turkish women with premature ovarian failure (POF).

Method

A karyotype analysis was performed at the Medical Genetics Department of Zekai Tahir Burak Women's Hospital, Ankara, Turkey, for 75 women younger than 40 years found to have POF over a 5-year period.

Results

There were 18 familial cases (24%), 1 of which involving an abnormality of the X chromosome [46,X,del(X)(q22)]. Sixteen patients (21.3%) had chromosomal abnormalities such as Xq and Xp deletions, translocations, and numerical aberrations; 2 had Swyer syndrome; 2 were fragile X premutation carriers; and 1 had galactosemia.

Conclusion

A genetic cause of POF was identified in 39 (52%) of 75 patients. A thorough genetic evaluation of women with POF should be performed regardless of clinical features suggestive of chromosomal abnormality.     

Novel X-chromosomal defect associated with abnormal ovarian function

Abstract Premature ovarian failure (POF) may be idiopathic or may be associated with genetic or autoimmune disorders. It is well known that chromosomal defects can impair ovarian development and its function. It is estimated that X-chromosome abnormalities occur in 10-25% of women with abnormal ovarian function. Of these, the common chromosome defects reported are either true Turner's karyotype or its variants. We describe a novel X-chromosome aberration in a woman with primary amenorrhea. Cytogenetic and fluorescence in situ hybridization analysis revealed a short-arm deletion of X-chromosome as a Turner's variant [mos,45,XO/46,Xdel(X)(p11.1-p22.3)]. This interesting and rare case with unique X-chromosome defect reveals an additional mechanism for the cause of POF.     

Two unusual chromosome aberrations ascertained by sonographic anomalies

We describe two cases of sonographic abnormalities associated with unusual chromosomal aberrations. Case 1 presented with a cystic hygroma at 12 weeks' gestation. Cytogenetic analysis revealed an unbalanced complex chromosome rearrangement implicating chromosomes 6, 13 and 21 (karyotype: 47,XX,t(6;21;14)(q14;q21;q21)mat,+21) and corresponding to a complete trisomy 21. This anomaly resulted from malsegregation of a maternal balanced three-way translocation. For case 2, an alobar holoprosencephaly was identified by ultrasonography at 23 weeks' gestation. Chromosomal analysis showed a recombinant rec (13), dup q chromosome, secondary to unequal crossing-over of a paternal pericentric inversion of chromosome 13, giving rise to partial trisomy 13q (karyotype: 46,XX,rec(13)dup(13q)inv(13)(p11q21)pat). These two cases illustrate the role of ultrasound in leading to detection not only of foetal chromosomal aberrations but also of rare balanced chromosomal rearrangements presented by one of the two parents.     

Premature ovarian failure,short stature,and Hashimoto’s disease in an 18-year-old adolescent girl with 46, X,i(X)(q10)

Abstract

Premature ovarian failure (POF) is a heterogeneous condition affecting girls and women. We detected a previously healthy 18-year-old adolescent girl, presented with amenorrhea over six months, as well as circulating levels of estradiol lower decreased and follicle-stimulating hormone (FSH) increased. She was 138?cm tall. Results of laboratory tests and/or ultrasound investigations showed 46, X, i(X)(q10) karyotype and Hashimoto’s disease. This case suggests that pubertal onset and progression, as well as karyotype analysis, should be evaluated in girls with Hashimoto’s disease and short stature.     

Molecular cytogenetic characterization of del(X)(p22.33)mat and de novo dup(4)(q34.3q35.2) in a male fetus with multiple anomalies of facial dysmorphism,ventriculomegaly, congenital heart defects,short long bones and clinodactyly

ObjectiveWe present molecular cytogenetic characterization of del(X) (p22.33)mat and de novo dup(4) (q34.3q35.2) in a male fetus with multiple anomalies of facial dysmorphism, ventriculomegaly, congenital heart defects, short long bones and clinodactyly.Case reportA 36-year-old, gravida 3, para 1, woman with short stature (152 cm) underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,Y,del(X)(p22.33)mat, dup(4)(q34.3q35.2). The mother had a karyotype of 46,X,del(X)(p22.33). Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from cultured amniocytes revealed arr Xp22.33 × 0, 4q34.3q35.2 × 3. Prenatal ultrasound at 23 weeks of gestation revealed multiple anomalies of flat nasal bridge, ventriculomegaly, atrioventricular septal defect (AVSD) and clinodactyly. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism. Cytogenetic analysis of the umbilical cord revealed 46,Y,del(X)(p22.33)mat, dup(4)(q34.3q35.2)dn. aCGH analysis on the DNA extracted from the umbilical cord revealed arr [GRCh37 (hg19)] 4q34.3q35.2 (181,149,823–188,191,938) × 3.0, arr Xp22.33 (470,485–2,985,006) × 0 with a 7.042-Mb duplication of 4q34.3-q35.2 and a 2.514-Mb deletion of Xp22.33.ConclusionA male fetus with del(X)(p22.33) and dup(4)(q34.3q35.2) may present congenital heart defects and short long bones on prenatal ultrasound.     

A unique case of der(11)t(11;22),-22 arising from 3:1 segregation of a maternal t(11;22) in a family with co-segregation of the translocation and breast cancer

OBJECTIVE: To report the first tertiary monosomy in a pregnancy loss to a female t(11;22) carrier. METHODS: The patient was a 34-year-old G10P1 female known to have a balanced translocation t(11;22)(q23;q11.2). She had one female livebirth (a translocation carrier) and eight miscarriages. Five female relatives known to be translocation carriers had a history of breast cancer, three of them premenopausally. The patient herself had a malignant melanoma. RESULTS: During the 10th pregnancy, ultrasound showed a viable embryo at 6 weeks of gestation, but loss of embryonic heartbeat by 7.5 weeks. Culture of the products of conception at 8 weeks of gestation showed the karyotype: 46,XY,+2,der(11)t(11;22)(q23;q11.2)mat,-22[4]/45,XY,der(11)t(11;22)(q23;q11.2)mat,-22[4], resulting from fertilization of the maternal 3:1 segregation product containing only the der(11) by a normal gamete. Subsequently, she became pregnant with a normal 46,XX fetus. FISH analysis indicated that the breakpoints on 11q and 22q in the patient were in the previously described region common to typical recurrent t(11;22). In addition, a nested-PCR-based approach showed that they were located within the same palindromic AT-rich sequence previously described. CONCLUSION: This case demonstrates that the tertiary monosomy resulting from the 3:1 segregation is compatible with embryonic survival into the first trimester. It is also another example of apparent association of the constitutional translocation t(11;22) and breast cancer.     

Molecular cytogenetic characterization of 1q42.3q44 deletion and 8q24.3 duplication in a fetus with single umbilical artery and ventricular septal defects

ObjectiveWe present prenatal diagnosis and molecular cytogenetic characterization of a chromosome 1q42.3q44 deletion and 8q24.3 duplication in a fetus with single umbilical artery and ventricular septal defects, and we discuss the genotype–phenotype correlation.Case reportHere, we describe a fetus with abnormal sonography findings showing a single umbilical artery and ventricular septal defects. Conventional karyotyping initially described the fetus as 46,XX,1q? and molecular cytogenetic analysis (CMA) revealed a 13-Mb deletion and 4.6-Mb duplication of regions 1q42.3q44 and 8q24.3, respectively. The father's karyotype was 46,XY. The mother's karyotype was 46,XX,t(1;8)(q42;q24). Therefore, the karyotype of the fetus was identified as 46,XX,der(1)t(1;8)(q42;q24) mat. After genetic counseling, the couple chose to terminate the pregnancy. We suggest that the ACTN2, RYR2 and PUF60 genes may be responsible for the ultrasound abnormalities observed in the fetus.ConclusionTo the best of our knowledge, this is the first report of a 1q deletion and 8q duplication identified by prenatal detection. The application of karyotype analysis and CMA provides more accurate characterization for unidentified chromosomal anomalies, and benefits appropriate genetic counseling in the clinic.     

A case of 46,X,der(X)(pter-->q21::p21-->pter) with gonadal dysgenesis, tall stature, and endometriosis

Objective: To report a case of 46,X,der(X)(pter→q21::p21→pter) with gonadal dysgenesis, tall stature, and endometriosis.

Design: Case report.

Setting: A university hospital.

Patient(s): A 20-year-old primary amenorrheal woman receiving estrogen-progestogen substitution.

Intervention(s): G-banding, comparative genomic hybridization, fluorescence in situ hybridization (FISH), and laparoscopy.

Main Outcome Measure(s): A recombinant X chromosome, 46,X,der(X)(pter→q21::p21→pter), and pelvic endometriosis.

Result(s): The patient’s chromosomal abnormality was misjudged by the use of G-banding as a distal part deletion of the long arm in one X chromosome. Comparative genomic hybridization and fluorescence in situ hybridization analyses with locus-specific probes revealed 46,X,der(X)(pter→q21::p21→pter). The laparoscopic examination showed bilateral streak gonads and blue berry spots at the pelvic peritoneum, which were confirmed by evaluation of biopsy specimens.

Conclusion(s): Recent advances of genetic strategies make it easy to determine karyotype and phenotype abnormalities. We have to keep our mind on the potential of endometriosis with patients who are receiving estrogen-progestogen substitution.     

Karyotype determination and reproductive guidance for short stature women with a hidden Y chromosome fragment

Two unrelated couples came to the Reproductive and Genetic Hospital of Citic-Xiangya to ask for reproductive guidance. One couple had an affected son and the other couple had secondary infertility. Conventional GTG banding showed that the women in both couples had a 46,X,add(X)(p22) karyotype. Further molecular cytogenetic studies showed that both women had a 46,X,der(X)t(X;Y)(p22;q11.2) karyotype and that the affected boy had inherited the derivative X chromosome, which resulted in an Xp contiguous gene syndrome. After an assessment of reproductive risk, the first couple conceived naturally and opted for prenatal diagnosis (PND) by amniocentesis. No abnormal karyotypes were found for the twin pregnancy and healthy twin girls were born after a full-term normal pregnancy. The second couple chose to undergo IVF with preimplantation genetic diagnosis (PGD). Two PGD cycles were performed by fluorescence in-situ hybridization. In the first PGD cycle, all three embryos had abnormal hybridization signals. In the second cycle, a male embryo with normal hybridization signals was transferred into the womb and a normal pregnancy was achieved. The results show the importance of detecting the derivative chromosome followed by PND or PGD if a woman carries an Xp;Yq translocation.Two unrelated couples came to our clinic to ask for reproductive guidance. The first couple had an affected son. Conventional GTG banding showed the woman carried a derivative metacentric X chromosome. Further molecular cytogenetic study identified this derivative X chromosome originated from a cryptic translocation between Xp and Yq and the karyotype of the woman was determined as 46,X,der(X)t(X;Y)(p22;q11.2), and the affected boy had inherited the derivative X chromosome, which resulted in an Xp contiguous gene syndrome. After assessment of reproductive risk, the couple conceived naturally. Prenatal diagnosis by amniocentesis showed a normal karyotype for the twin pregnancy and healthy twin girls were born at full term. The other couple was affected by secondary infertility. They chose to undergo IVF with preimplantation genetic diagnosis (PGD). Two PGD cycles was performed by fluorescence in-situ hybridization. In the second cycle, a male embryo with normal hybridization signals was transferred to the womb and a normal pregnancy was achieved. We emphasize the importance of identifying the hidden Y chromosome fragment to avoid the delivery of unbalanced offspring among women with a normal phenotype apart from short stature. This is the first report of the application of PGD for this unbalanced translocation 46,X,der(X)t(X;Y)(p22;q11.2).     

121例遗传咨询门诊病例的细胞遗传学分析

就1982年121例遗传咨询门诊所查7例染色体异常进行报道与分析。常规进行淋巴细胞培养G显带,部分病例选加C带。7例的异常核型是:46,XX,-21,t(21q21q);46,X,i(Xq);45,X/46,XX;45,X/46,XY;45,XX,t(13q14q)mat;45,XX,t(13q14q);46,XY,nv(q)。     

Ovulation induction in a woman with premature ovarian failure resulting from a partial deletion of the X chromosome long arm, 46,X,del(X)(q22)

Objective: To report successful ovulation induction in a woman with premature ovarian failure (POF) resulting from a partial Xq deletion.Design: An uncontrolled study. Setting: University hospital.Patient(s): A 27-year-old woman with 46,X,del(X)(q22) who had hypergonadotropic secondary amenorrhea.Intervention(s): Injections of hMG (225 IU/d) for 8 consecutive days after endogenous gonadotropin suppression with a long-acting GnRH agonist (900 μg/d) for 12 weeks, together with cyclic sex steroid replacement therapy.Main Outcome Measures: Serum concentrations of E₂ and P as well as ultrasonography.Result(s): Folliculogenesis and ovulation.Conclusion(s): Ovulation induction is possible in patients with POF caused by X chromosome aberrations.     

Cytogenetic analysis of 179 Iranian women with premature ovarian failure

Abstract

The importance of chromosomal abnormalities in etiology of premature ovarian failure (POF) is well known but in many cases, POF still remains idiopathic. We investigated the frequency and type of chromosomal aberrations in Iranian women diagnosed with idiopathic POF. Standard cytogenetic analysis was carried out in a total of 179 patients. Karyotype analysis of these patients revealed that 161 (89.95%) patients had normal female karyotype and 18 (10.05%) patients had abnormal karyotypes. The abnormal karyotypes included sex reverse sex determining region Y (SRY) negative (five Cases), X chromosome mosaicism (five cases), abnormal X chromosomes (three cases), abnormal autosomes (three cases) and X-autosome translocation (two cases). The overall prevalence of chromosomal abnormalities was 10.05% in this first large-scale report of chromosomal aberrations in Iranian women with POF. The results confirm previous observations and emphasis on the critical role of X chromosome abnormalities as one of the possible etiologies for POF.     

Premature ovarian failure and fragile X premutation: a study on 45 women

OBJECTIVE: The aim of this study was to test for the presence of the fragile X (FRAXA) premutation a group of women with early menopause. STUDY DESIGN: 45 women with idiopathic premature ovarian failure (POF), five with a familial and 40 with a sporadic form, were screened for the presence of FRAXA premutation. A control group of 28 women >45 years, with one or more children and no signs of POF, was also studied. RESULTS: We found three cases of fragile X premutations in women all belonging to the group with sporadic POF. CONCLUSION: Our results seems to confirm previous observations on the non random association between POF and FRAXA premutation.     

连续多发性流产夫妇的高分辨染色体研究——附6例世界首报异常核型

选择407对连续流产2-8次的夫妇进行染色体G显带分析,发现异常核型23例。407对夫妇中,采用高分辨技术精细定位46例,发现的15例异常核型中有6例鉴定为世界首报,对其中4例进行了绒毛染色体检查,均发现与父(母)相同的异常核型,说明非同源染色体相互易位和倒位携带者的后代必须接受宫内诊断,智力低下或生育力降低可能与易位染色体有关。     

Mosaicism for Robertsonian jumping translocation at amniocentesis: 45,XY,der(15;22)(q10;q10)mat/46,XY,i(15)(q10)/46,XY,genetic counseling,prenatal diagnosis and postnatal follow-up in a pregnancy with a favorable fetal outcome

ObjectiveWe present genetic counseling, prenatal diagnosis and postnatal follow-up of 45,XY,der(15;22)(q10;q10)mat/46,XY,i(15)(q10)/46,XY at amniocentesis in a pregnancy with a favorable fetal outcome.Case reportA 27-year-old, primigravid woman underwent amniocentesis at 19 weeks of gestation because increased nuchal translucency thickness, and the result was 45,XY,der(15;22)(q10;q10)[29]/46,XY,i(15)(q10)[3]/46,XY[5]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr (1–22) × 2, (X,Y) × 1. The maternal karyotype was 45,XX,der(15;22)(q10;q10), and the paternal karyotype was 46,XY. She was referred for genetic counseling, and repeat amniocentesis performed at 23 weeks of gestation revealed 45,XY,der(15;22)(q10;q10)mat[23]/45,XY,-22[2]. aCGH analysis on uncultured amniocytes detected no genomic imbalance, and polymorphic DNA marker analysis excluded uniparental disomy (UPD) 15. Fluorescence in situ hybridization (FISH) analysis using the chromosome 15q specific probe and the chromosome 22q specific probe detected three 15q signals in 4/104 cells (3.8%). The woman was advised to continue the pregnancy, and, a 3186-g phenotypically normal male baby was delivered at 38 weeks of gestation. The umbilical cord had a karyotype of 45,XY,der(15;22)(q10;q10) (40/40 cells). When follow-up at age seven months, the neonate was normal in development, the peripheral blood had a karyotype of 45,XY,der(15;22)(q10;q10) (40/40 cells), and the buccal mucosal cells had normal signals in all 100 cells.ConclusionsMosaicism for Robertsonian jumping translocations at amniocentesis can be a transient condition and can be associated with a familial Robertsonian translocation and a favorable fetal outcome. Prenatal diagnosis of a Robertsonian jumping translocation involving chromosome 15 should include UPD 15 testing to exclude UPD 15.     

High-level mosaicism for 45,X in 45,X/46,X,idic(Y)(q11.2) at amniocentesis in a pregnancy with a favorable outcome and postnatal progressive decrease of the 45,X cell line

ObjectiveWe present prenatal diagnosis of high-level mosaicism for 45,X in 45,X/46,X,idic(Y)(q11.2) at amniocentesis in a pregnancy with a favorable outcome and postnatal progressive decrease of the 45,X cell line.Case reportA 36-year-old, gravida 4, para 3, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 45,X[22]/46,X,idic(Y)(q11.2)[4]. Prenatal ultrasound was unremarkable, and the fetus had normal male external genitalia. Repeat amniocentesis was performed at 20 weeks of gestation, and the second amniocentesis revealed a karyotype of 45,X[24]/46,X,idic(Y)(q11.2)[3]. Simultaneous interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes revealed that 60% (62/103 cells) were Y-deleted cells. After genetic counseling, the parents decided to continue the pregnancy, and a 3020-g male baby was delivered with a body length of 52 cm, normal male genital organs and no phenotypic abnormalities. The karyotypes of cord blood, umbilical cord and placenta were 45,X[20]/46,X,idic(Y)(q11.2)[20], 45,X[31]/46,X,idic(Y)(q11.2)[9] and 45,X[40], respectively. At age one month, FISH analysis on urinary cells and buccal mucosal cells revealed 11.5% (7/61 cells) and 13.6% (16/118 cells), respectively for mosaicism for the Y-deleted cells. At age five month, the karyotype of peripheral blood was 45,X[9]/46,X,idic(Y)(q11.2)[31]. FISH analysis on buccal mucosal cells showed no abnormal Y-deleted cell (0/101 cells). At age 11 month, the karyotype of peripheral blood was 45,X[5]/46,X,idic(Y)(q11.2)[35]. FISH analysis on 102 buccal mucosal cells showed no abnormal signals. The infant was doing well with normal physical and psychomotor development.ConclusionHigh-level mosaicism for 45,X in 45,X/46,X,idic(Y)(q11.2) at amniocentesis can be associated with a favorable outcome and progressive decrease of the 45,X cell line.     

Microphthalmia with linear skin defects (MLS) syndrome evaluated by prenatal karyotyping, FISH and array comparative genomic hybridization

OBJECTIVE: To explore the utility of comparative genomic hybridization to BAC arrays (array CGH) for prenatal diagnosis of microphthalmia and linear skin defects syndrome. METHODS: We used karyotype analysis, FISH and array CGH to investigate an X;Y translocation. Replication studies were done on cultured amniocytes and lymphoblasts. RESULTS: We describe a severe case of MLS syndrome that presented prenatally with multiple anomalies including cystic hygroma, microphthalmia, intrauterine growth restriction and a complex congenital heart defect. Cytogenetic analysis of amniocytes revealed an unbalanced de novo translocation between chromosomes X and Y [karyotype 46,X,der(X)t(X;Y)(p22.3;q11.2).ish der(X)(DXZ1+,DMD+,KAL-,STS-,SRY-),22q11.2 (Tuple1 x 2)]. MLS diagnosis was made at birth and the prenatal karyotype was confirmed. Replication studies showed the derivative X chromosome was the inactive X. Array CGH confirmed the X and Y imbalances seen in the karyotype and also showed twelve BACs in the MLS region were deleted as a result of the translocation. FISH with BAC clones verified the array findings and placed the X breakpoint in Xp22.2, resulting in the amended karyotype, 46,X,der(X)t(X;Y)(p22.2;q11.2).ish der(X)(DXZ1+,DMD+,KAL-,STS-,SRY-),22q11.2(Tuple1 x 2) arr cgh Xp22.33p22.2(LLNOYCO3M15D10 -->GS1-590J6)x 1,Yq11.222q23(RP11-20H21-->RP11-79J10)x 1. CONCLUSION: The sensitivity of array CGH was valuable in detecting monosomy of the MLS critical region. Array CGH should be considered for the prenatal diagnosis of this syndrome.     

应用荧光原位杂交技术检测卵巢早衰患者X染色体嵌合型

目的　探讨卵巢早衰与低百分率 45 ,X/ 46,XX嵌合核型的关系 ,了解荧光原位杂交(FISH)技术检测染色体嵌合核型的敏感性和特异性。方法　取 18例卵巢早衰患者和 9例正常妇女(对照 )的外周血进行培养 ,行常规G显带和用X染色体记数探针行FISH ,对每例计数 60 0～ 70 0个细胞的荧光信号。结果　 18例卵巢早衰患者的常规染色体分析核型为 46,XX。卵巢早衰患者的 45 ,X/46,XX染色体嵌合型比率为 7.6% ,显著高于对照者的 2 .2 % ,两者比较 ,差异有极显著性 (P <0 .0 1)。结论　某些卵巢早衰患者的致病机理可能与 45 ,X/ 46,XX嵌合核型比例增高 ,X染色体数量不足有关。对此类低百分率染色体嵌合核型 ,FISH技术在敏感性和特异性上优于常规核型检查     

Molecular and Cytogenetic Characterization of Two Azoospermic Patients with X-Autosome Translocation

Purpose : To report two azoospermic patients with reciprocal X–autosome translocations. Methods : Cytogenetic analysis utilizing GTG-banding and Yq microdeletions shown by polymerase chain reaction (PCR) with 12 sequence-tagged site (STS) markers for Y chromosome microdeletions. Results : Cytogenetic analysis showed one man with 46,Y,t(X;19)(q22;q13.3) and the other with 46,Y,t(X;8)(p22;q11). Neither had any Yq microdeletions shown. The patient with 46,Y, t(X;8)(p22;q11) showed a slightly lower than normal testosterone level. By NCBI-Blast search, we found four testis-specific genes, t-complex-associated-testis-expressed 1-like (TCTE1L), Ferritin, heavy polypeptide-like 17 (FTHL17), Testis expressed sequence 13A (TEX13A), and Testis expressed sequence 13B (TEX13B) located near breakpoints on X chromosome. FTHL17, TEX13A, and TEX13B are spermatogonially-expressed, germ-cell-specific genes. Conclusion : This is the first clinical report of azoospermia with reciprocal X–autosome translocations on Xp22 and q22. These translocations on Xp22 and q22 may be direct genetic risk factors for azoospermia.     

Prenatal diagnosis of a fetus with distal 10q trisomy.

Distal 10q trisomy is a well-defined but rare syndrome. Most cases are diagnosed in infancy or in childhood and rarely include prenatal findings. We present a case of fetal distal 10q trisomy with abnormal prenatal sonographic findings. A 19-year-old primigravida was referred for genetic counselling at 18 gestational weeks because her husband had a familial history of congenital anomalies. Genetic amniocentesis was thus performed and showed fetal distal 10q trisomy (10q24.1-->qter), 46,XX,der(22)t(10;22)(q24.1;p11.2)pat, resulting from paternal t(10;22) reciprocal translocation. Level II ultrasonograms further demonstrated bilateral hydronephrosis, ventricular septal defect and facial dysmorphism ascertained by three-dimensional ultrasound. The pregnancy was terminated at 22 gestational weeks. Post-mortem autopsy confirmed the sonographic findings. We suggest that abnormal prenatal sonographic findings such as cardio-vascular, renal and facial malformations should alert cytogeneticists to search for subtle chromosomal abnormalities.