Efficiency of Noninvasive Prenatal Testing for Sex Chromosome Aneuploidies

<b><i>Objective:</i></b> This study was designed to investigate the efficiency of noninvasive prenatal testing (NIPT) for screening fetal sex chromosome aneuploidies (SCAs) through sequencing of cell-free DNA in maternal plasma. <b><i>Methods:</i></b> This is a retrospective study on the positive NIPT results for SCAs collected from our hospital between January 2012 and December 2018. Samples with positive NIPT results for SCAs were then confirmed by prenatal or postnatal karyotyping analysis. <b><i>Results:</i></b> After cytogenetic analysis, abnormal karyotypes were confirmed in 104 cases and the overall positive predictive value (PPV) of NIPT for SCAs was 43.40% (102/235). The most frequently detected karyotypes included 47,XXY (<i>n</i> = 42), 47,XXX (<i>n</i> = 20), 47,XYY (<i>n</i> = 16), and 45,X (<i>n</i> = 2). Meanwhile, 10 cases were confirmed with mosaic karyotype 45,X/46,XX and 14 cases with numerical or structural chromosome abnormalities, including a double trisomy 48,XXX,+18. Cytogenetic results from the other 131 cases showed normal XX or XY, which were discordant with NIPT results. Upon analysis of parental karyotypes, 29 (12.34%) showed false positivity in NIPT results that were caused by maternal sex chromosome abnormalities. <b><i>Conclusion:</i></b> NIPT is an effective screening tool for SCA with a PPV of 43.40%. Maternal karyotype abnormalities occurred in 12.34% of the cases with abnormal NIPT. Diagnostic testing of the fetus and the mother are recommended.

A toddler with phylloid-type pigmentary mosaicism and ambiguous genitalia resulting from trisomy 14 induced by a der(Y)t(Y;14)

A 1-year-old baby with phylloid-type pigmentary mosaicism, hypotonia, ambiguous genitalia, and a positive screening test for congenital adrenal hyperplasia was referred. Previous sonograph, cytogenetics, and metabolic profile were inconclusive, therefore we performed an additional karyotype and a molecular cytogenetics studies. A mosaic karyotype 45,X/46,X,der(Y)t(Y;14) was characterized in peripheral blood. Congenital adrenal hyperplasia genes were sequenced and the results were negative. The ambiguous genitalia was the result of the special gonosomal mosaicism. The low level of trisomy 14 led to minor physical characteristics and mild mental retardation; also, Turner syndrome features can be expected rather than severe trisomy 14 stigmata.

Congenital Malformations in a Holstein-Fresian Calf with a Unique Mosaic Karyotype: A Case Report

A Holstein-Fresian calf with multiple congenital malformations was subjected postmortem to anatomical and genetic investigation. The calf was small (20 kg), had shortened limbs and was unable to stand up. It lived only 44 days. Detailed anatomical investigation revealed the following features: head asymmetry, the relocation of the frontal sinus and eye orbits, hypoplastic thymus without neck part, ductus Botalli, unfinished obliteration in umbilical arteries, and a bilateral series of tooth germs in the temporal region. Cytogenetic examination, performed on in vitro cultured fibroblasts, showed a unique mosaic karyotype with a marker chromosome—60,XX[9 2%]/60,XX,+mar[8%], which was for the first time described in cattle. No other chromosome abnormalities indicating chromosome instabilities, like chromatid breaks or gaps were identified, thus teratogenic agent exposure during pregnancy was excluded. The marker chromosome (mar) was small and it was not possible to identify its origin, however, sequential DAPI/C (4’,6-diamidino-2-phenylindole) band staining revealed a large block of constitutive heterochromatin, which is characteristic for centromeric regions of bovine autosomes. We suppose that the identified marker chromosome was a result of somatic deletion in an autosome and its presence could be responsible for the observed developmental malformations. In spite of the topographic distance among the affected organs, we expected a relationship between anatomical abnormalities. To the of our best knowledge, this is the first case of a mosaic karyotype with a cell line carrying a small marker chromosome described in a malformed calf.

Bifid cardiac apex in Pallister-Killian syndrome

Aim: Pallister-Killian syndrome (PKS) is a rare chromosomal disorder, caused by tissue-limited mosaicism for an isochromosome 12p. Prenatal diagnosis of PKS is generally incidental. Although clinical presentation of PKS varies, cytogenetic findings are constant, and include a tetrasomy of chromosome 12p. We report a case of prenatally diagnosed PKS with unique dysmorphic feature: bifid cardiac apex, a type of morphology that has not been documented before. Case presentation: Our patient was the 38-year-old pregnant woman who underwent amniocentesis. Cytogenetic analysis of amniotic fluid detected a mosaic karyotype with a supernumerary chromosome (SMC) in 64 % of fetal amniocytes. To determine the chromosomal origin of SMC, fluorescence in situ hybridization was performed and tetrasomy 12p was confirmed: mos 47,XY,+mar[18]/46,XY[10].ishi(12p)(8M16/SP6++,CEP12+,VIJyRM2196-). Ultrasound examination showed a fetus with cleft lip, echogenic focus in the left ventricle of the heart and shortened fetal long bones. After receiving a genetic counseling for PKS, the woman requested a termination of pregnancy. A postmortem inspection of the fetus revealed a complex heart anomaly that includes bifid cardiac apex and ventricular septal defect. Conclusions: This report expands the clinical manifestations of PKS with a unique feature of bifid cardiac apex, and highlights the targeted prenatal diagnosis of PKS if specific ultrasound markers are present.

Cytogenetic findings in Serbian patients with Klinefelter syndrome

Klinefelter syndrome (KS) describes the phenotype of the most common sex chromosome abnormality in humans (1/600 newborn males). The most widespread karyotype in affected patients is 47,XXY, but various others have been described. The aim of this study was to examine the karyotypes of a group of patients suspected of having Klinefelter's syndrome. Between January 1993 and April 2018 104 adult KS patients were evaluated. Cytogenetic analysis was carried out on metaphases obtained from phytohemagglutinin-stimulated peripheral lymphocytes using a standard procedure. Fluorescence in situ hybridization (FISH) analysis was performed on peripheral blood specimens. Vysis CEP X/Y- alpha satellite DNA probes were used to detect X and Y chromosomes. We identified KS presenting the ?standard? or 47,XXY karyotype in eighty three (80%) patients, while five (5%) KS patients showed the mosaic karyotype 47,XXY/46,XY and three (3%) patients had the mosaic karyotype 47,XXY/46,XX. In six (6%) cases KS patients with the ?standard? karyotype also had autosomal chromosomal abnormalities, while numerical sex chromosome abnormalities, with karyotypes 48,XXYY occurred in two (2%) subjects, 47,XYY in three (3%) and 47,XYY/46,XY in two (2%) individuals. Thus, most of our KS patients had the 'standard', 47,XXY karyotype, but some men formed a group of patients with a diversity of other karyotypes. These disparate chromosomal variants may have different physical and mental implications for the general symptomatology of KS. Therefore, it is important to determine the nature of the karyotype of every male with clinical characteristics of KS in very early childhood in order to initiate an adequate, personalized, medical approach.

Family case of mosaic variant of Turner syndrome with ring X chromosome

Представлен клинический случай синдрома Шерешевского-Тернера (СШТ) у матери и двух её дочерей. При стандартном цитогенетическом исследовании c использованием GTG-окрашивания у всех пациенток выявлен мозаичный кариотип с двумя клеточными линиями, один клон с Х моносомией (45,Х), другой - с наличием кольцевой Х-хромосомы 46,Х,r(Х)(p22.3q28). Методом флуоресцентной in situ гибридизации установлено, что в лимфоцитах периферической крови и в клетках буккального эпителия у всех пациенток присутствует мозаицизм Х/Х,r(Х). Количество клеток, содержащих кольцевую хромосому Х, в лимфоцитах пациенток сходно (8-11%), а в буккальном эпителии вариабельно (26-47%). Анализ инактивации Х-хромосомы (XCI), выполненный матери и ее старшей дочери, позволил установить, что кольцевая хромосома Х преимущественно инактивирована. Все три пациентки имеют схожий фенотип с характерными для СШТ признаками. Однако репродуктивная функция, по крайней мере, у матери и ее старшей дочери сохранена. Обсуждаются тканевая вариабельность гоносомного мозаицизма и семейные случаи СШТ с кольцевой хромосомой Х из литературы. The article presents a clinical case of Turner syndrome (TS) in a mother and her two daughters. Standard cytogenetic examination using by GTG-staining technique found mosaic karyotype with two cell lines, one clone with monosomy X (45,X) and other one with ring X-chromosome - 46,X,r(X)(p22.3q28). Fluorescent in situ hybridization revealed gonosomal mosaicism mos X/X,r(X) in peripheral blood lymphocytes and buccal epithelial cells in all patients. There number of cells containing ring X chromosome were similar in lymphocytes (8-11%), and were more varied in buccal epithelium (26-47%) between patients. Analysis of X chromosome inactivation (XCI), performed in the mother and her eldest daughter, revealed skewed inactivation of ring X chromosome. The patients had a similar phenotype signs characterized to Turner syndrome, but fertility was preserved at least in the mother and her eldest daughter. Reported in the literature familial TS cases with ring X chromosome are reviewed.

Clinical, cytogenetic, and molecular findings in a patient with ring chromosome 4: case report and literature review

Background Since 1969, 49 cases have been presented on ring chromosome 4. All of these cases have been characterized for the loss of genetic material. The genes located in these chromosomal regions are related to the phenotype. Case presentation A 10-year-old Ecuadorian Mestizo girl with ring chromosome 4 was clinically, cytogenetically and molecularly analysed. Clinical examination revealed congenital anomalies, including microcephaly, prominent nose, micrognathia, low set ears, bilateral clinodactyly of the fifth finger, small sacrococcygeal dimple, short stature and mental retardation. Cytogenetic studies showed a mosaic karyotype, mos 46,XX,r(4)(p16.3q35.2)/46,XX, with a ring chromosome 4 from 75 to 79% in three studies conducted over ten years. These results were confirmed by fluorescence in situ hybridization (FISH). Loss of 1.7 Mb and gain of 342 kb in 4p16.3 and loss of 3 Mb in 4q35.2 were identified by high-resolution mapping array. Conclusion Most cases with ring chromosome 4 have deletion of genetic material in terminal regions; however, our case has inv dup del rearrangement in the ring chromosome formation. Heterogeneous clinical features in all cases reviewed are related to the amount of genetic material lost or gained. The application of several techniques can increase our knowledge of ring chromosome 4 and its deviations from typical “ring syndrome.”

Turner Syndrome with Isochromosome Xq

Short stature and growth retardation in girls commonly occur in patients with Turner syndrome. We present a 19-year-old-girl with primary amenorrhea and growth retardation, who has a mosaic karyotype, 46X,i(Xq)[17]/45,X[8]. Classic Turner syndrome has a more severe phenotype than variant causes of Turner syndrome. We present a patient with 46,X,i(Xq) karyotype and compare the clinical and laboratory findings with the classic description of Turner syndrome. Our patient has normal social and psychomotor skills unlike previously reported cases in the literature. This case expands the phenotype–genotype description of Turner syndrome, which makes it an important contribution to the literature.

Correlation between Karyotype, Puberty Stage and Volume of Reproductive Organs in Turner Syndrome: The First Transrectal Sonography Study in Indonesia

Background: Turner syndrome is characterized by the absence of part of or the entire X chromosome in a woman, resulting in short stature, gonadal dysgenesis, and congenital anomaly. Based on karyotype, Turner syndrome is categorized as classical (45XO) and mosaic. The aim of this study is to evaluate the correlation of the karyotype with the puberty stage, volume of the uterus, and ovary in Turner syndrome’s adolescent with estrogen therapy. Methods: Analytic correlative cross-sectional study was done in Pediatric Endocrinology Outpatient Clinic at Cipto Mangunkusumo National Hospital since July to December 2018. Pubertal staging based on Tanner stage, uterine, and ovary volume were measured by transrectal sonography. Results: Of 21 study subjects, 8 were having classical karyotype and 13 were having mosaic karyotype in 12–21-year-old subjects. There was a significant correlation between karyotype and Tanner M stage (mammae stage) (p = 0.035). Breasts development in Turner syndrome with mosaic karyotype showed better development compared to classic karyotype. No significant correlation was found between karyotype and uterine and ovary volume in sonography transrectally. Conclusion: Karyotype correlates to mammae stage of Tanner but not in uterine and ovary volume in adolescents with Turner syndrome who underwent estrogen therapy.