Measurement of inferior facial angle and prefrontal space ratio in first trimester fetuses with aneuploidies: a retrospective study.

Objective To determine whether the measurement of inferior facial angle (IFA) and prefrontal space ratio (PFSR) in two-dimensional (2D) ultrasound images in the first trimester of pregnancy is reliable and to describe these markers in normal and aneuploid fetuses. Methods IFA and PFSR were measured in stored 2D midsagittal images of 200 normal and 140 aneuploid fetal profiles between 11 + 0 and 13 + 6 weeks of gestation. Limits of agreement (LOAs) and intraclass correlation coefficients (ICCs) for inter- and intraobserver differences were calculated. Results The mean IFA in normal fetuses was 76.5° ± 6.3. Between the two measurement rounds of the same observer, the LOAs were -5.4 to 7.1 (obs. 1) and 7.4 to 8.4 (obs. 2). For IFA measurements by the same observer the ICC was 0.88 (obs. 1) and for measurements by two different observers the ICC was 0.74. The mean PFSR was 0.76 ± 0.40 and the intraobserver LOAs were -0.372 to 0.395 (obs. 1) and -0.555 to 0.667 (obs. 2). For PFSR measurements by the same observer the ICC was 0.89 (obs. 1) and for measurements by two different observers the ICC was 0.65. Among aneuploid fetuses, IFA was below the normal range in one third of the cases with trisomy 18. PFSR was below the 95% prediction limit in 16.2% of fetuses with trisomy 21% and 17.9% of fetuses with trisomy 18. Conclusion IFA can be reliably measured in 2D ultrasound images in the first trimester of pregnancy with a high interobserver agreement and may provide information about retrognathia associated with various syndromes and aneuploidies at early stages of pregnancy.

Early 2D/3D ultrasound diagnosis of pleural effusion in fetuses with Turner syndrome.

Most guidelines on ultrasound examinations during pregnancy do not recommend routine early pregnancy scan in uncomplicated and asymptomatic pregnancies (ie, before 10 weeks based on last menstrual period). There is, however, a growing patient's expectation to have an early scan to confirm dating and verify the pregnancy is intrauterine and viable. We present three well-documented cases of patients who had an early (7-8 weeks) dating transvaginal scan revealing pleural effusion in the embryo. In all cases cytogenetic analysis confirmed monosomy for the X chromosome, consistent with a clinical diagnosis of Turner syndrome.

A CASE OF CONFINED PLACENTAL MOSAICISM WITH TRISOMY 15 ASSOCIATED WITH TURNER SYNDROME.

We here present a rare case of a Turner syndrome with mosaic trisomy 15 identified on chorionic villous sampling (CVS). Although there are several reports in the literature indicating confined placental mosaicism (CPM), counseling parents of a fetus with trisomy 15 mosaicism at CVS remains difficult because of the phenotypic variability. To illuminate that condition an amniocentesis or cord blood study should be offered in conjunction with genetic counseling.

Bicuspid aortic valve morphology and associated cardiovascular abnormalities in fetal Turner syndrome: a pathomorphological study.

INTRODUCTION: Bicuspid aortic valve (BAV) is common in Turner syndrome (TS). In adult TS, 82-95% of BAVs have fusion of the right and left coronary leaflets. Data in fetal stages are scarce. The purpose of this study was to gain insight into aortic valve morphology and associated cardiovascular abnormalities in a fetal TS cohort with adverse outcome early in development. MATERIAL AND METHODS: We studied post-mortem heart specimens of 36 TS fetuses and 1 TS newborn. RESULTS: BAV was present in 28 (76%) hearts. BAVs showed fusion of the right and left coronary leaflet (type 1 BAV) in 61%, and fusion of the right coronary and non-coronary leaflet (type 2 BAV) in 39%. There were no significant differences in occurrence of additional cardiovascular abnormalities between type 1 and type 2 BAV. However, all type 2 BAV hearts showed ascending aorta hypoplasia and tubular hypoplasia of the B segment, as opposed to only 55 and 64% of type 1 BAV hearts, respectively. DISCUSSION: The proportion of type 2 BAV seems higher in TS fetuses than in adults. Fetal type 2 BAV hearts all had severe aortic pathology, possibly contributing to a worse prognosis of type 2 than type 1 BAV in TS.

Association between increased yolk sac diameter and abnormal karyotypes.

AIMS: To investigate the association between increased yolk sac diameter and abnormal karyotype. METHODS: Retrospective analysis of 42 patients with no history of diabetes between 6 and 12 weeks of gestation with increased yolk sac diameter measuring ≥6 mm was evaluated by transvaginal ultrasound. Sonographic findings were correlated with karyotype. The Fisher's exact test and exact conditional logistic regression analysis were used for statistical analysis. RESULTS: Chromosome abnormalities were found in 76.2% of chorionic villi samples. A statistically significant relationship between karyotype and missed abortion was detected (P=0.001). None of the patients with a yolk size diameter ≥8 mm and viable pregnancy had a normal karyotype. Trisomy 15 or 16 was strongly associated with missed abortion (unadjusted odds ratio=14.97, P=0.01). Nine patients with viable pregnancy had a yolk sac ≥6 mm (six patients with normal karyotype, one patient with monosomy X, one patient with trisomy 16, and one patient with trisomy 21). CONCLUSION: Our data indicate that enlarged yolk sac may also be visualized in viable pregnancies. Patients with an enlarged yolk sac and normal karyotype require detailed ultrasound evaluation in the second and third trimester.

Laboratory guideline for Turner syndrome.

Turner syndrome is a disorder that has distinct clinical features and has karyotypic aberrations with loss of critical regions of the X chromosome. Several clinical guidelines on the diagnosis and management of patients with Turner syndrome have been published, but there is relatively little on the laboratory aspects associated with this disorder. This disease-specific laboratory guideline provides laboratory guidance for the diagnosis/study of patients with Turner syndrome and its variants. Because the diagnosis of Turner syndrome involves both a clinical and laboratory component, both sets of guidelines are required for the provision of optimal care for patients with Turner syndrome.

Early detection (9+6 weeks) of cardiac failure in a fetus diagnosed as Turner syndrome by 2D transvaginal ultrasound-guided coelocentesis.

A 28-year-old woman was diagnosed by transvaginal ultrasound at 9+6 weeks with early fetal cardiac failure (hydrothorax and bradycardia). Doppler analysis of ductus venosus showed a negative A-wave pattern. The follow-up sonogram obtained at 11+6 weeks documented a missed abortion. A transvaginal ultrasound-guided coelocentesis was performed under local cervical anesthesia before uterine suction and 8 mL of clear extracoelomic fluid were successfully aspirated. Cytogenetic analysis demonstrated a 45,X karyotype. Ultrasound and Doppler waveform analysis of ductus venosus allowed early diagnosis of fetal cardiac failure. Coelocentesis may be the method of choice for early fetal karyotyping and may be used in the future to induce immunologic tolerance.

Studying early lethality of 45,XO (Turner's syndrome) embryos using human embryonic stem cells.

Turner's syndrome (caused by monosomy of chromosome X) is one of the most common chromosomal abnormalities in females. Although 3% of all pregnancies start with XO embryos, 99% of these pregnancies terminate spontaneously during the first trimester. The common genetic explanation for the early lethality of monosomy X embryos, as well as the phenotype of surviving individuals is haploinsufficiency of pseudoautosomal genes on the X chromosome. Another possible mechanism is null expression of imprinted genes on the X chromosome due to the loss of the expressed allele. In contrast to humans, XO mice are viable, and fertile. Thus, neither cells from patients nor mouse models can be used in order to study the cause of early lethality in XO embryos. Human embryonic stem cells (HESCs) can differentiate in culture into cells from the three embryonic germ layers as well as into extraembryonic cells. These cells have been shown to have great value in modeling human developmental genetic disorders. In order to study the reasons for the early lethality of 45,XO embryos we have isolated HESCs that have spontaneously lost one of their sex chromosomes. To examine the possibility that imprinted genes on the X chromosome play a role in the phenotype of XO embryos, we have identified genes that were no longer expressed in the mutant cells. None of these genes showed a monoallelic expression in XX cells, implying that imprinting is not playing a major role in the phenotype of XO embryos. To suggest an explanation for the embryonic lethality caused by monosomy X, we have differentiated the XO HESCs in vitro an in vivo. DNA microarray analysis of the differentiated cells enabled us to compare the expression of tissue specific genes in XO and XX cells. The tissue that showed the most significant differences between the clones was the placenta. Many placental genes are expressed at much higher levels in XX cells in compare to XO cells. Thus, we suggest that abnormal placental differentiation as a result of haploinsufficiency of X-linked pseudoautosomal genes causes the early lethality in XO human embryos.

Morphology studies of the human fetal cochlea in turner syndrome.

OBJECTIVES: Turner syndrome (TS) is the most frequent sex chromosome abnormality, and sensorineural hearing loss is common. We aimed to determine whether there are consistent morphologic cochlear abnormalities during gestational development that could be associated with TS. DESIGN: The histology of nine fetal temporal bones of TS autopsied after spontaneous abortion was studied. RESULTS: Gross morphologic examination of the TS cochleae failed to reveal a pattern of structural abnormalities that would explain the development of sensorineural hearing loss. Mondini-like cochlear dysplasia was observed in one 13-wk-old TS fetus. CONCLUSION: We could not demonstrate a consistent pattern of cochlear malformations.

Jugular lymphatic maldevelopment in Turner syndrome and trisomy 21: different anomalies leading to nuchal edema.

Increased nuchal translucency (NT), morphologically known as nuchal edema, is an ultrasound marker for aneuploidy. Turner syndrome presents with massive NT, called cystic hygroma. Conflicting data exist as to whether cystic hygroma and increased NT are different entities. Both are associated with jugular lymphatic distension. The authors investigated jugular lymphatics of trisomy 21, Turner syndrome, and normal karyotype fetuses. Fetuses were investigated using immunohistochemistry for blood vascular, lymphatic, and smooth muscle cell markers. Trisomy 21 fetuses showed nuchal cavities within the mesenchymal edema negative for endothelial markers. These were extremely large in Turner fetuses, showing similar characteristics. The skin showed numerous dilated lymphatics in the case of trisomy 21 and scanty small lymphatics in Turner fetuses. A jugular lymphatic sac was present in control and trisomy 21 fetuses and was enlarged in trisomy 21 cases. In Turner fetuses, no jugular lymphatic sac was observed. Nuchal edema in trisomy 21 and Turner syndrome appears to be a similar entity caused by different lymphatic abnormalities.

Wnt pathway anomalies in developing amygdalae of Turner syndrome-like mice.

Certain neurobehavioral deficiencies associated with Turner Syndrome have been attributed to brain volumetric abnormalities, particularly of the amygdala. Haplo-insufficiency of a non-dosage compensated gene or genes on the X chromosome has been hypothesized to be the cause of the neuroanatomical defect. We examined gene expression levels of 6,628 genes in developing amygdalae of late-stage embryos of a mouse model for Turner Syndrome. In total, 161 genes show significant differences in expression level between TS and normal female amygdala. In silico pathway analysis of both X-linked and autosomal mis-regulated genes suggests that modulation of Wnt signaling is a critical factor in the normal growth and development of the amygdala.

Gastroschisis with fetal chromosomal abnormality: a case report.

Gastroschisis is a rare anomaly and it is usually not associated with other syndromic or nonsyndromic anomalies. The first case of gastroschisis with aneuploidy (Turner syndrome) is presented. A fetal huge cystic hygroma was diagnosed by prenatal sonography at 12 weeks of pregnancy and chorionic villi sampling (CVS) was performed. Cytogenetic analysis revealed 45, X0. The pregnancy was terminated by induction of labor at 16 weeks of pregnancy. The female fetus had a big membrane of cystic hygroma surrounding the fetal neck. Additionally, a full abdominal thickness defect with multiple loops of bowel outside the abdomen, which could not be diagnosed on prenatal ultrasound scan, was detected on postnatal examination.

Fetal trunk and head volume in chromosomally abnormal fetuses at 11+0 to 13+6 weeks of gestation.

OBJECTIVE: To examine the pattern of growth in chromosomally abnormal fetuses at 11+0 to 13+6 weeks of gestation and compare the trunk and head volume to crown-rump length (CRL) in defining the growth deficit in such fetuses. METHODS: The fetal trunk and head volume was measured using three-dimensional (3D) ultrasound in 140 chromosomally abnormal fetuses at 11+0 to 13+6 (median 12) weeks of gestation, and the values were compared to 500 chromosomally normal fetuses. In each chromosomally abnormal fetus, the observed fetal trunk and head volume was subtracted from the expected mean (delta value) of the chromosomally normal fetuses of the same gestational age, and this difference was expressed as a percentage of the appropriate normal mean. The Mann-Whitney U-test was used to determine the significance of differences between the chromosomally normal and abnormal groups. RESULTS: In trisomy 21 (n=72) and Turner syndrome (n=14) fetuses, compared to chromosomally normal fetuses, the CRL for gestation was similar (P=0.335 and P=0.317, respectively), but the fetal trunk and head volume was about 10-15% lower (P<0.001 and P=0.004, respectively). In trisomy 18 (n=29), trisomy 13 (n=14) and triploidy (n=11), the deficit in volume was about 45% (P<0.001), whereas the deficit in CRL was less than 15% (P<0.001). CONCLUSIONS: In the quantification of the degree of early growth impairment in chromosomally abnormal fetuses, measurement of the fetal trunk and head volume using 3D ultrasound may be better than measurement of CRL.

Number of ovarian follicles in human fetuses with the 45,X karyotype.

OBJECTIVE: To evaluate the numbers of ovarian follicles during fetal life in the gonads of human female fetuses with the 45,X karyotype (Turner syndrome, TS) and to compare them with those from age-matched 46,XX fetuses. DESIGN: Retrospective study. SETTING: An academic hospital. PATIENT(S): Ovarian samples from TS fetuses (aged 17-37 weeks), mainly obtained after induced abortion, and ovaries from eight control fetuses (matching gestational ages). INTERVENTION(S): Embedded blocks of ovaries were collected from anatomy-pathology departments of three university hospitals and were sectioned and stained with hematoxylin-eosin. MAIN OUTCOME MEASURE(S): Observation of primordial and growing follicles. RESULT(S): In the fetal ovaries of controls, numerous oogonia were observed at 18 weeks. Primordial follicles were present in all ovaries from 20 weeks' gestation onward, whereas preantral and antral follicles were observed from 26 weeks onwards. In ovaries from 45,X TS fetuses, oogonia were observed in some ovaries, but no primordial, preantral, or antral follicles were found, even in ovaries from the third trimester of gestation. CONCLUSION(S): Follicle formation and growth are severely reduced in ovaries from aborted 45,X TS fetuses.

Turner's syndrome in fetal life.

OBJECTIVE: To compare the incidence and type of heart disease found in association with 45X karyotype in fetal life with postnatal life and to examine the outcome after fetal diagnosis. METHODS: Fifty-three fetuses with a 45X karyotype were examined echocardiographically over a 4-year period between 1999 and 2002. Of these, 47 were referred because of increased nuchal translucency (NT). RESULTS: A cardiac abnormality was detected in 33/53 (62.2%) fetuses. The most common diagnosis was coarctation of the aorta in 24/53 (45.3%) fetuses, followed by the hypoplastic left heart syndrome (HLHS) in 7/53 (13.2%) fetuses. The mean NT was significantly higher in fetuses with a heart defect than in those with normal echocardiography. Termination of pregnancy was carried out in 45/53 (84.9%) fetuses and intrauterine death occurred in six cases. Two of four fetuses with a mosaic karyotype are currently alive. CONCLUSION: Turner's syndrome is associated with a higher incidence of heart defects detected prenatally when compared to postnatal reports. The commonest associated heart defects detected prenatally are HLHS and coarctation of the aorta, in contrast to postnatal life where a bicuspid aortic valve is the most common diagnosis. The typical intrauterine presentation of Turner's syndrome with a markedly increased NT or with hydrops and with a typical 45X karyotype has an extremely poor prognosis for intrauterine survival.

A characteristic cluster of fetal sonographic markers that are predictive of fetal Turner syndrome in early pregnancy.

OBJECTIVE: The purpose of this study was to describe a characteristic cluster of sonographic features of fetuses with Turner syndrome in early pregnancy. STUDY DESIGN: A targeted transvaginal ultrasound examination of all fetal organs was performed for 40123 consecutive pregnant women at 14 to 16 weeks of gestation. Both low- and high-risk pregnancies were included. Fetal karyotyping was performed in 9348 cases. The main indications were major fetal anomalies, advanced maternal age, abnormal biochemical markers, maternal anxiety, and request. RESULTS: Turner syndrome was detected in 13 fetuses (0.03%, 1/3086 early pregnancies). Huge septated cystic hygroma, severe subcutaneous edema, and hydrops were observed in all cases. A short femur was detected in 12 of 13 fetuses. A narrow aortic arch was visualized in all 8 fetuses who were scanned after 1995, when scanning of the aortic arch became mandatory in our institution. Four other fetuses had three or four of the five markers, 2 of the fetuses had trisomy 21, 1 fetus was normal, and one case of missed abortion occurred without a karyotype. CONCLUSION: A reliable diagnosis of Turner syndrome by sonographic means is possible in early pregnancy.

The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator.

Functional impairment of the human homeobox gene SHOX causes short stature and Madelung deformity in Leri-Weill syndrome (LWS) and has recently been implicated in additional skeletal malformations frequently observed in Turner syndrome. To enhance our understanding of the underlying mechanism of action, we have established a cell culture model consisting of four stably transfected cell lines and analysed the functional properties of the SHOX protein on a molecular level. Results show that the SHOX-encoded protein is located exclusively within the nucleus of a variety of cell lines, including U2Os, HEK293, COS7 and NIH 3T3 cells. In contrast to this cell-type independent nuclear translocation, the transactivating potential of the SHOX protein on different luciferase reporter constructs was observed only in the osteogenic cell line U2Os. Since C-terminally truncated forms of SHOX lead to LWS and idiopathic short stature, we have compared the activity of wild-type and truncated SHOX proteins. Interestingly, C-terminally truncated SHOX proteins are inactive with regards to target gene activation. These results for the first time provide an explanation of SHOX-related phenotypes on a molecular level and suggest the existence of qualitative trait loci modulating SHOX activity in a cell-type specific manner.

Estrogen receptors in the normal adult and developing human inner ear and in Turner's syndrome.

The influence of estrogens, the female sex hormone, on the ear and hearing is yet not fully investigated, though some studies have suggested that estrogens may influence hearing functions. The presence of estrogen receptors alpha and beta has earlier been shown in the inner ear of mice and rats. The aim of this study was to map possible estrogen receptors in the human inner ear. Inner ear tissue from human adults, aborted human normal fetuses and fetuses with Turner's syndrome were collected. Paraffin embedded sections of adult and fetal inner ears were immunostained with antibodies against estrogen receptors alpha and beta. Estrogen receptor alpha containing cells were found in the adult human inner ear only in the spiral ganglion, and estrogen receptor beta in the stria vascularis solely. The human fetal inner ear tissue from both normal and Turner fetuses showed a very weak staining of estrogen receptor alpha in the spiral ganglion cells, but no specific labeling of the Kölliker's organ of Corti at 13, 14 and 18 weeks of age. No staining of estrogen receptor beta was seen in the fetal inner ear.