Additional Structural Abnormalities Research Articles

8138 Pituitary Stalk Interruption Syndrome (PSIS) in a patient with Isolated Hypogonadotropic Hypogonadism

Abstract Disclosure: A. Thomson: None. R. Osman: None. Pituitary Stalk Interruption Syndrome in a Patient with Isolated Hypogonadotropic Hypogonadism Pituitary Stalk Interruption syndrome (PSIS) is a rare cause of hypopituitarism, characterized by a radiologic constellation of thin or interrupted pituitary stalk, hypoplasia, or aplasia of the anterior lobe and with the presence of an ectopic posterior pituitary (EPP). It is most commonly associated with isolated growth hormone deficiency (IGHD) and is often diagnosed in childhood. We present one case of a patient with isolated hypogonadotropic hypogonadism in adulthood, subsequently found to have an PSIS on MRI. A 45 year old male patient presented to our clinic with hypogonadism. He gradually started developing decreasing libido, fatigue, and loss of erections. He had normal puberty and childhood growth, and has fathered one child. He denied history of anosmia or visual symptoms. Subsequent hormonal testing showed: morning Total Testosterone: 145 ng/dl (normal 264-916 ng/dl), Free testosterone 1.5 pg/ml (normal 6.8-21.5 pg/ml), LH 1.1 mIU/ml (normal 1.7-8.6 mIU/ml) and FSH of 3.6 mIU/ml (normal 1.5-12.4 mIU/ml). Prolactin was minimally elevated at 21 ng/ml (normal 4.0 - 15.2 ng/ml). Thyroid, IGF-1, cortisol, and ferritin levels were within normal limits. Repeat levels showed similar findings. He denied ever taking any form of exogenous testosterone. His pituitary MRI revealed a small volume of anterior pituitary tissue, measuring 0.2cm x 0.7cm x 0.7cm, without discrete pituitary adenoma, a hypoplastic midline stalk measuring 1.3 mm in AP diameter (nl 2-3 mm), with a T1 hyperintense nodularity measuring 0.6cm x 0.4cm along the posterior aspect of the sella turcica consistent with EPP. No additional structural abnormality or any mass lesions were identified. He was subsequently started on replacement testosterone therapy and his symptoms resolved. PSIS usually presents in childhood with IGHD. Patients may have other pituitary hormone deficiencies and congenital central nervous system defects, although panhypopituitarism is rare. There have been reports in children with delayed puberty and isolated hypogonadotropic hypogonadism who have been found to have PSIS. Only one othercase of an adult female patient exhibiting hypogonadotropic hypogonadism as the only manifestation of PSIS has been documented in the literature. Our case highlights the potential for an adult male to present later in life with hypogonadotropic hypogonadism as a manifestation of PSIS. The marginally elevated prolactin level may be due to lack of inhibition of hypothalamic dopamine on lactotroph cells within the pituitary caused by the EPP, although it is doubtful that this has clinical significance. This is a rare presentation of PSIS, clinicians should be mindful ofthis radiological constellation and the potential for isolated hypogonadotropic hypogonadism presenting unusually in the adulthood. Presentation: 6/3/2024

Fetal Cystic Lymphatic Malformations: Systematic Review on Pregnancy and Neonatal Outcomes.

Evaluate pregnancy and neonatal outcomes with fetal cystic lymphatic malformations (LMs), excluding those arising from the posterior neck, to facilitate patient counseling. A systematic review was performed in accordance with PRISMA guidance. Case series and case reports published between 2000 and 2022 were included. Sixty-five studies (96 fetuses) met the inclusion criteria. The average gestational age at diagnosis was 25.5 weeks with the commonest location being the anterior neck (28%). All patients were diagnosed with LM using two-dimensional (2D) ultrasound. Prenatal progression in LM size, presence of intralesional bleeding, or fetal hydrops occurred in 70% (41/59), 9% (5/59), and 3% (2/59), respectively. Chromosomal and structural abnormalities were reported in 4% (2/52) and 2% (2/96), respectively. Overall livebirth rate was 94% (79/84); 12/96 resulted in termination and 5/84 in in utero demise. The average gestational age of delivery was 37.7 weeks. Exactly 19% (15/79) had a vaginal birth, of which shoulder dystocia occurred in one infant. Ex utero intrapartum treatment (EXIT) procedure was performed in 13% (10/79). Postnatal treatment commonly involved surgical excision 38% (30/79), sclerotherapy in 21.5% (17/79), or combination of both in 11.4% (9/79). Of those with reported follow-up, 4 died within 1 year, 1 developed heart failure at 2 years of life, and the remaining 44 had normal developmental outcomes. Fetal cystic LMs, excluding those in the posterior neck, are not commonly associated with chromosomal, or additional structural abnormalities. They usually increase in size before delivery with only a minority developing complications. The good developmental outcome was reported in all survivors.

A Multicenter Cross-Sectional Study of the Swiss Cohort of LAMA2-Related Muscular Dystrophy.

LAMA2-related muscular dystrophy (LAMA2-RD) is an autosomal-recessive disorder and one of the most common congenital muscular dystrophies. Due to promising therapies in preclinical development, there is an increasing effort to better define the epidemiology and natural history of this disease. The present study aimed to describe a well-characterized baseline cohort of patients with LAMA2-RD in Switzerland. The study used data collected by the Swiss Registry for Neuromuscular Disorders (Swiss-Reg-NMD). Diagnostic findings were derived from genetics, muscle biopsy, creatine kinase-level and electrophysiological testing, as well as from brain MRIs. Further clinical information included motor assessments (CHOP INTEND, MFM20/32), joint contractures, scoliosis, ophthalmoplegia, weight gain, feeding difficulties, respiratory function, cardiac investigations, EEG findings, IQ and schooling. Eighteen patients with LAMA-RD were included in the Swiss-Reg-NMD as of May 2023 (age at inclusion into the registry: median age 8.7 years, range 1 month - 31 years F = 8, M = 10). Fourteen patients presented with the severe form of LAMA2-RD (were never able to walk; CMD), whereas four patients presented with the milder form (present or lost walking capability; LGMD). All patients classified as CMD had symptoms before 12 months of age and 11/14 before the age of six months. 15 carried homozygous or compound heterozygous pathogenic or likely pathogenic variants in LAMA2 and two were homozygous for a variant of unknown significance (one patient unknown). Brain MRI was available for 14 patients, 13 had white matter changes and 11 had additional structural abnormalities, including cobblestone malformations, pontine hypoplasia and an enlarged tegmento-vermial angle not reported before. This study describes the Swiss cohort of patients with LAMA2-RD and gives insights into measuring disease severity and disease progression, which is important for future clinical trials, as well as for a better clinical understanding and management of patients with LAMA2-RD.

Omphalocele with umbilical cord cyst and mesomelia: A case report

Omphalocele is a rare congenital abdominal wall defect with a reported prevalence of 3.38 per 10,000 pregnancies. It is associated commonly with chromosomal abnormalities (10%–30%) and additional structural abnormalities (55%–58%). Trisomy 13 and 18 are most commonly associated with aneuploidies, which are also associated with umbilical cord cysts and mesomelia.

Prenatal diagnosis of microcephaly through combined MRI and ultrasonography: Analysis of a case series.

Intrauterine microcephaly is a complex and lifelong condition that poses significant ethical challenges for clinicians and parents. The prognosis of microcephaly is highly variable and depends on the underlying cause and severity. In addition, microcephaly is often associated with various comorbidities, including intellectual disability, developmental delay, and epilepsy. Ultrasonography (US) is currently the most commonly used imaging modality for detecting microcephaly in the second trimester of pregnancy. However, antenatal brain magnetic resonance imaging (MRI) is increasingly being used as a more sensitive tool to identify structural abnormalities that may suggest a specific diagnosis. In this study, we report a case series of microcephaly diagnosed through the combination of MRI and US. How to utilize a combination of MRI and US to screen for fetal microcephaly. Based on the results of US and MRI examinations, patient 1 was found to have other craniocerebral malformations, patient 2 demonstrated macrogyria, and patient 3 exhibited skull irregularities. The pregnancies of all 3 patients were terminated through the induction of labor by injecting Rivanol into the amniotic cavity. The 3 patients were discharged after a period of observation. US is an important tool for diagnosing fetal microcephaly. However, MRI can overcome the limitations of US and detect additional brain structural abnormalities, thereby providing more specific and valuable prenatal diagnostic information. Therefore, combining MRI and US has significant diagnostic value for fetal microcephaly.

Clinical, Cytogenetic and Immunophenotypic Spectra of Post-Transplant Relapse Following Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome

Introduction Allogeneic hematopoietic stem cell transplantation (HCT) is a curative therapy used to treat myelodysplastic syndrome (MDS). Relapse post-HCT confers poor outcomes and subsequent therapy is not standardized. Like acute myeloid leukemia (AML), several mechanisms are known to be involved in post-HCT relapse including clonal evolution in favor of chemotherapy-resistant clones and tumor immune escape. Systemic reviews are scarce in the MDS post-HCT relapse population. Accordingly, the present study aimed to investigate clinical, cytogenetic, and immunophenotypic (IP) spectra for MDS post-HCT relapse patients (pts), along with subsequent therapies, and clinical outcomes following post-HCT relapse. Patients and methods A retrospective study was conducted and found that 231 MDS pts received HCT between April 2010 and September 2022 at the Princess Margaret Cancer Centre (PMCC). The primary endpoint was overall survival (OS) following post-HCT relapse. Secondary endpoints explored time to relapse (TTR), relapse presentation (i.e., MDS or AML), clonal evolution (i.e., changes in cytogenetics or IP profiles), and therapeutic strategies delivered after relapse. Results Of the 231 MDS pts treated with HCT, 52 (23%) relapsed in a median of 4.5 months (range 0.9-59.8 months). Twenty-five (48%) pts relapsed with MDS (i.e., blast <20%), while 27 (52%) relapsed with AML (i.e., blast ≥20%) in the marrow. Fifteen (65%) pts showed cytogenetic changes at the time of post-HCT relapse. Eleven (48%) of which presented with more aggressive findings (i.e., additional structural abnormalities and monosomal karyotype). Ten of 17 (59%) pts presented with changes in their IP profile at post-HCT relapse, 7 (70%) of which relapsed with AML. Combined these findings give evidence of clonal evolution in favor of more aggressive malignant clones that are often responsible for post-HCT relapse. Treatment with hypomethylating agents (HMA) alone or in combination after post-HCT relapse increased OS to 5.6 months in comparison to those not receiving HMA of whom OS was 1.4 months (p=0.0003). Stratified by disease presentation cytogenetic clonal evolution was seen in 6/12 (50%) of the post-HCT MDS relapses, and 9/11 (82%) of the post-HCT AML relapses. Cytogenetic abnormalities at diagnosis and post-HCT relapse, respectively included in descending order: structural abnormalities (n=14/23, 61%; n=20/23, 87%), complex karyotype (n=12/23, 52%; 17/23, 74%), -5/del(5q) (n=11/23, 48%; n=10/23, 43%), -7/del(7q) (n=8/23, 35%; n=11/23, 48%), monosomy karyotype (n=8/23, 35%; n=11/23, 48%), -17 (n=3/23, 13%; n=5/23, 22%), der(5)/t(5;17) (n=2/23, 9%; n=5/23, 22%), -20 (n=2/23, 9%; n=3/23, 13%), and inv(3) (n=1/23, 4%, n=2/23, 9%). Seventeen pts had paired IP profiles available both prior to HCT and at post-HCT relapse, of which 10 (59%) had profile changes of at least 1 antigen. Seven of 10 (70%) pts that relapsed with AML post-HCT had IP expression changes, compared to 3/7 (42.9%) pts that relapsed with MDS post-HCT. Summarized IP findings include reduced expression of CD7 (n=2/6, 33%), altered expression of CD34 (n=3/15, 20%), altered expression of CD117 (n=3/14, 21%), and reduced expression of HLA DR (n=4/15, 27%). The presence of IP expression changes at post-HCT relapse suggests evidence of clonal evolution or immune escape as the mechanism behind the relapsed disease. Overall survival duration was 3.97 months; the 12-month OS rate was 20.0% (10.0-32.5%). Post-HCT relapse treatments included hypomethylating agents (HMA; n=13/46, 28%), HMA with donor lymphocyte infusion (DLI; n= 7/46, 15%), HMA with Venetoclax (VEN; n=7/46, 15%), chemotherapy (n=9/46, 19%), best supportive care (8/46, 17%) and second HCT (n=2/46, 4%). Patients that received HMA with or without DLI or VEN had a longer survival duration of 5.6 months (95% CI [3.4-13.2 months]) compared to those not receiving HMA 1.4 months (95% CI [0.6-0.39 months, p=0.0003]). The 12-month survival rate was also significantly in favor of pts that received HMA following post-HCT relapse (35.3% [95% CI 17.2-54.0%] vs 4.3% [95% CI 0.3-18.0%]). Conclusion Patients with MDS undergoing HCT may relapse with either MDS or AML. The relapsed disease often shows evidence of clonal evolution in its immunophenotype and/or cytogenetic profile toward a more aggressive disease. Approaches to post-HCT relapse remain heterogenous but HMA is beneficial.

The Investigation of Cerebroplacental Ratio and Some Cranial Biometric Measurements in Fetuses with Isolated Congenital Heart Disease

Objective: In this study, we aimed to compare the measurements of some fetal cranial structures and Doppler parameters between the groups with congenital heart disease and healthy pregnant women. Materials and Methods: The study included 30 patients with intrauterine congenital heart disease and 30 healthy pregnant women. Fetuses with additional structural and genetic abnormalities were excluded from the study. In both groups, biparietal diameter (BPD), head circumference (HC), transcerebellar diameter (TCD), middle cerebral artery pulsatility index (MCA-PI), umbilical artery pulsatility index (UA-PI), umbilical artery resistance index (UA-RI), and umbilical artery systole/diastole ratio (UA S/D), as well as superior-inferior diameter of the cavum septum pellucidum (CSP) were measured by ultrasound. The cerebroplacental ratio (CPR), which is an indicator of the protective effect on the brain, was calculated. Data were statistically compared between the two groups, and P < 0.05 was considered statistically significant. Results: A statistically significant difference was found between the groups in UA-RI and UA S/D values. The UA-RI and UA S/D values were significantly higher in the patient group than in the control group (P=0.048; P < 0.001). HC values were lower in the congenital heart disease group, and this result was statistically significant (P=0.047). There was no statistically significant difference between groups in BPD, HC, and TCD Z-scores. There was no statistically significant difference between groups in MCA-PI < 5th percentile, UA-PI > 95th percentile, and CPR < 1 scores. Conclusion: Congenital heart disease may cause chronic fetal hypoxia during the intrauterine process and lead to changes in the fetomaternal circulation. This study suggests that there may be relationships between fetal cranial biometric retardation and cerebral perfusion changes.

Should Prenatal Chromosomal Microarray Analysis Be Offered for Pulmonary Atresia? A Single-Center Retrospective Study in China.

(1) Objective: To evaluate the application of chromosomal microarray analysis (CMA) in fetuses with pulmonary atresia (PA) and to explore the risk factors for predicting chromosomal imbalances and adverse perinatal outcomes. (2) Methods: This study investigated 428 cases of PA singleton pregnancies that were tested using CMA and quantitative fluorescent polymerase chain reaction (QF-PCR) as first-line genetic testing. The PA cases were divided into two groups: an isolated group and a non-isolated group. (3) Results: CMA revealed clinically relevant copy number variations (CNVs) in 9/139 (6.47%) PA fetuses, i.e., pathogenic copy number variations (pCNVs) in 8/139 (5.76%) fetuses and likely pathogenic CNVs in 1/139 (0.72%) fetuses. Stratified analysis showed that the incidence of clinically significant variants was higher in non-isolated PA fetuses than in isolated PA fetuses (12.50%, 6/48 vs. 3.30%, 3/91, p = 0.036). Regression analysis showed that a combination of other structural abnormalities at diagnosis of PA represented the principal risk factor for chromosomal imbalances (OR = 2.672). A combination of other structural abnormalities and a high maternal age increased the risk of adverse pregnancy outcomes in PA cases, including intrauterine fetal death (IUFD), termination of pregnancy (TOP), and preterm delivery. (4) Conclusions: The value of CMA for locating imbalanced genetic variations in fetuses with PA was highlighted by this study, particularly when combined with additional structural abnormalities.

Severe fetal ventriculomegaly: Fetal morbidity and mortality, caesarean delivery rates and obstetrical challenges in a large prospective cohort.

Severe fetal ventriculomegaly (VM) is defined as an enlargement of the atria of the lateral cerebral ventricles (Vp) of greater than 15mm. While it is well established that it confers significant risk of morbidity and mortality to the neonate, there is limited information pertaining to the caesarean delivery rates and the obstetric management of these complex cases. The aim of this study was twofold: firstly, to determine survival rates in fetuses with severe VM, and secondly to determine the caesarean delivery rates in continuing pregnancies. We explore the obstetric challenges associated with these difficult cases. This was a prospective observational study of patients with antenatal severe VM, attending the Department of Fetal Medicine, National Maternity Hospital, Dublin, Ireland, from 1st January 2011 to 31st July 2020. Data were obtained from the hospital database and those with severe VM (Vp>15mm) were identified. The rates of chromosomal abnormalities, the survival rates and the caesarean delivery (CD) rates for the overall group were then determined. The data were then further sub-divided into two groups: 1. Vp<20mm and 2. Vp>20mm, and the results compared. Statistical analysis was performed using the Chi-Square test. A total of N=95 pregnancies with severe VM were included for analysis, of which additional structural abnormalities on ultrasound were apparent in 67/95 (70.5%) and 28/95 (29.5%) had isolated severe VM. Chromosomal abnormalities were diagnosed in 15/95 (15.8%) of cases, with (2/28) 7.1% in the isolated SVM group versus (13/67) 19.4% in the non-isolated SVM group. The overall survival rate (excluding TOP) was 53/74 (71.6%), with 20/23 (86.9%) in the isolated SVM group. The overall CD rate was 47/72 (65.3%), which was significantly higher than the CD for the hospital during the same time period of 25.4% (P<0.01). The data were subdivided into Vp<20 and Vp>20 and those with a Vp>20 had higher rates of additional intracranial findings on ultrasound (Vp<20 13/41 (31.7%) versus Vp>20 32/54 (59.3%) (P<0.05)) and macrocrania (Vp<20 14/41 (34.1%) versus Vp>20 35/54 (64.8%) (P<0.05)). No significant difference was observed in the overall survival or CD rates between the two groups. In conclusion this study reports significant fetal morbidity and mortality with severe VM with high CD rates observed in this cohort. Significant challenges exist in relation to the obstetric management and counseling of parents regarding an often uncertain neonatal prognosis. In continuing pregnancies with significant macrocrania delivery plans should be individualized to improve neonatal outcomes where possible and minimize harm to the mother.

VP48.02: Factors precluding open fetal surgery for spina bifida repair in Mexico

To assess factors precluding open fetal surgery in pregnancies with prenatal diagnosis of open spina bifida (OSB). From October 2015 to January 2021, a prospective cohort of pregnancies with prenatal diagnosis of OSB selected for intrauterine OSB repair in our national referral fetal surgery centre at Queretaro, Mexico was constructed. All exclusion criteria for fetal surgery were analysed. During the study period, 236 OSB cases were evaluated, 75 (31.7%) underwent open fetal surgery and 161 fetuses were excluded. Within the population excluded for fetal surgery, 39.75% (64/161) were diagnosed or referred beyond 28 weeks of gestation, 35.40% (57/161) showed additional structural or chromosomal abnormalities, 13.66% (22/161) refused fetal intervention, 4.99% (8/161) did not show Chiari II Malformation, 1.24% (2/161) showed maternal medical contraindications for surgery, 1.24% (2/161) procedures were abandoned before performing maternal laparotomy due to anaphylactic shock, 1.24% (2/161) showed short cervical length (< 25mm), 1.24% (2/161) were twin pregnancies, and 1.24% (2/161) the diagnosis was not confirmed. In pregnancies complicated with OSB late prenatal diagnosis is the main factor precluding fetal surgery. This finding highlights the need to improve strategies to enhance access to advanced fetal evaluations in Mexico which will allow an accurate diagnosis and early referral to fetal surgery centres.

Fetal exome sequencing for isolated increased nuchal translucency: should we be doing it?

ObjectiveTo evaluate the utility of prenatal exome sequencing (ES) for isolated increased nuchal translucency (NT) and to investigate factors that increase diagnostic yield.DesignRetrospective analysis of data from two prospective cohort studies.SettingFetal medicine centres in the UK and USA.PopulationFetuses with increased NT ≥3.5 mm at 11–14 weeks of gestation recruited to the Prenatal Assessment of Genomes and Exomes (PAGE) and Columbia fetal whole exome sequencing studies (n = 213).MethodsWe grouped cases based on (1) the presence of additional structural abnormalities at presentation in the first trimester or later in pregnancy, and (2) NT measurement at presentation. We compared diagnostic rates between groups using Fisher exact test.Main outcome measuresDetection of diagnostic genetic variants considered to have caused the observed fetal structural anomaly.ResultsDiagnostic variants were detected in 12 (22.2%) of 54 fetuses presenting with non‐isolated increased NT, 12 (32.4%) of 37 fetuses with isolated increased NT in the first trimester and additional abnormalities later in pregnancy, and 2 (1.8%) of 111 fetuses with isolated increased NT in the first trimester and no other abnormalities on subsequent scans. Diagnostic rate also increased with increasing size of NT.ConclusionsThe diagnostic yield of prenatal ES is low for fetuses with isolated increased NT but significantly higher where there are additional structural anomalies. Prenatal ES may not be appropriate for truly isolated increased NT but timely, careful ultrasound scanning to identify other anomalies emerging later can direct testing to focus where there is a higher likelihood of diagnosis.

430 Prenatal findings and associated survival rates in fetal ventriculomegaly: a prospective observational study

The aim was to present the antenatal experience of fetal ventriculomegaly in a large European center in relation to; 1.Grade of ventriculomegaly; 2.Additional chromosomal/structural abnormalities and 3.Perinatal survival rates. This was a prospective observational study of patients referred with fetal ventriculomegaly to the National Maternity Hospital, Dublin, from January 2010 through July 2020 (with Institutional Review Board Approval). Data was obtained from the hospital database and categorized as mild (10-12mm), moderate (13-15 mm) or severe ventriculomegaly (>15mm), as per SMFM recommendations. Data was analyzed and statistical analysis performed using the Chi-Square test. 213 were included for analysis. The mean maternal age was 31.6 years, the mean gestation at diagnosis was 25+6 weeks (17 to 38+5 weeks) and the mean gestation at delivery was 38+3 weeks (33 -41+7 weeks). There was bilateral and unilateral ventriculomegaly in 186/213 (87.3%) and 27/213 (12.7%) cases respectively. Ventriculomegaly was mild in 92/213 (43.2%), moderate in 25/213 (11.7%) and severe in 96/213 (45.1%). 114/213 (53.5%) had additional structural abnormalities on ultrasound (US), of which 43/213 (20.2%) had intracranial findings only. 27/213 (12.7%) had underlying chromosomal abnormalities (21 diagnosed antenatally, 6 postnatally). No difference was observed in the rate of chromosomal abnormalities between the groups, though those with mild ventriculomegaly and additional US features had higher rates of chromosomal abnormalities than those with isolated ventriculomegaly (IVM), 12/49 (24.5%) vs 4/43 (9.3%), P<0.05 (Table 1). 28/213 (13.1%) had termination of pregnancy and 18/213 (8.5%) had a subsequent neonatal death. The overall survival was 167/213 (78.4%) . No difference was observed in the survival rates between the groups, though those with additional US findings in the mild and the severe groups had worse survival rates of 61.2% and 67.31% (P<0.05)(Table 1). In this cohort, fetuses with IVM had survival rates greater than 90% and chromosomal abnormalities under 10% in all groups.

The chromosomal abnormalities associated defects and outcomes of fetuses diagnosed prenatally with clubfoot

Aim: To assess associated findings, chromosomal abnormalities and outcomes of the pregnancies diagnosed with fetal clubfoot.Materials and Methods: Ultrasonographic characteristics, pregnancy work-up and fetal outcomes of the pregnancies diagnosed with fetal clubfoot between January 2015 and October 2019 were evaluated retrospectively. Clubfoot was considered as complex or isolated depending on the presence or absence of additional structural abnormalities. The results of cases, which grouped according to the presence of additional abnormalities and laterality, were compared.Results: A total data of 46 pregnancies diagnosed with fetal clubfoot during the study period were included. The most associated abnormality with clubfoot was central nervous system (CNS) anomalies. Nineteen (41%) of fetuses were considered complex, and 27 (59%) were considered isolated. The ratio of the cases with poor outcomes was higher in the complex group than in the isolated group and was 15 (79%) and 1(3%) respectively (p=0.000 for bilateral group and p=0.013 for unilateral group). There were 7 (36%) cases with a chromosomal abnormality in the complex group and 1(4%) case in the isolated group. The deformity was unilateral in 16 (35%) and bilateral in 30 (65%) cases. The rate of poor outcomes was not different in cases with bilateral and unilateral clubfoot deformity (p=0.356).Conclusion: The prognosis of the fetuses diagnosed with clubfoot mostly depends on associated abnormalities. Therefore a careful evaluation of these fetuses must be performed even if karyotyping is normal. The laterality did not have any impact on the prognosis of cases with clubfoot.

Perinatal outcome and prognostic factors of fetal megacystis diagnosed at 11-14 week's gestation.

To evaluate aneuploidy rate, prognostic factors, and perinatal outcomes following a diagnosis of fetal megacystis at 11-14 week's gestation. A retrospective study of first trimester fetal megacystis from 2010 to 2020 was performed, including ultrasound finding, perinatal outcomes, pathology reports, genetic tests, and neonatal investigations. A total of 98 cases of first trimester fetal megacystis was identified with an overall aneuploidy rate of 12%. There were 54% live births and 46% fetal losses including spontaneous fetal demise and elective termination. Among the 45 fetal losses, 64% had additional structural abnormalities at index ultrasound and final diagnoses were achievable in 64% cases. Among the 53 livebirths, additional ultrasound abnormalities were detected in only 1 fetus and spontaneous resolution of megacystis was detected in 96% of cases. The two cases where fetal megacystis persisted had major postnatal diagnoses: cloacal malformation and megacystis-microcolon-intestinal hypoperistalsis syndrome, respectively. Our data showed LBD ≥ 12 mm was the best individual predictor of adverse perinatal outcome and all 11 cases of lower urinary tract obstruction (LUTO) were diagnosed in fetuses with LBD ≥ 12 mm. First trimester ultrasound provides important prognostic factors and isolated megacystis <12 mm is associated with a positive outcome.

Confirmatory testing illustrates additional risks for structural sex chromosome abnormalities in fetuses with a non-invasive prenatal screen positive for monosomy X.

More and more women rely on non-invasive prenatal screening (NIPS) to detect fetal sex and risk for aneuploidy. The testing applies massively parallel sequencing or single nucleotide polymorphism (SNP) microarray to circulating cell-free DNA to determine relative copy number. In addition to trisomies 13, 18, and 21, some labs offer screening for sex chromosome abnormalities as part of their test. In this study, an index neonate screened positive for monosomy X and had discordant postnatal chromosomes indicating an X;autosome translocation. This patient prompted a retrospective chart review for similar cases at a large NIPS testing center. The review found 28 patients with an abnormal NIPS for monosomy X who were eventually diagnosed with additional discrepant structural sex chromosome abnormalities including translocations, isochromosomes, deletions, rings, markers, and uniparental disomy. The majority of these were mosaic with monosomy X, but in seven cases, there was no evidence of mosaicism on confirmatory testing. The identification of multiple sex chromosome aneuploidies in these cases supports the need for additional genetic counseling prior to NIPS testing and following abnormal NIPS results that are positive for monosomy X. This finding broadens our knowledge about the variable outcomes of positive monosomy X NIPS results and emphasizes the importance of confirmatory testing and clinical follow up for these patients.

Prenatal diagnosis and clinical significance of cephalocele-A single institution experience and literature review.

To determine the frequency of genetic and additional structural abnormalities as well as pregnancy outcomes in fetuses with prenatally diagnosed cephalocele. A retrospective analysis of data retrieved from ultrasound examinations and genetic testing in fetuses with cephalocele diagnosed between 2006 and 2018 in a tertiary referral hospital along with a systematic literature search in the PubMed database on fetuses with prenatally diagnosed cephalocele. Twenty-one out of 36 fetuses were found to have additional structural anomalies (58.3%). In four fetuses, anomalies were consistent with limb-body wall complex, in five with Meckel-Gruber syndrome, and in one with amniotic band syndrome. Genetic abnormalities were present in 11.1% of fetuses (trisomy 6; microdeletion 22q11.21; microduplication 16p13.11; pathogenic variant in gene CC2D2A). Twenty-eight pregnancies were terminated (77.8%; 28/36); two were miscarried (5.6%; 2/36). All six children from pregnancies that continued were liveborn but only two survived the surgery and developed neurological sequence. Overall survival rate was 25% (2/8) with 0% intact survival. Additional structural anomalies are common in fetuses with cephalocele. A significant number of fetuses have genetic abnormalities, and a detailed genetic testing should be performed in all cases. The prognosis is poor with high mortality rate and 0% intact survival.

Percutaneous closure of patent foramen ovale and atrial septal defect

A 67-year old man with a hemodynamically significant type secundum atrial septal defect (ASD), large patent foramen ovale (PFO) and significant septal aneurism presented with shortness of breath and limited exercise tolerance. There was no evidence of additional structural abnormalities nor significant coronary artery disease. Simultaneous percutaneous closure of both defects was planned. Since the wire could have been passed only through PFO and the second wire not through the ASD, only PFO was closed with 35 mm Amplatz PFO occluder. After 3 months, which served for tissue ingrowth of Amplatz PFO occluder and aneurism stabilization, ASD located in posterior-inferior part of fossa ovalis documented by three-dimensional transesophageal echocardiography (3D-TEE) was easily crossed and successfully closed with a 12 mm Amplatz ASD occluder. Stable position without unwanted interference between the devices was obtained. There was noresidual shunting on color Doppler and no bubble shunting during Valsalva maneuver. Within 6 months after the procedure, symptoms significantly improved and right heart chambers decreased. 3D-TEE revealed both devices in good position with only trivial shunting through PFO occluder documented by color Doppler.

7. Additional structural chromosomal abnormalities have a negative prognostic effect in patients with inv(16)/t(16;16) acute myeloid leukemia (AML)

Additional chromosomal abnormalities (ACAs) are considered as having no prognostic effect in inv(16)/t(16;16)/CBFB-MYH11 AML patients. However, many patients with ACAs cannot be cured by the standard-of-care therapy. This study included 264 inv(16)/t(16;16)/CBFB-MYH11 AML patients (M/F = 148/116; median age: 49, range 2-89 years). During a median follow-up of 34 months (range 1-190 months), 82 patients died, 169 achieved a complete remission and 13 had a partial response. Among 234 patients with abnormal karyotype, 218 had inv(16)(p13q22) and 16 had t(16;16)(p13;q22); and 110 (47%) had inv(16)/t(16;16) as the sole abnormality (Group A), 72 (30.8%) had one additional abnormality (Group B), and 52 (22.2%) had two or more abnormalities (complex karyotype, Group C). Of the additional abnormalities, +8 (n = 53) and +22 (n = 52) were most common, followed by 7q-/-7 (n = 28), +21 (n = 19 and –Y (n = 9). Structural abnormalities other than inv(16)/t(16;16) were found in 39 (16.7%) patients. Patients with ACA as a group (Groups B&C, n = 124) did not show inferior overall survival compared to Group A (median survival: 66 vs. 71 months, p = 0.5828). However, Group C showed a significantly shorter survival compared to patients in Groups A&B (n = 182) (median survival: 48 vs. 76 months, p = 0.0165). More interestingly, patients with additional structural abnormalities (n = 39) had a poorer prognosis than patients with additional numerical changes (n = 85) (median survival: 42 vs.146 months, p = 0.0123). This study shows that a complex karyotype, especially, additional structural abnormalities, predicts a poorer prognosis. Conventional chromosomal analysis of inv(16)/t(16;16)/CBFB-MYH11 AML patients appears to have value in stratifying patients with these neoplasm.

Correlation between fetal borderline ventriculomegaly and chromosomal abnormalities

Objective: To assess the association between fetal borderline ventriculomegaly (VM) diagnosed by prenatal ultrasound and chromosomal abnormality. Methods: Sonographic manifestation and chromosome of 129 cases with borderline VM diagnosed by prenatal sonography were analyzed retrospectively. All subjects were divided into 3 groups, 80 cases (62.0%, 80/129) in isolated VM (IVM) group, 27 cases (20.9%, 27/129) of VM with no additional structural abnormality group (including ultrasonic soft marker, abnormal volume of amniotic fluid and fetal growth restriction) and 22 cases (17.1%, 22/129) of VM with structural abnormality. Furthermore, the IVM group was sub-grouped according to fetal sex, lesion position and degree of expansion. The results of chromosome detection in different sub-group were analyzed statistically. Results: (1) Overall situation: in 129 enrolled cases of borderline VM, 8 cases of chromosomal abnormality were detected by CMA and the positive detection rate was 6.2% (8/129) , of which 2 cases were abnormal karyotype and 6 cases were pathologic copy number variation (p-CNV) . (2) The results of fetal chromosomal abnormalities detected in 3 groups: there were no case of abnormal karyotype and 4 cases of p-CNV in IVM group, the detection rate of chromosome abnormalities was 5.0% (4/80) . One case of abnormal karyotype and 2 cases of p-CNV in VM with no additional structural abnormality group, the detection rate was 11.1% (3/27) . One case of abnormal karyotype and no case of p-CNV in VM with structural abnormality group, the detection rate was 4.5% (1/22) . There were no significant difference among 3 groups (all P>0.05) . Conclusions: The risk of chromosomal abnormaliy increases in fetus with borderline VM. When the fetal VM is found by ultrasound, it is necessary to perform comprehensive scanning and regular follow-up. Fetal chromosomes examination is recommended.

Prognostic significance of monosomal karyotype in myelodysplastic syndrome: a meta-analysis

ABSTRACTObjectives: In myelodysplastic syndrome (MDS), the prognostic role of monosomal karyotype (MK), defined as at least two autosomal monosomies or a single monosomy associated with at least one additional structural abnormality, remained controversial. Therefore, we conducted a meta-analysis to address this issue.Methods: PubMed, Embase, Web of Science, Medline, and the Cochrane Library were retrieved. We extracted hazard ratios (HRs) and the corresponding 95% confidential intervals (CIs) for overall survival (OS) on patients with MK versus those without, as well as on MK patients with monosomies of chromosome 7 and/or 5 versus those without from the available studies.Results: Seventeen studies covering 7500 patients were included this meta-analysis. The pooled HRs indicated MK had a negative impact on OS in MDS (pooled HR: 2.484, 95%CI: 2.033–3.036, P < .001), in MDS patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) (pooled HR: 2.150, 95%CI: 1.861–2.48, P < .001), and in MDS with complex karyotype (CK) (pooled HR: 2.56, 95%CI: 2.032–3.036, P = .01). However, monosomies of chromosome 5 and/or 7 had no impact on OS in MDS with MK (pooled HR: 1.330, 95%CI: 0.827–2.139, P = .240). Meta-regression indicated that therapy was the origin of the heterogeneity (P = .012).Discussion: Our meta-analysis indicated that MK has a negative impact on OS in MDS, in MDS patients undergoing allo-HSCT, and MDS with CK, but monosomies of chromosome 5 and/or 7 have no impact on OS in MDS with MK. The heterogeneity reflected the biologic and therapeutic heterogeneity of MDS.Conclusion: MK is associated with poor prognosis in MDS, the underlying mechanism needs further exploring.