Prenatal phenotype of Kabuki syndrome: A case series and literature review.

OBJECTIVES: Kabuki syndrome (KS) is a genetic disorder characterized by intellectual disability, facial dysmorphism and congenital anomalies. We aim to investigate the prenatal features of fetuses with KS and to provide a comprehensive review of the literature on prenatal sonographic abnormalities associated with KS. METHODS: We retrospectively reviewed the prenatal ultrasound findings of all mothers of children with molecularly confirmed KS in Hong Kong, between 1991 and 2019. We also performed systematic review of the literature to identify studies on the prenatal findings in KS. RESULTS: We identified 11 cases with KS with detectable fetal ultrasound findings ranging from no detectable abnormalities to a variety of non-specific findings including increased nuchal translucency, pleural effusion, cardiac anomalies, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. In combining our cases with the 77 cases published, 42 (50.6%) of them had more than one abnormal antenatal ultrasound finding. The most frequent ultrasound features observed were cardiac anomalies (49.4%), followed by polyhydramnios (28.9%), genitourinary anomalies (26.5%), single umbilical artery (15.7%), intrauterine growth restriction (14.5%) and hydrops fetalis/pleural effusion/ascites (12.0%). CONCLUSIONS: These cases demonstrate the prenatal phenotypic heterogeneity associated with KS. Although the ultrasound abnormalities are non-specific, KS should be considered in the differential diagnosis when these fetal findings following normal microarray analysis/karyotyping.

Optimal timing of hepatitis B virus DNA quantification and clinical predictors for higher viral load during pregnancy.

INTRODUCTION: Authorities publish recommendations on the hepatitis B virus (HBV) viral load threshold to initiate antiviral treatment but the timing of quantification during pregnancy is not well defined. HBV DNA levels in pregnancy women at 28-30 weeks predict the risk of immunoprophylaxis failure. This study compared and evaluated the correlation between HBV DNA levels before 22 and 28-30 weeks' gestation. Clinical predictive factors for HBV DNA >6, 7 and 8 log10  IU/mL were studied. MATERIAL AND METHODS: A retrospective analysis of HBV DNA levels of women <22 and 28-30 weeks of gestation was carried out in 352 pregnant HBV carriers. HBV DNA was examined using the COBAS TaqMan HBV Monitor Test coupled with the COBAS Ampliprep extraction system (Both Roche Diagnostics, Branchburg, NJ, USA). RESULTS: A strong positive correlation was found between the viral loads of women <22 weeks (mean 16.7 weeks) and 28-30 weeks of gestation, which was independent of the viral load level and gestational age of quantification (r = 0.942, P < 0.001). Univariate analysis showed that positive hepatitis B e antigen (HBeAg), maternal age <35 years old and body mass index ≤21 kg/m2 were associated with a higher mean viral load at 28-30 weeks of gestation (P < 0.05). These factors were also associated with a higher chance of viral load >6, 7 and 8 log10  IU/mL at 28-30 weeks (P < 0.05). In multiple regression analysis, only the viral load of <22 weeks and positive HBeAg remained predictive of a higher mean viral load at 28-30 weeks of gestation (P < 0.05). The receiver operating characteristic curve showed that the HBV DNA of <22 weeks was an excellent predictor for different viral load cut-offs at 28-30 weeks. The area under curve was 0.986, 0.998 and 0.994 for viral load 6, 7 and 8 log10  IU/mL, respectively. CONCLUSIONS: HBV DNA quantification should be performed before 22 weeks of gestation. Viral load cut-offs similar to those at 28 weeks can be used to determine immunoprophylaxis failure at earlier gestation. Maternal positive HBeAg status was associated with a higher chance of viral load >6, 7 or 8 log10  IU/mL.

Prenatal diagnosis of 5p deletion syndrome: Report of five cases.

It is difficult to prenatally identify 5p deletion (-) syndrome. Here, we report five cases of 5p- syndrome diagnosed by invasive prenatal diagnosis. Of them, three had a small cerebellum in the second trimester. In one case, a prominent renal pelvis and an absent nasal bone were also found in the first trimester. However, there were no abnormal ultrasound findings in the other two cases. Two cases had noninvasive prenatal testing and one showed a '5p- syndrome positive result' because of reduced amount of cell-free DNA in 5p. Two had combined first-trimester screening performed where one had a high-risk result for trisomy 18 and a low pregnancy-associated plasma protein-A level. Two cases of 5p- syndrome resulted from a parental balanced translocation. Prenatal diagnosis will only be made on invasive prenatal diagnosis for abnormal ultrasound findings with small cerebellum, abnormal prenatal screening or a parental reciprocal translocation involving 5p.

An Unusual Hydrops Fetalis Associated with Compound Heterozygosity for Krüppel-like Factor 1 mutations.

Hydrops fetalis is commonly due to Hb Bart's (γ4) disease in South East Asia. Here, we report an unusual case of hydrops fetalis due to congenital dyserythropoietic anemia (CDA) associated with compound heterozygosity for Krüppel-like factor 1 (KLF1) gene mutations. Fetal cardiomegaly was first detected on routine mid-trimester scan in a pregnant woman with normal mean corpuscular volume (MCV) and Rhesus positive status. The fetus subsequently developed hydrops fetalis, and cordocentesis showed severe fetal anemia with a hemoglobin (Hb) level of 3.4 g/dL. Common causes of fetal anemia including Hb Bart's disease, parvovirus infection, and red cell antibodies were excluded. In view of the marked increase in erythroblasts at various stages of erythropoiesis, the diagnosis of CDA was suspected. We screened the couple for previously reported KLF1 gene mutations, showing that the mother was heterozygous for the c.525_526insCGGCGCC, p.Gly176Argfs*179 mutation, and her husband heterozygous for c.1012C>A, p.Pro338Thr mutation. The fetus was a compound heterozygote for these two KLF1 mutations. After counseling, repeated intrauterine transfusions were given at 27, 29, and 34 weeks' gestation; the hydrops fetalis was resolved. The baby was delivered at 34 weeks' gestation and required monthly blood transfusions but was otherwise thriving. Bone marrow aspiration at 10 months of age showed the features of ineffective erythropoiesis, compatible with CDA. In conclusion, hydrops fetalis can rarely be due to CDA associated with a compound heterozygous mutation for KLF1 gene mutations, and be managed by repeated intrauterine transfusions. Our present report adds to the wide clinical spectrum of KLF1 mutations.

Adrenomedullin has a pivotal role in trophoblast differentiation: A promising nanotechnology-based therapeutic target for early-onset preeclampsia.

Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation of its phenotypes is in late pregnancy. There is no reliable method for early prediction and treatment of EOPE. Adrenomedullin (ADM) is an abundant placental peptide in early pregnancy. Integrated single-cell sequencing and spatial transcriptomics confirm a high ADM expression in the human villous cytotrophoblast and syncytiotrophoblast. The levels of ADM in chorionic villi and serum were lower in first-trimester pregnant women who later developed EOPE than those with normotensive pregnancy. ADM stimulates differentiation of trophoblast stem cells and trophoblast organoids in vitro. In pregnant mice, placenta-specific ADM suppression led to EOPE-like phenotypes. The EOPE-like phenotypes in a mouse PE model were reduced by a placenta-specific nanoparticle-based forced expression of ADM. Our study reveals the roles of trophoblastic ADM in placental development, EOPE pathogenesis, and its potential clinical uses.

Prenatal ultrasound monitoring of homozygous α0-thalassemia-induced fetal anemia.

A noninvasive approach by serial ultrasound examination at 12-15, 18, and 30 weeks of gestation can be used to exclude homozygous α0-thalassemia-induced fetal anemia. At 12-15 weeks of gestation, the predictive values for the fetal cardio-thoracic ratio were better than that for the placental thickness. At 16-20 weeks of gestation, measuring middle cerebral artery peak systolic velocity is associated with a low false-positive rate. However, the false-positive rate of this noninvasive approach can be about 3%, requiring an invasive test to confirm the diagnosis. A false-negative may result in a delay in diagnosis. The success of this noninvasive approach depends on an accurate measurement of the fetal cardiothoracic ratio which can be improved by adequate training and subsequent quality control. Currently, there is a lack of data reporting the performance of a noninvasive approach before 12 weeks of gestation.