Clinical and molecular characteristics of 26 fetuses with lethal multiple congenital contractures.

Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.

Fetal skeletal dysplasia cohort of a single tertiary referral center in Istanbul, Turkey.

We report on 314 fetal cases from 297 unrelated families with skeletal dysplasia evaluated in the postmortem period from 2000 to 2017 at a single clinical genetics center in Istanbul, Turkey. The definite diagnostic yield was 40% during the prenatal period, while it reached 74.5% when combined with postmortem clinical and radiological evaluation. Molecular analyses were performed in 25.5% (n: 76) of families, and 21 novel variants were identified. Classification according to International Skeletal Dysplasia Society-2019 revision revealed limb hypoplasia-reduction defects group (39) as the leading one, 24.5%, then followed by FGFR3 chondrodysplasias, osteogenesis imperfecta, and decreased mineralization and polydactyly-syndactyly-triphalangism groups 13.6, 11.1, and 8.9%, respectively. The inheritance pattern was autosomal recessive in 54% and autosomal dominant in 42.6% of index cases. The overall consanguinity rate of the cohort was 33%. The high prevalence of ultrarare diseases along with two or more unrelated autosomal recessive entities running in the same family was noteworthy. This study highlights the pivotal role of postmortem evaluation by an experienced clinical geneticist to achieve a high diagnostic yield in fetal skeletal dysplasia cohorts. The cohort is not only a representation of the spectrum of skeletal dysplasias in a population with a high consanguinity rate but also provides an ideal research group to work on to identify the unknowns of early fetal life.

Prenatal ultrasonographic features in Blomstrand osteochondrodysplasia: Antenatal case series confirmed by postmortem radiology and molecular diagnosis.

OBJECTIVE: Blomstrand osteochondrodysplasia (BOCD, MIM #215045) is an ultrarare lethal skeletal dysplasia (LSD) perinatally, characterized by extremely advanced bone maturation, generalized osteosclerosis, and severe tetramicromelia caused by biallelic loss-of-function mutations in the parathyroid hormone receptor-1 gene (PTHR1). We aim to describe prenatal ultrasonographic features in a retrospective fetal case series of BOCD and emphasize the importance of multidisciplinary antenatal evaluation of LSDs to improve the differential diagnosis. METHOD: Prenatal ultrasound findings of five fetal cases diagnosed with BOCD between 2000 and 2019 in the Prenatal Diagnosis Unit and Medical Genetics were reviewed, along with postmortem examination results and confirmatory molecular results. RESULTS: All fetuses presented with severe sonographic findings of LSDs comprising tetramicromelia, thoracic hypoplasia, and retro-micrognathia. Marked cervical hyperextension was present in three fetuses. Flared metaphyses were prenatally identified in only one fetus. X-rays of four fetuses evaluated postmortem showed advanced bone maturation, generalized osteosclerosis, and dumbbell-like appearance of long bones due to metaphyseal enlargement. CONCLUSION: The presence of retro-micrognathia along with a protruding tongue and severe metaphyseal flaring can suggest a diagnosis of BOCD, when prenatal ultrasound findings are indicative for LSD. The diagnosis can be ascertained through postmortem clinical and radiological evaluation and/or molecular testing.

The Giant Infantile Fibrosarcoma of Fetal Oropharynx and Anterior Neck.

Introduction: Infantile fibrosarcoma (IFS) usually arises in the extremities during the first 12 months of life and responds well to surgery. It is unusual in the oropharynx or the prenatal period. Case report: A giant solid mass was first detected in the oropharynx and anterior neck at 24 weeks of gestation by ultrasound and fetal MRI. An EXIT procedure with intrapartum intubation with appropriate supportive therapy was successful. The diagnosis of IFS was made postpartum, and the lesion responded to neoadjuvant chemotherapy. Conclusion: IFS may arise as early as 24 weeks of gestation. In this case, an EXIT procedure allowed postpartum diagnosis with subsequent treatment.

Prenatal diagnosis and outcome of unilateral multicystic kidney.

We reviewed the records of 144 patients. The mean gestational age at first US diagnosis was 27.5 ± 4.3 weeks. An anomaly of the contralateral kidney was detected in 25% of cases. An extrarenal anomaly was detected in 13.8%. Karyotype analysis was performed in 16.6% of cases and revealed trisomy 18 in 2 cases with extrarenal defects. Karyotype analysis was normal in all the patients who had isolated multicystic dysplastic kidney (MCDK). The diagnostic accuracy of prenatal ultrasound was 92.2%. Contralateral kidney anomaly was detected 33.9% of patients, and half of these were vesicoureteral reflux. Antihypertensive therapy was required in 2.6% of cases. Nephrectomy was performed in 8%, and partial or total involution of MCDK was achieved in 33.9% of patients. MCDK can be accurately diagnosed by prenatal sonography, and prognosis depends on extrarenal and contralateral renal abnormalities. In isolated cases, require of surgery is rare, and serial follow-up is suggested to determine involution.Impact statementWhat is already known on this subject? Multicystic dysplastic kidney (MCDK) is one of the most renal anomalies and is associated with numerous renal and extrarenal abnormalities. It can lead to severe consequences in the neonatal period.What do the results of this study add? The accuracy of prenatal ultrasonography is excellent for detecting MCDK. In isolated unilateral cases, chromosomal aberrations are low, and the majority of them involute spontaneously. A periodic follow-up of the contralateral kidney is mandatory due to an increased risk of an anomaly. Genital anomaly risk is increased in males.What are the implications of these findings for clinical practice and/or further research? Detailed evaluation and follow-up of the contralateral kidney are crucial for counselling in isolated cases. Karyotype analysis in isolated unilateral MCDK is debateable. Postnatal prognosis is encountering, and the majority of patients have no requirement of surgery.

Prenatal Diagnosis and Findings in Ureteropelvic Junction Type Hydronephrosis.

The widespread use of obstetric ultrasonography has increased the detection rate of antenatal hydronephrosis. Although most cases of antenatal hydronephrosis are transient, one third persists and becomes clinically important. Ultrasound has made differential diagnosis possible to some extent. Ureteropelvic junction type hydronephrosis (UPJHN) is one of the most common cause of persistent fetal hydronephrosis and occurs three times more in male fetuses. It is usually sporadic and unilateral. However, when bilateral kidneys are involved and presents with severe hydronephrosis, the prognosis may be poor. Typical ultrasound findings of UPJHN is hydronephrosis without hydroureter. The size and appearance of the fetal bladder is usually normal without thickening of the bladder wall. Several grading systems are developed and increasingly being used to define the severity of prenatal hydronephrosis and provides much more information about prediction of postnatal renal prognosis. If fetal urinary tract dilation is detected; laterality, severity of hydronephrosis, echogenicity of the kidneys, presence of ureter dilation should be assessed. Bladder volume and emptying, sex of the fetus, amniotic fluid volume, and presence of associated malformations should be evaluated. Particularly the ultrasonographic signs of renal dysplasia, such as increased renal parenchymal echogenicity, thinning of the renal cortex, the presence of cortical cysts, and co-existing oligohydramnios should be noticed. Unfortunately, there is no reliable predictor of renal function in UPJHN cases. Unilateral hydronephrosis cases suggesting UPJHN are mostly followed up conservatively. However, the cases with bilateral involvement are still difficult to manage. Timing of delivery is also controversial.

Antenatally detected ureterocele: Associated anomalies and postnatal prognosis.

OBJECTIVE: We purposed to review prenatal diagnoses of ureterocele, to determine the sonographic findings and additional abnormalities, and to illustrate the pregnancy outcomes of these patients. MATERIAL AND METHODS: We reviewed the records of 24 patients with the diagnosis of ureterocele in our referral center between January 2010-March 2017. Prenatal sonographic findings, antenatal course, and postnatal follow-up were obtained. RESULTS: The mean gestational age at first US diagnosis was 24.5 ± 2.9 weeks. 13 (54.1%) of fetuses were female, and 11 (45.9%) were male. Ureterocele was associated with the duplex kidney in 17 (70.8%), MCDK in 5 (20.8%) and hydronephrosis with a single system in 1 (4.2%) and pelvic kidney in 1 (4.2%) fetuses. Postnatal follow-up was achieved in 22 of 24 (91.6%) cases, and mean follow-up interval was 56 ± 14.2. Months. The diagnosis of ureterocele was confirmed in 22 (91.6%) cases postnatally. 15 of 22 (68%) cases were classified as extravesical ureterocele, and 7 (32%) cases were intravesical ureterocele. Postnatal confirmation of duplex kidney achieved in 16 of 17 (94.1%) patients. 17 (77.2%) patients were required surgical intervention, and 5 (22.8%) cases were managed conservatively. 15 of 16 (93.7%) cases who were diagnosed duplex kidney underwent surgery however 2 of 5 (40%) cases which were confirmed MCDK required an operation. Cystoscopic ureterocele incision was the initial approach for the surgical management and performed all of the cases which required surgery. It was curative in 10 of 17 (58.8%) patients and 7 (41.2%) cases needed to further operations. Ureteroselectomy and common-sheath ureteroneocystostomy was performed in 5 (29.1%) cases and. 2 (%11.7%) cases underwent partial nephrectomy. CONCLUSION: Ureterocele can be accurately diagnosed by prenatal sonography, and it is a significant clue for the diagnosis of a duplex kidney. Postnatal prognosis depends on associated anomaly and presence of reflux and upper pole function.

Is there a determining factor that predicts mortality in patients with congenital diaphragmatic hernia?

AIM: This study was designed to investigate the factors affecting the prognosis in neonates with congenital diaphragmatic hernia (CDH) who were treated in our clinic. These factors included prenatal lung-head ratio (LHR), prenatal stomach and liver presence in the thorax, blood gases in the first 24 h and the modified ventilation index (MVI). MATERIAL AND METHODS: The study was carried out retrospectively in 30 neonates with prenatally diagnosed left CDH who were treated in our clinic between January 2007 and 2013. Data were collected, evaluated, and statistically analyzed for gender, birth weight, gestational age, prenatal LHR, prenatal presence of stomach and liver in the thorax, postnatal initial blood gases in the first 24 h and MVI. RESULTS: The median LHR for non-survivors was 1.49 and for survivors 1.51. No statistically significant difference in LHR was detected between survivors and non-survivors. In 19 neonates, prenatal ultrasonography (USG) revealed intrathoracic stomach, and 9 of these infants died. Intrathoracic liver was seen in 15 neonates, and 9 of these died. A statistically significant difference was not found between survivors and non-survivors in the intrathoracic liver or intrathoracic stomach neonates. A comparison between the non-survivors and survivors showed a median pH value of 7.10 in non-survivors and 7.24 in survivors (p = 0.002). The median PaCO2 value was 69.4 mm Hg in non-survivors and 51.9 mm Hg in survivors (p = 0.01). There were statistically significant differences in pH and PaCO2 values. The median value of MVI was 33 in survivors and 100 in non-survivors. There was a statistically significant difference between overall non-survivors and survivors in the MVI value (p < 0.05). CONCLUSIONS: Based on the findings, postnatal pH, and PaCO2 and MVI values are favorable prognostic factors in CDH in our selected group of patients.

Prenatal diagnosis of tethered spinal cord associated with sacrococcygeal teratoma.

Tethered spinal cord is mostly caused by myelomeningocele and lipomyelomeningocele, while dermal sinus tract, diastematomyelia, lipoma, tumor, thickened/tight filum terminale, spinal trauma, and spinal surgery are among the other causes. Prenatal diagnosis of tethered cord has been reported, and it is usually associated with neural tube defects. We present an atypical presentation of a tethered spinal cord, which was associated with a sacrococcygeal teratoma and was diagnosed in the 23rd week of pregnancy by ultrasonography. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:506-509, 2016.

Bipolar cord coagulation in the management of complicated monochorionic twin pregnancies.

AIM: To report our experience in selective termination of monochorionic twin pregnancies with bipolar cord coagulation and to analyze the pregnancy outcomes and complications based on the indication of the procedure. METHODS: This is a retrospective study of 71 complicated monochorionic pregnancies treated with bipolar cord coagulation between August 2006 and March 2013. RESULTS: The rates of live birth and survival up to 28 days after birth were 73.2% (52/71) and 63.4% (45/71), respectively. The highest rates of survival up to 28 days after birth were in the procedures with an indication of selective intrauterine growth restriction, while the lowest rates of survival were recorded with the indication of twin reversed arterial perfusion sequence and discordant anomaly. However, there were no statistically significant differences in the live birth and perinatal survival rates among the four different groups of indications. CONCLUSION: The survival rate of bipolar cord coagulation in complicated monochorionic pregnancies such as twin-to-twin transfusion syndrome, twin reversed arterial perfusion sequence, selective intrauterine growth restriction and discordant anomaly was 63% in our series.

Stage-related outcome after fetoscopic laser ablation in twin-to-twin transfusion syndrome.

AIM: To review the perinatal outcome of twin-to-twin transfusion syndrome (TTTS) treated with fetoscopic laser coagulation in a developing country with detailed analysis according to the stage of the syndrome. METHODS: This was a retrospective study of 85 TTTS cases treated with fetoscopic laser coagulation at the Fetal Diagnosis and Treatment Unit of Istanbul Faculty of Medicine between January 2006 and March 2013. RESULTS: The surgical failure rate was 5.8% (5/85). Among all the cases of the total cohort, only 1 fetus survived in 27 pregnancies (31.8%), and both fetuses survived in 22 pregnancies (25.9%). In 49 pregnancies (57.6%) at least one fetus survived at the end of the neonatal period. The overall survival and live birth rates were 41.8% (71/170) and 56.4% (96/170), respectively, and they significantly decreased as the stage of disease increased. Delivery occurred before 32 weeks of gestation in 54 (63.5%) pregnancies. Logistic regression analysis showed that gestational age at delivery was the only independent factor, and the risk of nonsurvival significantly decreased with increasing age. CONCLUSION: Based on our experience, the outcome of fetoscopic laser coagulation of the placental anastomoses for TTTS became worse as the Quintero stage of the disease advanced.

Significance of septa in first trimester increased nuchal translucency thickness.

PURPOSE: The objective of this study was to investigate perinatal outcome in cases of increased nuchal translucency (NT) with or without cystic hygroma (CH), and to determine whether first-trimester CH engenders a greater risk than simple increased NT. METHODS: In this retrospective study, data from singleton pregnancies in which fetal NT was found to be 3 mm or more at the 11 + 0 to 13 + 6 weeks scan were reviewed. Cases were classified into two groups, namely 'CH' and 'increased NT'. RESULTS: Of the 76 cases with increased NT, 30 (39.4 %) presented with CH. NT measurement was significantly higher in the CH group (7.25 vs. 3.5 mm, p < 0.001). Abnormal fetal karyotype, major chromosomal anomalies in chromosomally normal fetuses, and adverse outcome were significantly more frequent in the CH group as compared with the increased NT group (p = 0.019, p = 0.021, and p = 0.001, respectively). Regression analysis revealed that NT thickness was the only significant variable in the prediction of chromosomal defect and/or major congenital anomaly (OR 2.05, 95 % CI 1.23-3.42, p = 0.005). CONCLUSION: Cystic hygroma results in poorer outcome due to higher NT measurement, and the thickness of NT rather than the presence of septa should be the mainstay of prenatal counseling in cases of increased NT in the first trimester.

Prenatal diagnosis of frontonasal dysplasia with anterior encephalocele.

Frontonasal dysplasia is a rare congenital anomaly affecting the eyes, nose and forehead, and occurs sporadically in most of the cases. A 24-year-old woman was referred to our unit at 27 weeks gestation due to the preliminary diagnosis of encephalocele. The sagittal and axial sonography of the fetal face depicted a midline mass measuring 3.8 × 4.2 cm, projecting anteriorly between the fetal orbits and extending from the the upper aspects of the forehead to the nasal bridge, which was consistent with the frontal (anterior) encephalocele. There were prominent hypertelorism and two facial clefts, and the nostrils were extremely separated. Following genetic counseling, the couple requested termination of pregnancy. Fetal pathologic examination confirmed the diagnosis of frontonasal dysplasia and anterior encephalocele with no additional major malformation. The fetal karyotype was normal and no mutation in the ALX1 gene was found, excluding ALX1-related frontonasal dysplasia in the differential diagnosis. Fetuses with neural tube defect may suffer from associated syndromes and disorders, as with our case. The presence of frontonasal dyplasia should be considered when an anterior encephalocele is detected by ultrasonography.

Fetal urinoma and prenatal hydronephrosis: how is renal function affected?

OBJECTIVE: In our study, the functional prognosis of kidneys with prenatal urinomas were investigated. MATERIAL AND METHODS: Between 2006 and 2010, fetal urinomas were detected in 19 fetuses using prenatal ultrasonography (US), and the medical records were reviewed retrospectively. Of the 19 cases, the follow-up data were available for 10 fetuses. The gestational age at diagnosis, prognosis of urinomas, clinical course and renal functions were recorded. Postnatal renal functions were assessed with renal scintigraphy. RESULTS: Unilateral urinomas and increased parenchyma echogenicity in the ipsilateral kidney were detected in all of the fetuses. Of the 10 fetuses with follow-up data, the option of termination was offered in 6 cases of anhydramnios, including 3 cases with signs of infravesical obstruction (a possible posterior urethral valve (PUV) and poor prognostic factors and 3 cases with unilateral hydronephrosis and increased echogenicity in the contralateral kidney. Only one family agreed the termination. The other 5 fetuses died during the early postnatal period. The average postnatal follow-up period in the 4 surviving fetuses was 22.5 months (8-38 months). One patient with a PUV underwent ablation surgery during the early postnatal period. In the postnatal period, none of the 4 kidneys that were ipsilateral to the urinoma were functional on scintigraphic evaluation. The urinomas disappeared in 3 cases. Nephrectomy was performed in one case due to recurrent urinary tract infections. CONCLUSION: In our study, no function was detected in the ipsilateral kidney of surviving patients with urinomas. Upper urinary tract dilatation accompanied by a urinoma is a poor prognostic factor for renal function.

Dandy-Walker malformation: a review of 78 cases diagnosed by prenatal sonography.

OBJECTIVE: The purpose of this study was to determine the associated abnormalities and clinical outcomes of fetuses with Dandy-Walker malformations. METHODS: Sonograms and medical reports of 78 cases were reviewed and information regarding each outcome was collected from autopsy records, hospital charts and specialists caring for the surviving infants. RESULTS: We identified 64 fetuses with classic Dandy-Walker malformation (DW) and 14 fetuses with Dandy-Walker variant (DWV). A high proportion (44.8%) of the parents were consanguineous. The spectrum and proportion of central nervous system (67.1 vs. 71.4%; p = 1.0) and other malformations (43.7 vs. 64.2%; p = 0.57) associated with DW and DWV were similar. Chromosome abnormalities were found in 9 of the 51 (17.6%) fetuses that underwent karyotype analysis. Only 4 of 64 (6.2%) DW and 3 of 14 (21.4%) DWV infants survived (p 0.14), and all surviving infants with DW or DWV had neurological disorders. CONCLUSIONS: DW and DWV cases show so many similarities that a clear-cut distinction is difficult. There was no significant difference in the spectrum of associated anomalies and postnatal prognosis between DW and DWV cases.

Partial molar appearance of the placenta in trisomy 13.

Although molecular studies have shown that more than 90% of partial moles are secondary to diandric triploidy, there are some rare cases with tetraploidy or unspecified aneuploidies. We diagnosed 3 cases of partial mole presentation during the 2nd trimester of pregnancy with multiple fetal abnormalities. In all 3 cases, cytogenetic studies showed trisomy 13. We present the cases and discuss the clinical and pathological aspects of the conditions presented as partial moles.

Effects of long-term oral hormone replacement therapy on plasma nitric oxide and beta-endorphin levels in postmenopausal women.

OBJECTIVES: The aim of this study is to evaluate the relationship between plasma nitric oxide (NO) and beta-endorphin levels in women using hormone replacement therapy (HRT) for 12 months. MATERIAL AND METHODS: Our study group was composed of 55 patients who were in at least their second postmenopausal year. Of the 55 patients, 25 were in the control group. All 30 women in the study group received 2 mg 17beta-estradiol + 1 mg norethisterone acetate tablets daily for 12 months. Plasma NO and beta-endorphin levels were measured both before and after the study period and possible relationships were analyzed. RESULTS: There was a significant increase in both beta-endorphin (p = 0.0001, 10.93 +/- 2.25 vs. 14.85 +/- 2.49) and NO (p = 0.0001, 19.79 +/- 4.01 vs. 27.83 +/- 10.27) levels measured after the study in the HRT group. A correlation was seen between the increments in beta-endorphin and NO levels in the HRT group. CONCLUSION: Continuous combined HRT raises both plasma NO and beta-endorphin levels and a close relationship was found between the two molecules after therapy. We postulate that the increment in these molecules may explain some of the beneficial effects of HRT on cognitive function and mood.