Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series.

OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.

Prenatal-onset of congenital neuronal ceroid lipofuscinosis with a novel CTSD mutation.

BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) form a clinically and genetically heterogeneous group of inherited neurodegenerative disorders that share common neuropathological features. Although they are the first cause of neurodegenerative disorders in children, their congenital forms are rarely documented. They are classically due to mutations in the CTSD gene (the CLN10 disease). Affected newborns usually present severe microcephaly, seizures and respiratory failure leading to death within the first postnatal days or weeks. CASES: We report on two siblings, in which exome sequencing identified a novel homozygous CTSD variant. The first sib presented at birth with seizures, rapidly progressive postnatal microcephaly and visual deficiency related to retinal dysfunction. Progressive neurological deterioration leads to death at the age of 24 months. Cathepsin D activity was reduced in the cultured fibroblasts of this patient. The second sib, a fetus of 36 weeks of gestation, was delivered after pregnancy termination for brain abnormalities (in accordance with French Legislation) suggesting a recurrence of the disease. Fetal postmortem examination disclosed neuropathological features consistent with NCL. CONCLUSIONS: Congenital NCL related to CTSD mutations is a neuronal storage disorder that produces in the developing brain diffuse neurodegeneration and white matter atrophy resulting in a progressive and rapidly lethal microcephaly.

Ultrasound and Fetal MRI Complementary Contributions to Appropriate Counseling in Small Bowel Obstruction.

OBJECTIVE: Bowel obstructions beyond the duodenum represent a heterogeneous group of congenital anomalies with a highly variable prognosis, the main issue being postnatal short bowel syndrome (SBS). The objective of our study was to evaluate the contributions of fetal MRI in cases of bowel obstruction. MATERIALS AND METHODS: A retrospective analysis of all newborns, for whom both ante-natal ultrasound and fetal MRI were available, referred to our center for suspected bowel obstruction was performed. Examinations were reviewed blinded to the postnatal outcome. Key outcome measures included exact diagnosis and the existence of postoperative SBS. We evaluated the contribution of MRI in determining precise location and etiology of the bowel obstruction, dilatation of the proximal bowel loops, and assessment of the quality of the remaining distal bowel loops. RESULTS: Twenty-five newborns were included. There were 19 single obstructions and 6 complex forms (4 apple peel syndromes and 2 multiple atresias). MRI correctly identified the affected segment of the small bowel in 59.1% of the cases. MRI identified the mechanism of obstruction in 72% of cases. MRI reliably predicted an abnormal appearance of the bowel distal to the obstruction in 100% of the severe cases (3/3) and in 66.7% of complex forms (4/6). CONCLUSION: Our study suggests that fetal MRI, when done in addition to prenatal ultrasound, is contributory in the management of fetuses with suspected bowel obstruction. MRI may be particularly useful in determining the location and origin of the bowel obstruction and in assessing the quality of the bowel distal to the obstruction, which might assist in the prediction of SBS and more detailed prenatal counseling.

Contribution of magnetic resonance imaging to the prenatal diagnosis of common congenital vascular anomalies.

BACKGROUND: Screening ultrasound (US) has increased the detection of congenital vascular anomalies in utero. Complementary magnetic resonance imaging (MRI) may improve the diagnosis, but its real utility is still not well established. OBJECTIVES: We aimed to describe the imaging findings on prenatal US and MRI of the most frequent congenital vascular anomalies (lymphatic malformations and congenital hemangiomas) to assess the accuracy of prenatal US and MRI exams for diagnosis and to evaluate the relevance of the additional information obtained by complementary fetal MRI. MATERIALS AND METHODS: All confirmed postnatal congenital vascular anomalies detected in the last 10 years at 3 university hospitals were retrospectively identified. The prenatal diagnosis was compared with the final diagnosis for both methods and the clinical relevance of additional MRI information was evaluated. A second MRI in advanced pregnancy was performed in fetuses with lesions in a sensitive anatomical location and the clinical relevance of the additional information was evaluated. RESULTS: Twenty-four cases were included in the study, 20 lymphatic malformations and 4 hemangiomas. MRI slightly improved the diagnosis of lymphatic malformation, 85% vs. 80% at US, especially for abdominal lesions. Both methods had a low identification rate (25%) for tumors. MRI performed late in five fetuses with lymphatic malformation allowed optimized management at birth. CONCLUSION: MRI improves the diagnosis of congenital lymphatic malformations whereas hemangiomas remain difficult to identify in utero. The main role of MRI is to provide high-defined anatomical data to guide management at birth.

Glial Periorbital Heterotopia: A Rare Type of Ocular Mass.

Congenital orbital masses are rare disorders. A wide variety of lesions, including malignant and benign tumors, may develop around the orbit; hemangioma, lymphangioma, and optic nerve meningioma are the most common. Counseling for the prognosis and postnatal treatment depends on antenatal suspicion. Glial heterotopia should also be considered for the differential diagnosis. Integration of antenatal ultrasound and magnetic resonance imaging characteristics could help in the differential diagnosis. For the first time to our knowledge, a literature review on fetal orbital tumors was performed, along with a systematic description of imaging characteristics, treatment, and the prognosis.

Retroperitoneal Approach for Ureteropelvic Junction Obstruction: Encouraging Preliminary Results With Robot-Assisted Laparoscopic Repair.

Introduction stating the aim of the study: Robot-assisted laparoscopic pyeloplasty (RALP) is gaining acceptance among pediatric urologists. Few studies have evaluated the retroperitoneal approach for RALP. We share our experience from the first 2 years of a multidisciplinary pediatric robotic program in our center. Patients (or Materials) and Methods: We performed a retrospective analysis of prospectively collected data of children undergoing RALP for ureteropelvic junction obstruction (n = 50). Diagnosis was confirmed by ultrasound and Tc-99m mercaptoacetyltriglycine renal scan or MRI; the same criteria were used to evaluate outcome. Surgical approach was chosen according to a specific algorithm. Transperitoneal approach (n = 13) was reserved for horseshoe kidney, ectopic kidney, and redo surgery. We analyzed the 37 cases performed by a lateral retroperitoneal approach. Dismembered pyeloplasty was done for all cases and anastomosis was performed using a running monofilament 6/0 absorbable suture. All were drained by double J stent. Patient data, operating room parameters and postoperative course were recorded. Results: The median age was 7.9 years (5.1-13.8); the youngest was 2 years old. The median weight was 23 kg (17-41) with the smallest weighing 12.4 kg. Aberrant crossing vessels were present in 18 children. Median set-up time, from skin incision until the end of the 4-port insertion, was 33 min (29-48). Median surgeon's console time was 151 min (136-182). No conversion to an open procedure was necessary. The postoperative course was free of complications, except urinary tract infection in 6 children. All but 4 patients were discharged on day one. Median follow-up was 9 months (5-13). Redo pyeloplasty was not required. Practical training of other colleagues was possible after 10 cases performed by the same surgeon. Conclusion: These preliminary results suggest that retroperitoneal RALP in children is feasible, safe and effective. It is an excellent option with ideal anatomical exposure. Longer term results as well as continued practice will identify and overcome any challenges and enable surgical mastery of this procedure which is still evolving.

Fetal MRI findings in a retrospective cohort of 26 cases of prenatally diagnosed CHARGE syndrome individuals.

"CHARGE syndrome" (CS) is a multifaceted syndrome associated with a poor prognosis. The prenatal diagnosis remains challenging especially as the fetal anomalies that may evoke suspicion of CS are not comprehensively described. OBJECTIVE: This study aims to identify the anomalies in MRI with suspected CHARGE syndrome and to propose a possible standardization in the image-based prenatal diagnosis of CS. METHODS: This was a retrospective study of 26 fetuses who underwent MRI and had a confirmed diagnosis of CS, as proven by histopathological and/or neonatal examinations and/or the presence of the CHD7 gene mutation. RESULTS: The three most frequent MRI anomalies confirmed at histopathological and/or neonatal examinations were arhinencephaly in 100% (26 of 26), dysplasia of the semicircular canals agenesis (SCA) in 100% (24 of 24), and posterior fossa anomalies in 100% (22 of 22). Our study also revealed short petrous bones with a particular triangular shape in 24 of 24 cases of SCA. Other relevant findings included external ear anomalies in 36% (9 of 25), cleft lip and palate (9 of 9), ventriculomegaly (VMG) (6 of 6), short corpus callosum (3 of 3), and ocular asymmetry in 36.6% (4 of 11). CONCLUSION: Our study emphasizes the interest of fetal MRI in the diagnosis of CS with an adapted knowledge of semiology.

A neuropathological study of novel RTTN gene mutations causing a familial microcephaly with simplified gyral pattern.

BACKGROUND: The RTTN gene encodes Rotatin, a large centrosomal protein involved in ciliary functions. RTTN mutations have been reported in seven families and are associated with two phenotypes: polymicrogyria associated with seizures and primary microcephaly associated with primordial dwarfism. CASE: A targeted exome sequencing of morbid genes causing cerebral malformations identified novel RTTN compound heterozygous mutations in a family where three pregnancies were terminated because a severe fetal microcephaly was diagnosed. An autopsy performed on the second sib showed moderate growth restriction and a microcephaly with simplified gyral pattern. The histopathological study discovered a malformed cortical plate. CONCLUSIONS: The present study confirms the involvement of RTTN gene mutations in microcephaly with simplified gyral pattern and describes the observed abnormal neuropathological findings.

In utero ultrasound diagnosis of corpus callosum agenesis leading to the identification of orofaciodigital type 1 syndrome in female fetuses.

BACKGROUND: OFD1 syndrome is a rare ciliopathy inherited on a dominant X-linked mode, typically lethal in males in the first or second trimester of pregnancy. It is characterized by oral cavity and digital anomalies possibly associated with cerebral and renal signs. Its prevalence is between 1/250,000 and 1/50,000 births. It is due to heterozygous mutations of OFD1 and mutations are often de novo (75%). Familial forms show highly variable phenotypic expression. OFD1 encodes a protein involved in centriole growth, distal appendix formation, and ciliogenesis. CASES: We report the investigation of three female fetuses in which corpus callosum agenesis was detected by ultrasound during the second trimester of pregnancy. In all three fetuses, fetopathological examination allowed the diagnosis of OFD1 syndrome, which was confirmed by molecular analysis. CONCLUSIONS: To our knowledge, these are the first case reports of antenatal diagnosis of OFD1 syndrome in the absence of familial history, revealed following detection of agenesis of the corpus callosum. They highlight the impact of fetal examination following termination of pregnancy for brain malformations. They also highlight the contribution of ciliary genes to corpus callosum development.

Fetal MRI compared with ultrasound for the diagnosis of obstructive genital malformations.

OBJECTIVE: To compare the accuracy of magnetic resonance imaging (MRI) and ultrasound (US) to diagnose and characterize congenital obstructive genital abnormalities. METHOD: Retrospective cohort of 20 fetuses who underwent a fetal MRI following a US diagnosis of obstructive urogenital malformation. We compared MRI and US findings and their correlation with the definitive diagnosis. RESULT: The correct diagnosis was obtained in 6/20 (30%) cases and 19/20 cases (95%) with US and MRI, respectively. MRI revealed additional information to US in 15/20 cases (75%) and modified the prenatal management in 14 fetuses (70%). The identification rates of the most important anatomical landmarks for the diagnosis, using US and MRI, were compared. Bladder: US 17/20 (85%) vs MRI 20/20 (100%) P = 0.23; vagina: US 6/19 (31.5%) vs MRI 19/19 (100%) P < 10-4 ; uterus: US 11/19 (57.8%) vs MRI 19/19 (100%) P = 0.003, kidneys: US: 40/40 (100%) MRI: 40/40 (100%) P = 1, ureters: US 14/40 (35%) vs MRI 30/40 (75%) P=0.001, rectum: US 6/20 (30%) MRI 20/20 (100%) P < 10-4 , and sacrum: US 20/20 (100%) vs MRI 17/20 (85%) P = 0.23. CONCLUSION: In fetuses with obstructive urogenital malformations, MRI facilitates assessment of major pelvic organs and provides significant information that may alter the prenatal management.

Large Duplications Can Be Benign Copy Number Variants: A Case of a 3.6-Mb Xq21.33 Duplication.

Segmental aneusomies are usually associated with clinical consequences, but an increasing number of nonpathogenic cytogenetically visible as well as large cryptic chromosomal imbalances have been reported. Here, we report a 3.6-Mb Xq21.33 microduplication detected prenatally on a female fetus which was inherited from a phenotypically normal mother and grandfather. It is assumed that male patients harboring Xq or Xp duplication present with syndromic intellectual disability because of functional disomy of the corresponding genes. Female carriers are generally asymptomatic because of preferential inactivation of the abnormal X. In the present case, the 3.6-Mb-duplicated segment encompasses only 2 genes, DIAPH2 and RPL4A. Since the asymptomatic grandfather carries the duplication, we hypothesize that these genes are not dosage sensitive and/or involved in cognitive function. Our observation further illustrates that large copy number variants can be associated with a normal phenotype, especially where gene density is low. Reporting rare cases of large genomic imbalances without a phenotypic effect can be very helpful, especially for genetic counseling in the prenatal setting.

Clinical, genetic and neuropathological findings in a series of 138 fetuses with a corpus callosum malformation.

BACKGROUND: Corpus callosum malformation (CCM) is the most frequent brain malformation observed at birth. Because CCM is a highly heterogeneous condition, the prognosis of fetuses diagnosed prenatally remains uncertain, making prenatal counseling difficult. METHODS AND RESULTS: We evaluated retrospectively a total of 138 fetuses, 117 with CCM observed on prenatal imaging examination, and 21 after postmortem autopsy. On ultrasound and/or magnetic resonance imaging, CCM was either isolated (N = 40) or associated with other neurological (N = 57) or extra cerebral findings (N = 21/20, respectively). RESULTS: Most fetuses (N = 132) remained without a diagnosis at the time of pregnancy termination. This emphasizes the need to establish a neuropathological classification and to perform a genomic screening using comparative genomic hybridization. A neuropathological examination performed on 138 cases revealed a spectrum of CCMs, classified as follows: agenesis of corpus callosum (55), CC hypoplasia (30), CC dysmorphism (24), and CCM associated with a malformation of cortical development (29). Of interest, after fetopathological examination, only 16/40 malformations were classified as isolated, highlighting the importance of the autopsy following termination of pregnancy. Among the 138 cases, the underlying etiology was found in 46 cases: diabetes (one case), cytomegalovirus infection (one case), 23 chromosome abnormalities, and 21 mendelian conditions. CONCLUSION: In our series of 138 cases of CCM, prenatal and postmortem examinations identified a variety of genetic causes. However, no diagnosis could be established in 67% of cases. The classification based on the underlying neurodevelopmental defects paves the way for further genetic studies and genotype-phenotype correlations.

Performance of prenatal diagnosis in esophageal atresia.

OBJECTIVE: The aim of this study was to evaluate the performance of prenatal diagnosis of esophageal atresia (EA) and its associated abnormalities. METHODS: We conducted a retrospective study from a pediatric database of EA managed postnatally in a single center. Prenatal data included ultrasound and magnetic resonance imaging parameters including amniotic fluid (AF) volume, stomach visualization, AF biochemistry, and associated malformations. Postnatal data included type of EA, mortality, and postnatal diagnosis of associated malformations. RESULTS: One hundred twenty-two cases were included. The diagnosis was suspected prenatally in 39/122 (32%) cases. Polyhydramnios was noted in 64/122 (52.4%), and the stomach was not visualized or small in 39 (32%). There was 14 (11.5%), 2 (1.6%), 101 (82.8%), 5 (4.1%), and 0 (0%) types I, II, III, IV, and V, respectively. EA was suspected prenatally in 12/14 (85.7%) in type I and in 27/108 (25%) in cases with tracheoesophageal fistula (II + III + IV + V). Magnetic resonance imaging was performed in 28 cases, which confirmed EA in 19/28 (sensitivity 67.8%). AF biochemistry was performed in 17 cases, which confirmed EA in 15/17 (sensitivity 88.2%) cases. Of the 69 syndromic associations, 41/69 (59.4%) cases were detected prenatally. Associated malformation was a strong predictor of postnatal death [19/69 vs 3/53, odds ratio 6.33 (1.76; 22.75), p < 0.01]. CONCLUSION: Prenatal diagnosis of EA remains challenging. MRI and AF biochemistry may prove useful in the diagnosis of EA. Prenatal ultrasound and MRI examination should also focus on associated anomalies. © 2015 John Wiley & Sons, Ltd.

Homozygous truncating mutation of the KBP gene, encoding a KIF1B-binding protein, in a familial case of fetal polymicrogyria.

Polymicrogyria (PMG) is a clinically heterogeneous malformation of cortical development, characterized by a loss of the normal gyral pattern that is replaced by many small and infolded gyri separated by shallow sulci that are partly fused in their depths. Causes of PMG are heterogeneous and include acquired and genetic causes. There are more than 100 syndromes possibly associated with PMG but mutations in specific genes such as SRPX2, GPR56, TUBB2B, TUBB3, NHEJ1, TUBA1A, TUBA8, and WDR62 have been reported only in a minority of patients.

MRI and ultrasound fusion imaging for prenatal diagnosis.

OBJECTIVE: A combination of magnetic resonance imaging (MRI) images with real time high-resolution ultrasound known as fusion imaging may improve prenatal examination. This study was undertaken to evaluate the feasibility of using fusion of MRI and ultrasound (US) in prenatal imaging. STUDY DESIGN: This study was conducted in a tertiary referral center. All patients referred for prenatal MRI were offered to undergo fusion of MRI and US examination. All cases underwent 1.5 Tesla MRI protocol including at least 3 T2-weighted planes. The Digital Imaging and Communications in Medicine volume dataset was then loaded into the US system for manual registration of the live US image and fusion imaging examination. RESULTS: Over the study period, 24 patients underwent fusion imaging at a median gestational age of 31 (range, 24-35) weeks. Data registration, matching and then volume navigation was feasible in all cases. Fusion imaging allowed superimposing MRI and US images therefore providing with real time imaging capabilities and high tissue contrast. It also allowed adding a real time Doppler signal on MRI images. Significant fetal movement required repeat-registration in 15 (60%) cases. The average duration of the overall additional scan with fusion imaging was 10 ± 5 minutes. CONCLUSION: The combination of fetal real time MRI and US image fusion and navigation is feasible. Multimodality fusion imaging may enable easier and more extensive prenatal diagnosis.

Comparison between ultrasound and magnetic resonance imaging in assessment of fetal cytomegalovirus infection.

OBJECTIVE: To evaluate whether fetal brain magnetic resonance imaging (MRI) adds useful information to the one obtained by ultrasound in fetuses with cytomegalovirus (CMV) infection. METHODS: MRI and ultrasonographic findings were analyzed retrospectively in 38 fetuses with proven congenital CMV infection. Both techniques were performed on the same week at a mean gestational age of 33 weeks (24-37). The referral indications were maternal seroconversion (n = 19), and ultrasound findings (n = 19). The results were compared with the fetopathologic examination in cases with fetal death or termination of pregnancy (TOP) or the infant's neurological examination. RESULTS: The 38 cases were classified into three groups, depending on ultrasound findings at referral. Group 1: no ultrasound features (n = 11); group 2: extracerebral features without cerebral abnormalities at ultrasound (n = 13); group 3: presence of cerebral features at ultrasound (n = 14). In group 1, MRI was always normal. In group 2, MRI revealed cerebral features in six cases (46%). In group 3, MRI always confirmed the lesions seen at ultrasound and highlighted other cerebral features. CONCLUSIONS: MRI can provide important additional information with regard to abnormal gyration, cerebellar hypoplasia, or abnormal signal in white matter. It is certainly useful in the assessment of fetuses with extracerebral features without brain abnormalities detected with ultrasounds. If the fetal ultrasound is strictly normal in an infected fetus, MRI may not detect brain anomalies; however, it seems difficult to not perform this noninvasive procedure.

Prenatal prognosis in isolated congenital diaphragmatic hernia.

OBJECTIVE: A monocentric retrospective study of 79 neonates with isolated diaphragmatic hernia antenatally diagnosed was performed to identify prenatal parameters that may characterize the severity of the disease. STUDY DESIGN: Postnatal treatment protocol included early high frequency ventilation, inhaled nitric oxide, and delayed surgery. Postnatal survival rate was 63.3%. RESULTS: Age at diagnosis, polyhydramnios, and left ventricle/right ventricle index were not related with survival. None of the 9 left diaphragmatic hernias with intraabdominal stomach died. Neonatal mortality was significantly related with the side of the defect, intrathoracic position of the liver, the ratio of fetal lung area to head circumference value, and fetal lung volume ratio measured by resonance magnetic imaging. CONCLUSION: No prenatal factor alone firmly predicts neonatal outcome. Clinicians should help stratify the severity of the disease and compare accurately different postnatal therapeutic strategies.

[MRI and fetal multidetector CT in the diagnosis of fetal malformations]. / Apport de l'IRM et du scanner foetal dans le diagnostic des malformations foetales.

Prenatal imaging has benefitted from rapid technological progress in the last ten years. Ultrasound remains the standard screening method for fetal malformations but can be hindered by the bony structure of the skull. In particular, it can be difficult to distinguish between white and grey matter. MRI is a useful complementary method for detecting brain malformations. In particular, MRI is necessary to detect associated malformations and to obtain a precise diagnosis when ultrasound examination shows ventricular dilation. MRI is taking an increasingly important place in the assessment and prognostication of extracranial malformations such as congenital diaphagmatic hernia. We reviewed 2885 fetal MRI examinations. Fetal computed tomography is gradually replacing plain maternal abdominal radiography. We examined 90 CT films for fetal bone malformations.