Prenatal presentation of glutaric aciduria type II: A case report with radiologic, clinical, biochemical, molecular, and pathological phenotyping.

We know that glutaric aciduria type II is an inborn metabolism. This case report highlights that polycystic kidneys with hepatomegaly in prenatal ultrasound are suggestive of glutaric aciduria type II and it identifies a new variant as pathogenic.

Intra-abdominal lymphatic malformation management in light of the updated International Society for the Study of Vascular Anomalies classification.

BACKGROUND: The International Society for the Study of Vascular Anomalies (ISSVA) classification distinguishes between common lymphatic malformations and complex lymphatic anomalies. These entities have overlapping features but differing responses to treatment. Surgery has been the mainstream treatment in intra-abdominal lymphatic malformation, with variable reported success in the literature. OBJECTIVE: The aim of this study was to review the outcome of different treatments for intra-abdominal lymphatic malformations in children. MATERIALS AND METHODS: We retrospectively reviewed all intra-abdominal lymphatic malformations from 1999 to 2019 in children treated by the surgical team or followed in the vascular anomalies clinic of our institution. Children were classified into one of three groups: group A, isolated intra-abdominal lymphatic malformation; group B, common lymphatic malformation in continuity with other regions; or group C, intra-abdominal involvement as part of a complex lymphatic anomaly or associated syndrome. RESULTS: Fifty intra-abdominal lymphatic malformations were diagnosed; five of these were excluded. In group A (n=28), the treatment was surgical resection (n=26) or sclerosing treatment (n=1), with one case of spontaneous regression; no recurrence was observed in 25 patients. In group B (n=7), three patients had partial resection and all had recurrence; four had sclerotherapy alone with good response. In group C (n=10), therapeutic options included surgery, sclerosing treatment and pharmacotherapy, with variable outcomes. CONCLUSION: The management of intra-abdominal malformations requires a team approach. Sclerotherapy is successful in treating macrocystic lymphatic malformation. Surgery is successful in treating isolated intra-abdominal common lymphatic malformation, albeit at times at the cost of intestinal resection, which could be avoided by combining surgery with preoperative sclerotherapy. With surgery there is often limited resectability, and therefore recurrence in intra-abdominal lymphatic malformations that are part of complex lymphatic anomalies associated with syndromes, or in common lymphatic malformations in continuity with other regions. Sclerotherapy is an effective modality in these instances along with pharmacotherapy.

A case report of severe tuberous sclerosis complex detected in utero and linked to a novel duplication in the TSC2 gene.

BACKGROUND: Disease severity is tremendously variable in tuberous sclerosis complex (TSC). In contrast with the detailed guidelines available for TSC diagnosis and management, clinical practice lacks adequate tools to evaluate the prognosis, especially in the case of in utero diagnosis. In addition, the correlation between genotypes and phenotypes remains a challenge, in part due to the large number of mutations linked to TSC. In this report, we describe a case of severe TSC diagnosed in utero and associated with a specific mutation in the gene tuberous sclerosis complex 2 (TSC2). CASE PRESENTATION: A mother was referred for a thorough investigation following the observation by ultrasound of cardiac abnormalities in her fetus. The mother was healthy and reported frequent, intense and long-lasting hiccups/spasms in the fetus. The fetus of gestational age 33 weeks and 4 days was found to have multiple cardiac tumors with cardiac ultrasound. Brain magnetic resonance imaging (MRI) performed in utero revealed the presence of sub-ependymal nodules and of abnormal signals disseminated in the white matter, in the cerebral cortex and in the cerebellum. Following diagnosis of definite TSC, pregnancy interruption was chosen by the parents. Genetic testing of the fetus exposed a duplication in exon 41 of TSC2 (c.5169dupA), which was absent in the parents. The autopsy ascertained the high severity of brain damage characterized by an extensive disorganisation of white and grey matter in most cerebral lobes. CONCLUSIONS: This case presentation is the first to depict the association between a de novo TSC2 c.5169dupA and multi-organ manifestation together with indications of a particularly high disease severity. This report can help physicians to perform early clinical diagnosis of TSC and to evaluate the prognosis.

Prenatal findings, neonatal symptoms and neurodevelopmental outcome of congenital cytomegalovirus infection in a university hospital in Montreal, Quebec.

Background Outcome of congenital cytomegalovirus (cCMV) infection in the absence of routine CMV screening and third-trimester scan in North America is scarcely documented. The aim of this study was to assess the severe outcomes related to cCMV according to the indication for screening. Methods This was a retrospective study of 84 mother-child pairs followed for cCMV between 2003 and 2017 at CHU Sainte-Justine in Montreal, Canada. Prenatal ultrasound, neonatal symptoms, neuroimaging and severe outcomes (cerebral palsy, severe cognitive impairment, bilateral hearing loss or neonatal death) were reviewed. Results Among 38 cases with abnormal prenatal ultrasound, 41.9% of live-born infants developed severe outcomes. Sixteen (42.1%) were detected in the third trimester. Among 16 cases diagnosed prenatally because of maternal history, all had normal prenatal ultrasound, and none developed severe outcomes. Among cases diagnosed postnatally because of neonatal symptoms, 25% developed severe outcomes. All infants who developed severe outcomes had moderate/severe neonatal symptoms. Conclusion Outcome of cCMV infection varies according to the reason for screening and timing of diagnosis. Any prenatal ultrasound anomaly might indicate a risk of severe outcome, and warrants a detailed ultrasound scan. However, late detection, or postnatal diagnosis, represented more than half of the cases, and awareness of this will help ensuring optimal management.

Retrospective analysis of fetal vertebral defects: Associated anomalies, etiologies, and outcome.

Our objectives were to describe fetal cases of vertebral defects (VD), assess the diagnostic yield of fetal chromosomal analysis for VD and determine which investigations should be performed when evaluating fetal VD. We performed a retrospective chart review for fetuses with VD seen between 2006 and 2015. Cases were identified from CHU Sainte-Justine's prenatal clinic visits, postmortem fetal skeletal surveys, and medical records. Cases with neural tube defects were excluded. Sixty-six fetuses with VD were identified at a mean gestational age of 20 weeks. Forty-seven (71.2%) had associated antenatal anomalies, most commonly genitourinary, skeletal/limb, and cardiac anomalies. Thirteen mothers (19.7%) had pregestational diabetes (95% CI [10.1%-29.3%]). Fifty-three cases had chromosomal analysis. Three had abnormal results (5.6%): trisomy 13, trisomy 22, and 9q33.1q34.11 deletion. Thirty-four (51.5%) pregnancies were terminated, one led to intrauterine fetal demise and 31 (46.9%) continued to term. Of 27 children who survived the neonatal period, 21 had congenital scoliosis and 3 had spondylocostal dysostosis. Seven had developmental delay. In conclusion, prenatal evaluation of fetuses with VD should include detailed morphological assessment (including fetal echocardiogram), maternal diabetes screening, and chromosomal microarray if non-isolated. Our findings provide guidance about management and counseling after a diagnosis of fetal VD.

Ultrasound findings in rapidly involuting congenital hemangioma (RICH) - beware of venous ectasia and venous lakes.

BACKGROUND: Bleeding, ulceration and cardiac failure can occur in rapidly involuting congenital hemangioma (RICH). Bleeding intensity ranges from superficial to life-threatening. OBJECTIVE: To determine whether there are sonographic criteria associated with an increased risk of bleeding, ulceration or cardiac failure in RICH in order to identify children who need close monitoring or prophylactic treatment. MATERIALS AND METHODS: This retrospective single-center study included RICH patients over a period of 13 years. We evaluated sonographic features of RICH on B-mode and Doppler ultrasound. We correlated the occurrence of bleeding, ulceration and cardiac failure with four sonographic findings: (1) visible vessel, (2) venous ectasia, (3) venous lake and (4) arteriovenous shunting. RESULTS: We included 24 patients. Ulceration occurred in five cases, bleeding in four cases, one of which was life-threatening. Cardiac failure was observed more frequently in RICH with venous lakes (P=0.028). Bleeding and ulceration appeared more frequently in RICH with venous ectasia and venous lakes. Cardiac failure was associated with the presence of venous ectasia. All children with cardiac failure or ulceration had arteriovenous shunts. CONCLUSION: RICH with venous lakes on ultrasound is prone to develop bleeding, cardiac failure and ulceration. This association was only significant for cardiac failure.

Genomic study of severe fetal anomalies and discovery of GREB1L mutations in renal agenesis.

PURPOSE: Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies. METHODS: We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia. RESULTS: A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB-related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort. CONCLUSION: Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power-but also the challenges-of WES in prenatal diagnosis.

[All large necrotic and hemorrhagic kidney tumors in children are not necessarily malignant: A case of a 7-month-old child]. / Les volumineuses tumeurs rénales nécrotiques et hémorragiques ne sont pas toutes malignes même en pédiatrie : à propos d'un cas chez un enfant de 7 mois.

We report the case of a large tumor in the left kidney with necrotic and hemorrhagic features in a 7-month-old child, which was clinically and radiologically suggestive of a nephroblastoma. The tumor was a nodular mass measuring 8cm in diameter occupying two thirds of the kidney and presenting areas of necrosis and hemorrhage. No capsular rupture or renal sinus infiltration were found. Adjacent renal parenchyma appeared mascroscopically normal. Histologically, the tumor showed a strictly tubulopapillary architectural pattern with numerous psammomas. The initial hypothesis was a purely epithelial nephroblastoma. However, this hypothesis was rejected due to some immunohistochemical and histological characteristics and the final diagnosis was a metanephric adenoma. Metanephric adenoma is an exceptionally rare benign renal tumor in children. However, pathologists need to keep it in mind because simple surgical excision is curative.

Neonatal congenital lung tumors - the importance of mid-second-trimester ultrasound as a diagnostic clue.

BACKGROUND: The differential diagnosis for primary lung masses in neonates includes a variety of developmental abnormalities; it also consists of the much rarer congenital primary lung tumors: cystic pleuropulmonary blastoma (cystic PPB), fetal lung interstitial tumor (FLIT), congenital peribronchial myofibroblastic tumor (CPMT), and congenital fibrosarcoma. Radiologic differentiation between malformations and tumors is often very challenging. OBJECTIVE: The objective was to establish distinctive features between developmental pulmonary abnormalities and primary lung tumors. MATERIALS AND METHODS: We conducted a retrospective study of 135 congenital lung lesions at a university mother and child center over a period of 10 years (2005-2015). During this time, we noted four tumors (two cystic PPBs and two FLITs) and 131 malformations. We recorded the following parameters: timing of conspicuity in utero (mid-second trimester, third trimester, or not seen prenatally), presence of symptoms at birth, prenatal and perinatal radiologic findings, and either histological diagnoses by pathology or follow-up imaging in non-operated cases. RESULTS: All lesions except the four tumors were detected during mid-second-trimester ultrasound. In none of the tumors was any pulmonary abnormality found on the mid-second-trimester sonogram, contrary to the developmental pulmonary abnormalities. CONCLUSION: The timing of conspicuity in utero appears to be a key feature for the differentiation between malformations and tumors. Lesions that were not visible at the mid-second-trimester ultrasound should be considered as tumor. A cystic lung lesion in the context of a normal mid-second-trimester ultrasound is highly suggestive of a cystic PPB. Differentiating the types of solid congenital lung tumors based upon imaging features is not yet feasible.

Significance of lung anomalies in fetuses affected by tetralogy of Fallot with absent pulmonary valve syndrome.

OBJECTIVES: Tetralogy of Fallot with absent pulmonary valve syndrome is a rare form of tetralogy of Fallot with dilatation of large pulmonary arteries. Prognosis is related to the severity of the cardiac malformation and to bronchial tree compression by dilated pulmonary arteries. This study analyses the prenatal echographic lung appearance in fetuses with tetralogy of Fallot with absent pulmonary valve and discusses its significance. METHODS: We carried out a retrospective review of fetal and postnatal files of nine fetuses diagnosed with tetralogy of Fallot with absent pulmonary valve syndrome in our institution. Correlations of prenatal ultrasound and cardiac imaging findings were obtained with outcome. RESULTS: Abnormal heterogeneous fetal lung echogenicity was detected in eight cases out of nine, always associated with significant lobar arterial dilatation. This aspect was well correlated with postnatal imaging and outcome in the four neonatal cases. The only fetus with normal lung echogenicity also had lower degree of pulmonary artery dilatation in the series. CONCLUSIONS: This study demonstrates that a heterogeneous ultrasound appearance of the fetal lungs can be detected in utero in the most severe cases. This aspect suggests an already significant compression of the fetal bronchial tree by the dilated arteries that may have prognostic implications.

A Novel PGM3 Mutation Is Associated With a Severe Phenotype of Bone Marrow Failure, Severe Combined Immunodeficiency, Skeletal Dysplasia, and Congenital Malformations.

Congenital disorders of glycosylation (CDGs) affect multiple systems and present a broad spectrum of clinical features, often including skeletal dysplasia. Exome sequencing has led to the identification of new CDG genes. Immune and skeletal phenotypes associated with mutations in PGM3, encoding a protein that converts N-acetyl-glucosamine-6-phosphate into N-acetyl-glucosamine-1-phosphate, were recently reported. Through exome sequencing, we identified a novel homozygous mutation (c.1135T>C; p.Phe379Leu) in PGM3 in two siblings with bone marrow failure, severe combined immunodeficiency, renal and intestinal malformations, and a skeletal dysplasia resembling Desbuquois dysplasia. Severe respiratory compromise secondary to lung hypoplasia and pulmonary hypertension, and intestinal obstruction led to their demise. We thus report the most severe phenotype described so far associated with PGM3 mutations. This CDG should be considered in the presence of skeletal dysplasia associated with severe immunodeficiency. © 2017 American Society for Bone and Mineral Research.

Traumatic sternal segment dislocation in a 3-year-old girl: Sonographic findings.

Sternal fractures are uncommon in the pediatric population, and sternal segment dislocations are even rarer with only a few cases reported in the literature. Most cases are secondary to direct trauma to the chest, but nontraumatic dislocations have been reported. The diagnosis can be difficult to establish with standard radiographs, while CT is not desirable in the pediatric population due to the associated irradiation. Ultrasound (US) can be used as the first-line modality to evaluate the sternum. We report the US findings associated with a case of traumatic sternal segment dislocation in a 3-year-old girl. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:45-49, 2017.

Association between Fetal Cerebral Ventriculomegaly and Platelet Alloimmunisation.

INTRODUCTION: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare condition that may lead to intracerebral haemorrhage (ICH) in the fetus or neonate. Platelet alloimmunisation causing FNAIT has been described in association with fetal cerebral ventriculomegaly (VM), presumably due to subclinical ICH. The objective of this study was to assess the association between fetal VM and platelet alloimmunisation. METHODS: This is a case series of pregnancies with fetal VM screened for platelet alloantibodies from 2003 to 2012. Cases of multiple pregnancies, structural anomalies, aneuploidies, or congenital infection were excluded. RESULTS: Of 45 pregnancies with fetal VM that were screened for platelet alloantibodies, 5 (11%) were positive. There was only one antenatal ICH, with confirmed fetal severe thrombocytopenia before termination of pregnancy. The other cases were treated with intravenous immunoglobulins without prior fetal blood sampling. No other case of neonatal thrombocytopenia was confirmed. CONCLUSIONS: The prevalence of platelet alloimmunisation was high in this series of fetal VM. Prospective large studies are needed to confirm the role of platelet alloimmunisation in fetal VM.

Joubert Syndrome in French Canadians and Identification of Mutations in CEP104.

Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166*]) and a de novo splice-site mutation (c.2572-2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs*3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population.

Prenatal diagnosis of femoral-facial syndrome: report of two cases.

BACKGROUND: Femoral-facial syndrome (FFS), also known as femoral hypoplasia-unusual facial syndrome (FHUFS) is a rare disorder, which has been more frequently described in females. Only a few cases diagnosed prenatally have been reported so far in the literature. FFS is characterized by femoral hypoplasia and various facial abnormalities, which can be associated with a variety of other malformations CASES: In this report, we present two male fetuses which were diagnosed with FFS after detection of short femora, micrognathia, and other anomalies by ultrasonography at the age of 14 and 16 weeks, respectively. The sonographic findings were confirmed at autopsy. The differential diagnosis of FFS with other disorders characterized by hypoplastic femora is discussed CONCLUSION: FFS represents a severe condition; hence, the importance of an early prenatal diagnosis, especially in light of offering counseling for affected parents.

Prenatal ultrasound screening of congenital heart disease in the general population: general concepts, guidelines, differential diagnoses.

Congenital heart diseases (CHDs) carry a high prevalence rate in the general population (0.8%-1%). Most fetal CHDs occur in patients without any risk factors. The prenatal recognition of CHD has major impacts on the pregnancy and its outcome. The aforementioned data justify prenatal ultrasound (US) screening of CHD in the general low-risk population. As demonstrated in the literature, the application of an extended basic US cardiac examination improves the detection of CHD, in particular the conotruncal anomalies. The stepwise method suggested for fetal heart US screening during the mid-second trimester sonogram is based on 4 routine axial views of heart and great vessels: (1) a transverse view of the superior abdomen, (2) a 4-chamber view, (3) a 3-vessel view, and (4) a transverse view of the aortic arch. This protocol can be obtained rapidly because these scans are easy to perform. Despite the fact that the sequential segmental approach universally used in the postnatal diagnosis of CHD is not specifically addressed here, the detected anomalies can be categorized according to these views, and a short differential diagnosis proposed. Abnormal cardiac and/or vascular landmarks shown on these key scans should lead to a referral in the fetal cardiac center for a more precise evaluation, as well as for counseling.

First-trimester prediction of birth weight.

OBJECTIVES: To determine whether the parameters used in first-trimester screening for aneuploidies contribute significantly to the prediction of birth weight. METHODS: In this retrospective cohort study (n = 4110), nuchal translucency (NT), free ß-chorionic gonadotropin (fß-hCG), and pregnancy-associated plasma protein-A (PAPP-A) blood concentrations were measured between 11 + 0 and 13 + 6 weeks. Multiple pregnancies, chromosomal anomalies, major fetal defects, and deliveries before 24 weeks were excluded. RESULTS: NT (0.95 versus 0.98 multiples of the expected median [MoM], p < 0.001) and PAPP-A (0.93 versus 1.06 MoM, p = 0.005) were significantly lower in small-for-gestational-age (SGA) newborns (<10th percentile) than the unaffected group, but not fß-hCG (0.89 versus 0.93 MoM, p = 0.113). NT was significantly higher (1.03 versus 0.98 MoM, p < 0.001) in the large-for-gestational-age (LGA) group (>90th percentile) compared with the unaffected group, and biomarkers did not differ. After controlling for gestational age, maternal weight, smoking status, ethnicity, and fetal sex, first-trimester markers contributed to the prediction of birth weight in a multiple linear model but did not significantly improved the prediction of SGA and LGA compared with maternal characteristics alone. CONCLUSIONS: Parameters used in first-trimester screening for aneuploidies contribute to the prediction of birth weight but their clinical utility to detect women at risk of SGA or LGA baby is limited.

Imaging of biliary disorders in children.

Biliary atresia and related disorders of the biliary tree, such as choledochal cyst, must be considered in the differential diagnosis of prolonged conjugated hyperbilirubinemia in infants and children. Pediatric biliary tract diseases include a variety of entities with a wide range of clinical presentations. Radiology plays an important role in the diagnosis and management of these pathologies. Unrecognized causes of biliary disease, like biliary atresia, can lead to liver transplantation during the first year of life. The aim of this article is to review the imaging of pediatric biliary disorders, including the implications of interventional radiology in some biliary diseases.