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The article presents case studies of two women with polyhydramnios and fetal cardiomegaly. Also includes risk of parenchymal ischemic lesions with vein of Galen aneurysmal malformation (VGAM), and diagnosis of capillary malformation-arteriovenous malformation (CM-AVM) syndrome through Doppler ultrasound.

We report the first series of cases of pericallosal curvilinear lipoma (CL) diagnosed prenatally and highlight the limitations in identifying a specific prenatal imaging pattern using ultrasound and magnetic resonance imaging (MRI). In all five of our cases, on ultrasound, the main feature leading to referral was a short corpus callosum. This subtle callosal dysgenesis was associated with a band of hyperechogenicity surrounding the corpus callosum, mimicking the pericallosal sulcus, which increased in size during the third trimester in three of the four cases in which sonographic follow-up was performed. On T2-weighted MRI, this band showed typical hypointensity in all cases; in contrast, on T1-weighted imaging, in only one case was there hyperintensity, suggestive of fat, as seen typically in the postnatal period. For appropriate prenatal counseling regarding outcome, it is important to identify or rule out CL when mild corpus callosal dysgenesis is observed. One should be aware of subtle diagnostic findings, such as a thin band of echogenicity surrounding the corpus callosum that is seen as a band of hypointensity on T2-weighted fetal MRI, and which may increase in size during gestation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

We report a specific sonographic cerebral pattern of cobblestone lissencephaly (CL) that has not been described previously. This pattern was encountered in four index cases and allowed prenatal diagnosis of CL associated with Walker-Warburg syndrome. The pattern included both an outer echogenic band with reduced pericerebral space, corresponding to an infra- and supratentorial extracortical layer of neuroglial overmigration on pathological examination, and a 'Z'-shaped appearance of the brainstem. This pattern was found as early as 14 weeks' gestation in one of our cases. [ABSTRACT FROM AUTHOR]

In HMEG, a postzygotic I PIK3CA i variant was found in 3 fetuses with extra-cerebral features of I PIK3CA i -related overgrowth spectrum (PROS), and in 7 fetuses with "isolated HMEG". To describe clinical and molecular findings in fetuses with localised overgrowth disorders (LOD) involving the brain (BO) and/or a limb (LO) diagnosed on prenatal imaging (ultrasonography or MRI), suggesting involvement of the PI3K-AKT-mTOR signalling pathway. OC18.04: Clinical and molecular data in case of prenatal localised overgrowth disorders: major implication of variants in the PI3K-AKT-mTOR signalling pathway. [Extracted from the article]

A letter to the editor is presented in response to the article "Prenatal diagnosis of multiple cortical and deep cerebral vein thromboses in the absence of dural venous malformation" by N. Winer in the 2008 issue.

ABSTRACT Objective To define imaging patterns of unilateral cerebellar hypoplasia ( UCH), discuss possible pathophysiological mechanisms and underline the etiology and prognosis associated with these lesions. Methods In this retrospective study we reviewed the charts of 26 fetuses diagnosed between 2003 and 2011 with UCH, defined by asymmetrical cerebellar hemispheres with or without decreased transverse cerebellar diameter. The review included analysis of the anatomy of the cerebellar hemispheres, including foliation, borders and parenchymal echogenicity, and of the severity of the hypoplasia. Data from clinical and biological work-up and follow-up were obtained. Results Our series could be divided into two groups according to whether imaging features changed progressively or remained constant during follow-up. In Group 1 ( n = 8), the progression of imaging features, echogenic cerebellar changes and/or hyposignal in T2*-weighted MR images were highly suggestive of ischemic/hemorrhagic insult. In Group 2 ( n = 18), imaging features remained constant during follow-up; UCH was associated with abnormal foliation in three proven cases of clastic lesions, a cystic lesion was noted in three cases of PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac abnormalities/aortic coarctation, eye abnormalities) syndrome and, in the remaining cases, UCH remained unchanged, with no imaging pattern typical of hemorrhage. In 24 cases the infant was liveborn and follow-up was continued in 23, for a mean period of 3 years. Among these, neurological complications were identified in seven (in one of seven (at a mean of 46 months) in Group 1 and in six of 16 (at a mean of 35 months) in Group 2). The surface loss of cerebellar hemisphere was > 50% in 19/24 fetuses and the vermis was clearly normal in appearance in 19/24. Predisposing factors for fetal vascular insult were identified in eight cases: these included maternal alcohol addiction, diabetes mellitus, congenital cytomegalovirus infection and pathological placenta with thrombotic vasculopathy and infarctions. Conclusion UCH is defined as a focal lesion of the cerebellum that may be secondary to hemorrhage and/or ischemic insult, suggesting a clastic origin, particularly when imaging follow-up reveals changes over time. UCH may also be a clue for the prenatal diagnosis of PHACE syndrome. The amount of surface loss of cerebellar hemisphere does not correlate with poor prognosis. UCH with normal vermis is often associated with normal outcome. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT In order to illustrate the significance of a new anatomical finding, distortion of the interhemispheric fissure ( DIHF) associated with impacted medial borders of the frontal lobes, we report a retrospective observational study of 13 fetuses in which DIHF was identified on prenatal imaging. In 10 cases there were associated anatomical anomalies, including mainly midline anomalies (syntelencephaly (n = 2), lobar holoprosencephaly (n = 1), Aicardi syndrome (n = 2)), but also schizencephaly (n = 1), cortical dysplasia (n = 1) and more complex cerebral malformations (n = 3), including neural tube defect in two cases. Chromosomal anomaly was identified in two cases, including 6p deletion in a case without associated central nervous system anomalies and a complex mosaicism in one of the cases with syntelencephaly. In two cases, the finding was apparently isolated on both pre- and postnatal imaging, and the children were doing well at follow-up, aged 4 and 5 years. The presence of DIHF on prenatal imaging may help in the diagnosis of cerebral anomalies, especially those involving the midline. If DIHF is apparently isolated on prenatal ultrasound, magnetic resonance imaging is recommended for careful analysis of gyration and midline, especially optic and olfactory structures. Karyotyping is also recommended. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd [ABSTRACT FROM AUTHOR]

Joubert syndrome and related disorders (JSRD) are characterized by absence or underdevelopment of the cerebellar vermis and a malformed brainstem. This family of disorders is a member of an emerging class of diseases called ciliopathies. We describe the abnormal features of the brain, particularly the fourth ventricle, in seven fetuses affected by JSRD. In three cases abnormality of the fourth ventricle was isolated and in four cases there were associated malformations. The molar tooth sign (MTS) was always present and visible on two-dimensional ultrasound and, when performed, on three-dimensional ultrasound and magnetic resonance imaging. The fourth ventricle was always abnormal, in both axial and sagittal views, presenting pathognomonic deformities. It is important to identify JSRD, preferably prenatally or at least postnatally, due to its high risk of recurrence of about 25%. A detailed prenatal assessment of the fourth ventricle in several views may help to achieve this goal. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses agenesis of the corpus callosum with interhemispheric cyst, linked with deviant cortical sulci near cystic structure, without any hidden cortical dysplasia.

ABSTRACT By review of a series of cases, we set out to identify sonographic features suggestive of an obstructive mechanism in second-trimester fetuses with ventriculomegaly and describe developmental disorders related to pathological differentiation of the diencephalon, mesencephalon and rhombencephalon that lead to obstruction of cerebrospinal fluid flow. We studied retrospectively 11 fetuses referred for severe second-trimester ventriculomegaly of undetermined origin. Neurosonography was performed with detailed analysis of the third ventricle, thalami, cerebral aqueduct and cerebellum. The cerebral imaging data were compared with neuropathological data in eight patients, with a focus on the level and etiology of the obstruction. Parenchymal thinning and reduction of the pericerebral spaces were highly suggestive of ventriculomegaly due to an obstructive mechanism. The ventriculomegaly was related to diencephalosynapsis (thalamic fusion and third ventricle atresia) in five cases and partial/complete aqueduct stenosis in six; it was associated with cerebellar hypoplasia in six cases, including rhombencephalosynapsis in two cases. In nine patients, disorders of the diencephalon, mesencephalon and rhombencephalon were present. In cases of severe isolated ventriculomegaly in which sonographic features are suggestive of an obstructive mechanism, close examination of the third ventricle, thalami, aqueduct of Sylvius and cerebellum may reveal pathological differentiation of the diencephalon, mesencephalon or rhombencephalon, often in combination. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Several inborn errors of metabolism (IEM) present with antenatal signs. They involve the metabolic pathways essential for the fetal development which cannot be supplied by maternal or placental metabolisms. Their diagnosis relies on ultrasonic signs. The main signs are hydrops fetalis, echogenic kidneys, cerebral abnormalities (abnormal gyration, corpus callosum hypoplasia, posterior fossa abnormalities or abnormal cranial perimeter), epiphysal dysplasia, fetal growth retardation, echogenic colon... Biochemical investigations should be carried out before termination of the pregnancy. It relies on measurement of metabolites or enzyme activities in the supernatant of amniotic fluid or fetal blood, together with enzymatic and/or genetic studies in cultured amniotic fluid cells. However, the diagnosis of an IEM is often suggested at pathological examination of the fetus and placenta. Both macroscopic and microscopic examinations of the fetus and placenta are very hepful: they allow identifying undetectable signs at ultrasound. Radiological examination of the fetus allows to precise bone abnormalities. In all cases, it is essential to confirm the diagnosis of IEM, in order to propose genetic counselling. This implies that all involved scientists must work in close collaboration. [ABSTRACT FROM AUTHOR]

The article examines a subjective and reproducible method for Sylvian fissure operculization (SFO) assessment between 22 and 32 weeks of pregnancy. According to the authors, the inter- and intraobserver agreement correlation coefficients were 0.91 and 0.95, respectively, with a standard error of measurement <1 scoring unit, which corresponds to an accuracy of within one week.

The article discusses two cases of rapidly involuting congenital hemangioma (RICH) of the skull diagnosed in the third trimester of gestation. Ultrasound examination showed a soft tissue vascular mass of the skull with a specific sonographic finding, a thin hyperechogenic line over the lesion and continuous with the calvaria. In each case, the diagnosis of RICH was confirmed by demonstrating a decrease in reduction in the size of the tumor and regression of the vascular component.

Abstract: Intrahepatic portosystemic anastomoses are macroscopic communications between the venous portal system and the systemic circulation and located partly in the liver. We report 4 new cases of type II shunts, which illustrate the circumstances of the diagnosis of these exceptional anomalies. For 2 children, the diagnosis was done antenataly by US and spontaneous involution in a few months was observed. In the third case the malformation was evidenced fortuitously at 3 weeks of life, and this 6-year-old child remains completely asymptomatic so far. Then, in the fourth case, a cerebral venous thrombosis was fortuitously and antenatally evidenced in an otherwise uneventful pregnancy and portosystemic shunt was demonstrated postnataly in the extensive work up of the neonate. [Copyright &y& Elsevier]

The article discusses the rare disorder called the Pai syndrome. The disorder is characterized by the association of a midline pericallosal lipoma, median cleft and cutaneous polys of the face. It cites a case of a pregnant woman who was evaluated during gestation because of what were detected during the ultrasound examination.

The article presents a case study of a 27-year-old woman who was referred at 23 weeks' gestation for deformation of the spine. Using ultrasound and computed tomography, the patient was diagnosed of isolated partial agenesis of a vertebral body or asoma. Prenatal diagnosis of asoma facilitates optimization of postnatal management and reduces neonate's risk of developing paralysis. It also allows informed discussion to decide the most appropriate mode of delivery.

A letter to the editor is presented citing the authors' prenatal cerebral ultrasound and magnetic resonance imaging (MRI) findings from a de novo case of glutaric aciduria Type 1.

Several photographs showing the results of a prenatal diagnosis using ultrasound and magnetic resonance imaging (MRI) of cerebellar cortical dysplasia associated with abnormalities of foliation during the third trimester, are presented.

A letter to the editor is presented which demonstrates the case of 24-year-old primigravida who was diagnosed with complete cerebellar agenesis.

Rationale: Sirolimus is a treatment for slow-flow vascular malformations (SFVMs). However, the long-term management remains challenging., Objectives: The SIROLO study assessed the long-term effects and real-life management of oral sirolimus for SFVMs by investigating data from 15 French tertiary centres for vascular anomalies., Methods: Participants were retrospectively included if they had a SFVM that was being/had been treated with sirolimus for at least 3 years in total. Data were collected on treatment goals when initiating sirolimus, investigator-reported efficacy, safety, dosages and treatment withdrawal., Results: The cohort involved 67 patients with various SFVM entities (mean [±SD] age 19.6 ± 12.5 years, 35 children, 52.2%). We found a heterogeneity of predefined treatment goals, the most frequent being cessation of pain. The investigators considered that sirolimus had persistent efficacy for bleeding, ulceration and pain but only slight efficacy for reducing volume. It was reported to be well-tolerated, although serious adverse events (mainly infections and also two ovarian cysts) were reported in 6 patients (9.0%) and required definitive sirolimus discontinuation for one. Overall, 11 patients (16.4%) had at least one temporary withdrawal period, leading to symptom recurrence and sirolimus resumption at a mean of 6.4 ± 9.6 months. The mean sirolimus concentration was 6.4 ± 3.7 ng/mL during the first 6 months and decreased over time (mean concentration during the last 6 months: 4.2 ± 3.2 ng/mL), probably to target the minimal efficient dosage. Eight patients (11.9%) switched to alpelisib because of insufficient efficacy of sirolimus., Conclusion: This real-life study gives answers to frequent questions patients and parents ask before sirolimus initiation for SFVMs, such as persistence of efficacy over time, long-term side effects and time to recurrence in case of withdrawal., (© 2024 European Academy of Dermatology and Venereology.)

Background: Next-generation sequencing has greatly increased our understanding of vascular birthmarks. Many port-wine birthmarks are due to somatic mutations in GNAQ/GNA11 exon 183, but other genomic causes have been identified. Most congenital hemangiomas are due to somatic mutations in GNAQ/GNA11 at exon 209. Although genomically distinct, clinical overlap of congenital hemangiomas and port-wine birthmarks has occasionally been described., Objective: We report a case series of a unique segmentally distributed vascular anomaly with overlapping characteristics of port-wine birthmarks and congenital hemangiomas with other distinctive features including ulceration, atrophy, and scarring., Methods: This was a multicenter study with retrospective identification of patients via a detailed review of medical records. We also reviewed previously published cases., Results: The clinical, histological, radiological, and genomic characteristics of 19 new and 13 previously reported cases characterized by segmental distribution, sharply demarcated borders, with variable thickening are presented. All cases had central atrophy with or without episodic ulceration. Those with genomic studies (13 out of 32) had somatic activating missense mutations in GNA11 or GNAQ codon 209., Conclusions: We describe the features and propose a descriptive name segmental congenital vascular anomaly with atrophy, ulceration, and scarring (SeCVAUS) for this condition., (© 2024 Wiley Periodicals LLC.)

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations' occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations., (© 2024. The Author(s).)

Competing Interests: None disclosed.

Introduction: Congenital microgastria (CM) is a rare condition due to early interruption of stomach development between the 4th and 8th week of gestation, leading to a small midline tubular stomach. Prenatal diagnosis of CM is a challenge with important implications. This study explores the value of biochemical amniotic fluid (AF) analysis and fetal magnetic resonance imaging (MRI) for the prenatal diagnosis of CM in case of nonvisible stomach on fetal ultrasound., Case Presentation: Four cases of CM were retrospectively investigated in terms of fetal ultrasound, MRI findings, and biochemical AF analyses. The patients were referred to the Prenatal Diagnosis Unit of the Hôpital Femme Mère Enfant (Lyon, France) at a mean age of 21 weeks of gestation for absent or small fetal stomach on ultrasound with a suspected diagnosis of esophageal atresia (EA). Ultrasound examination confirmed that the stomach was absent in two of the four fetuses and small in the other two. This feature was associated with a congenital heart defect in two cases and a terminal transverse limb defect in one case. Standard genetic workup (array-CGH) results were normal. Biochemical AF analysis, including the EA index, was not suggestive of EA. Fetal MRI showed a small midline tubular stomach, associated with a dilated esophagus, highly suggestive of CM., Conclusion: If the fetal stomach is absent on ultrasound, CM should be considered if the AF volume is normal, especially during the third trimester, and if the EA index is not suggestive of gastrointestinal obstruction. In these cases, the diagnosis can be confirmed by fetal MRI, through observation of a small midline tubular stomach associated with a dilated esophagus., (© 2024 S. Karger AG, Basel.)

Purpose: To retrospectively evaluate sclerotherapy using consecutive polidocanol and bleomycin foam (CPBF) for large untreated venous malformations (VMs) and/or those resistant to prior treatment., Materials and Methods: This retrospective study included all patients treated with CPBF for untreated VMs larger than 10 mL and/or refractory to treatment between May 2016 and October 2019. Baseline and follow-up VM volumes were measured on fat-suppressed T2-weighted magnetic resonance (MR) imaging. Outcome was evaluated on postprocedural MR imaging volumetry and by a retrospective survey assessing clinical response and adverse events. Imaging response was considered good for volume reduction from 50% to 70% and excellent for volume reduction ≥70%. Symptoms and quality-of-life (QoL) scores were compared before and after CPBF sclerotherapy., Results: Forty-five patients (mean age, 16 years; range, 1-63 years; 25 males) with 57 VMs were analyzed and treated by 80 sclerotherapy. Sixty percent (27 of 45) of patients had undergone prior treatment for VM. Median VM volume was 36.7 mL (interquartile range, 84 mL) on pretherapy MR imaging. Good and excellent results after the last sclerotherapy were achieved in 36% (16 of 45) and 29% (13 of 45) of patients, respectively, corresponding to a decrease of >50% in 60% (34 of 57) of VMs. QoL score increased by at least 3 points, regardless of initial symptoms. Most patients did not desire additional sclerotherapy owing to near complete symptomatic relief, even for patients who did not achieve a good response. Swelling, pain, and motor impairment scores significantly improved after CPBF. Adverse events included fever (44%, 15 of 34) and nausea/vomiting (29%, 10 of 34)., Conclusions: CPBF sclerotherapy represents an effective therapy for large and/or refractory VMs with minimal adverse events., (Copyright © 2023. Published by Elsevier Inc.)

Hemifacial myohyperplasia (HFMH) is a rare cause of facial asymmetry exclusively involving facial muscles. The underlying cause and the mechanism of disease progression are unknown. Here, we identified a somatic gain-of-function mutation of PIK3CA in five pediatric patients with HFMH. To understand the physiopathology of muscle hypertrophy in this context, we created a mouse model carrying specifically a PIK3CA mutation in skeletal muscles. PIK3CA gain-of-function mutation led to striated muscle cell hypertrophy, mitochondria dysfunction, and hypoglycemia with low circulating insulin levels. Alpelisib treatment, an approved PIK3CA inhibitor, was able to prevent and reduce muscle hypertrophy in the mouse model with correction of endocrine anomalies. Based on these findings, we treated the five HFMH patients. All patients demonstrated clinical, esthetical, and radiological improvement with proof of target engagement. In conclusion, we show that HFMH is due to somatic alteration of PIK3CA and is accessible to pharmacological intervention., (© 2023 Bayard et al.)

Background: EPHB4 loss of function is associated with type 2 capillary malformation-arteriovenous malformation syndrome, an autosomal dominant vascular disorder. The phenotype partially overlaps with hereditary haemorrhagic telangiectasia (HHT) due to epistaxis, telangiectases and cerebral arteriovenous malformations, but a similar liver involvement has never been described., Methods: Members of the French HHT network reported their cases of EPHB4 mutation identified after an initial suspicion of HHT. Clinical, radiological and genetic characteristics were analysed., Results: Among 21 patients with EPHB4 , 15 had a liver imaging, including 7 with HHT-like abnormalities (2 female patients and 5 male patients, ages 43-69 years). Atypical epistaxis and telangiectases were noted in two cases each. They were significantly older than the eight patients with normal imaging (median: 51 vs 20 years, p<0.0006).The main hepatic artery was dilated in all the cases (diameter: 8-11 mm). Six patients had hepatic telangiectases. All kind of shunts were described (arteriosystemic: five patients, arterioportal: two patients, portosystemic: three patients). The overall liver appearance was considered as typical of HHT in six cases.Six EPHB4 variants were classified as pathogenic and one as likely pathogenic, with no specific hot spot., Conclusion: EPHB4 loss-of-function variants can be associated with HHT-like hepatic abnormalities and should be tested for atypical HHT presentations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Intramuscular capillary-type hemangiomas (ICTHs) are rare entities, belonging to the group of intramuscular "hemangiomas." The diagnosis remains challenging. We aimed to assess the diagnostic criteria, treatments and outcomes of ICTHs., Methods: This retrospective study collected all cases of ICTH followed up in 9 French hospital centers, reviewed by an adjudication expert group., Results: Among 133 patients screened, 66 with ICTH were included. The median age of patients at diagnosis was 28.0 years, interquartile range (21.0---36.0). The lesion, mainly presenting as a gradually increasing mass (83.9%), was painless (88.9%) and was located in the head and neck (42.4%). MRI (available in all cases) mainly revealed a well-delineated lesion, isointense to the muscle on T1-weighted images, with enhancement after contrast injection; hyperintense on T2-weighted images; and containing flow voids. Among the 66 cases, 59 exhibited typical ICTH features and 7 shared some imaging features with arteriovenous malformations. These latter were larger than typical ICTHs and more painful and appeared on imaging as less well delimited and more heterogeneous tissue masses, with larger tortuous afferent arteries, earlier draining vein opacification and mild arteriovenous shunting. We propose to name these lesions arteriovenous malformation (AVM)-like ICTH. Pathological reports were similar in typical and AVM-like ICTH, showing capillary proliferation with mainly small-size vessels, negative for GLUT-1 and positive for ERG, AML, CD31 and CD34, with low Ki67 proliferation index (<10%), and adipose tissue. The most frequent treatment for ICTH was complete surgical resection (17/47, 36.2%), preceded in some cases by embolization, which led to complete remission., Conclusions: ICTH can be diagnosed on MRI when it is typical. Biopsy or angiography are required for atypical forms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Recent studies have evaluated prenatal exome sequencing (pES) for abnormalities of the corpus callosum (CC). The objective of this study was to compare imaging phenotype and genotype findings., Method: This multicenter retrospective study included fetuses with abnormalities of the CC between 2018 and 2020 by ultrasound and/or MRI and for which pES was performed. Abnormalities of the CC were classified as complete (cACC) or partial (pACC) agenesis of the CC, short CC (sCC), callosal dysgenesis (CD), interhemispheric cyst (IHC), or pericallosal lipoma (PL), isolated or not. Only pathogenic (class 5) or likely pathogenic (class 4) (P/LP) variants were considered., Results: 113 fetuses were included. pES identified P/LP variants for 3/29 isolated cACC, 3/19 isolated pACC, 0/10 isolated sCC, 5/10 isolated CD, 5/13 non-isolated cACC, 3/6 non-isolated pACC, 8/11 non-isolated CD and 0/12 isolated IHC and PL. Associated cerebellar abnormalities were significantly associated with P/LP variants (OR = 7.312, p = 0.027). No correlation was found between phenotype and genotype, except for fetuses with a tubulinopathy and an MTOR pathogenic variant., Conclusions: P/LP variants were more frequent in CD and in non-isolated abnormalities of the CC. No such variants were detected for fetuses with isolated sCC, IHC and PL., (© 2023 John Wiley & Sons Ltd.)

In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its noncoding gene, RNU4ATAC , has been found mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy, and immunodeficiency. Here, we report bi-allelic RNU4ATAC mutations in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS, thus widening the clinical spectrum of RNU4ATAC -associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. Intriguingly, all five patients carry the n.16G>A mutation, in the Stem II domain, either at the homozygous or compound heterozygous state. A gene ontology term enrichment analysis on minor intron-containing genes reveals that the cilium assembly process is over-represented, with no less than 86 cilium-related genes containing at least one minor intron, among which there are 23 ciliopathy-related genes. The link between RNU4ATAC mutations and ciliopathy traits is supported by alterations of primary cilium function in TALS and JBTS-like patient fibroblasts, as well as by u4atac zebrafish model, which exhibits ciliopathy-related phenotypes and ciliary defects. These phenotypes could be rescued by WT but not by pathogenic variants-carrying human U4atac. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.

Background: Subjects with Megalencephaly-Capillary Malformation-Polymicrogyria syndrome (MCAP) can present with a Chiari Malformation Type 1 and resulting alterations in cerebrospinal fluid (CSF) dynamics, which may require surgical treatment. The aim of this paper is to describe the features of children with MCAP who underwent surgical decompression for CM1, and to explore the PIK3CA variant allele frequency (VAF) identified in cerebellar parenchyma and other adjacent structures., Methods: This study reviewed two cases of children with CM1 and MCAP who underwent surgical decompression treatment. These two cases were part of a national cohort of 12 MCAP patients who had CM1, due to their surgical eligibility. Tissue samples were obtained from the cerebellar tonsils and adjacent anatomical structures during the surgical procedures. Samples were then subsequently analyzed for PIK3CA postzygotic variants., Results: In both cases, alterations in CSF dynamics, specifically hydrocephalus and syringomyelia, were observed and required surgical treatment. PIK3CA targeted sequencing determined the VAF of the postzygotic variant in both cerebellar and adjacent bone/connective tissues., Discussion: The recognition of a CM1 comorbidity in MCAP patients is of paramount importance when considering personalized treatment options, especially because these patients are at higher risk of developing complications during surgical decompression surgery. The variable PIK3CA VAF identified in the different analyzed tissues might help explain the heterogeneous nature and severity of anomalies observed in the volume of the posterior fossa structures in MCAP patients and associated CSF and venous disorders., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Masson SAS.)

Competing Interests: Conflicts of interest: the authors declare they have no conflicts of interest.

Cystic lymphatic malformations (LMs) are rare chronic conditions which management differs according to the type (macrocystic LMs, microcystic LMs or both). Studies are lacking due to rarity of the pathology. We aimed to establish a French National Diagnosis and Care Protocol (PNDS: Protocole National de Diagnostic et de Soins), to provide health professionals with free open access synthesis on optimal management and care of patients with LMs ( https://www.has-sante.fr/upload/docs/application/pdf/2021-03/malformations&#95;lymphatiques&#95;kystiques&#95;-&#95;pnds.pdf ). The process included a critical review of the literature and multidisciplinary expert consensus. LMs are congenital but are not always discovered at birth. Nearly 75% of them are located in the head and neck because of the highly dense lymphatic system in this region. Physical examination (showing painless masses with normal skin color and depressible consistency, or cutaneous/mucosal lymphangiectasia) and color Doppler ultrasonography, usually allow for diagnosis. MRI (involving T2 sequences with fat saturation in at least two spatial planes) is the tool of choice for evaluating anatomical extension, characterizing lesions (microcystic and macrocystic), and before considering therapeutic management. A biopsy, coupled to a blood sample, can also be used for molecular biology analyses, to search for activating mutations of the PIK3CA gene, particularly with LM integrating in a syndromic form (CLOVES or Klippel-Trenaunay syndrome) but also in certain isolated (or common) LMs. The spontaneous evolution of LMs, in particular microcystic forms, is often toward progressive aggravation, with an increase in the number of vesicles, thickening, increased oozing and bleeding, while pure macrocystic LMs may regress due to "natural sclerosis", i.e. fibrosis secondary to an inflammatory reorganization after common infantile infections. In case of voluminous LMs or syndromic forms, functional and psychological repercussions can be major, deteriorating the patient's quality of life. LMs must be treated by physicians integrated in multidisciplinary teams, and be personalized. Management is a life-long process that involves one or several of these therapies: conservative management, physical therapy (compression), sclerotherapy, surgery, drugs such as mTOR inhibitors (sirolimus), that has shown efficacy in decreasing the volume of LMs, and, more recently, PI3K-inhibitors in syndromic forms. Psychological and social support is necessary, taking into account the patient and his family., (© 2023. The Author(s).)

Introduction: Our objective was to evaluate the outcome of fetuses with first- and second-trimester fetal cytomegalovirus infection (CMVi) according to prenatal imaging patterns, especially fetuses presenting with mild imaging features (MF), being currently of uncertain prognosis., Material and Methods: In a retrospective study of 415 suspected CMVi cases, 59 cases were confirmed. Among prenatal imaging features, microcephaly, cortical disorder, and cerebellar hypoplasia as well as severe IUGR and fetal hydrops were considered as severe imaging features (SF). Other imaging features were considered as MF. Postnatal outcome was classified as "normal outcome," "mild sequelae" characterized mainly by sensorineural disorder (SND) and "severe sequelae" characterized by cognitive impairment., Results: Only first-trimester (T1) and second-trimester (T2) CMVi cases were included in our study (n = 49) since all third-trimester cases (n = 10) had normal imaging and outcome. Sixteen fetuses had normal prenatal imaging and normal outcome, except one showing SND. Abnormal ultrasound findings were present in 33 fetuses, including SF noted in 16 fetuses, related exclusively to first-trimester CMVi. Termination of pregnancy was performed in 18 cases. Twelve first-trimester infected fetuses presented SF, whereas 6 fetuses (T1: n = 5, T2: n = 1) presented isolated MF. Four fetal deaths were encountered. Live-born babies with abnormal imaging included 10 fetuses with MF and one with SF. Among the 10 live babies with isolated MF, SND was encountered in 5 cases, whereas 5 children demonstrated normal outcome. Overall, 50% of our babies showing MF suffered from SND. No case of cognitive disorders was reported in babies showing only MF., Conclusion: SF were encountered only in first-trimester CMVi and should be distinguished from MF. Among our 10 live babies with prenatal MF following first- or second-trimester infection, 50% showed SND, whereas none presented severe sequelae. In 16 fetuses displaying normal fetal imaging, SND was encountered in one first-trimester case (6%)., (© 2023 S. Karger AG, Basel.)

PIK3CA -related overgrowth syndrome (PROS) is a genetic disorder caused by somatic mosaic gain-of-function mutations of PIK3CA . Clinical presentation of patients is diverse and associated with endocrine disruption. Adipose tissue is frequently involved, but its role in disease development and progression has not been elucidated. Here, we created a mouse model of PIK3CA -related adipose tissue overgrowth that recapitulates patient phenotype. We demonstrate that PIK3CA mutation leads to GLUT4 membrane accumulation with a negative feedback loop on insulin secretion, a burst of liver IGFBP1 synthesis with IGF-1 sequestration, and low circulating levels. Mouse phenotype was mainly driven through AKT2. We also observed that PIK3CA mutation induces metabolic reprogramming with Warburg-like effect and protein and lipid synthesis, hallmarks of cancer cells, in vitro, in vivo, and in patients. We lastly show that alpelisib is efficient at preventing and improving PIK3CA -adipose tissue overgrowth and reversing metabolomic anomalies in both animal models and patients.

Intra-mandibular arteriovenous malformations (IM-AVM) are rare congenital lesions sadly known by the appearance of cataclysmic haemorrhages. It represents a therapeutic challenge which requires a multidisciplinary approach. This paper aims to evaluate the characteristics and management of IM-AVM through the illustration of six case reports, the largest serie in the literature to our knowledge. This retrospective study included all patients with IM-AVM treated in the hospital of Lyon and Saint-Etienne between 1982 and 2021, in France. The management of mandibular AVMs should be individualized and permanently adjusted according to their stage of development, which makes their management difficult. Furthermore, long-term follow-up is essential to detect and manage the subclinical progression of the lesion. Based on these results and a systematic review of the literature, an algorithm has been developed to guide the treatment strategy for this are pathology., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Ewing sarcoma (ES) is a highly malignant round cell sarcoma, characterized by gene fusion involving FET (FUS, EWSR1, TAF15) and ETS family genes, respectively. The involvement of the EWSR1 gene has been reported in approximately 90% of cases of ES, with the EWSR1::FLI1 fusion being the most frequent. We report the case of a newborn with a localized soft tissue paravertebral neoplasm diagnosed prenatally. Histopathology and immunophenotype were consistent with a CD99 + , NKX2.2 + undifferentiated round cell sarcoma (URSC); whole-exome RNA-sequencing demonstrated an undescribed in-frame TAF15::ETV4 fusion transcript, while consensus clustering analysis showed high transcriptomic proximity to the ES group. Given clinical context, high tumor chemosensitivity to ES conventional drugs, morphological characteristics, nature of the fusion partners involved, and high transcriptomic proximity to bona fide ESs, this case may represent a new genetic variant of ES., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well-known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27-41%) or presenting with an overlapping syndrome (5/27-19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases., (© 2022 Wiley Periodicals LLC.)

Background: Severe neonatal jaundice resulting from elevated levels of unconjugated bilirubin in the blood induces dramatic neurological impairment. Central oxidative stress and an inflammatory response have been associated with the pathophysiological mechanism. Cells forming the blood-brain barrier and the choroidal blood-CSF barrier are the first CNS cells exposed to increased plasma levels of unconjugated bilirubin. These barriers are key regulators of brain homeostasis and require active oxidative metabolism to fulfill their protective functions. The choroid plexus-CSF system is involved in neuroinflammatory processes. In this paper, we address the impact of neonatal hyperbilirubinemia on some aspects of brain barriers. We describe physiological changes in the neurovascular network, blood-brain/CSF barriers integrities, and CSF cytokine levels during the postnatal period in normobilirubinemic animals, and analyze these parameters in parallel in Gunn rats that are deficient in bilirubin catabolism and develop postnatal hyperbilirubinemia., Methods: Gunn rats bearing a mutation in UGT1a genes were used. The neurovascular network was analyzed by immunofluorescence stereomicroscopy. The integrity of the barriers was evaluated by [ 14 C]-sucrose permeability measurement. CSF cytokine levels were measured by multiplex immunoassay. The choroid plexus-CSF system response to an inflammatory challenge was assessed by enumerating CSF leukocytes., Results: In normobilirubinemic animals, the neurovascular network expands postnatally and displays stage-specific regional variations in its complexity. Network expansion is not affected by hyperbilirubinemia. Permeability of the blood-brain and blood-CSF barriers to sucrose decreases between one- and 9-day-old animals, and does not differ between normobilirubinemic and hyperbilirubinemic rats. Cytokine profiles differ between CSF and plasma in all 1-, 9-, and 18-day-old animals. The CSF cytokine profile in 1-day-old animals is markedly different from that established in older animals. Hyperbilirubinemia perturbs these cytokine profiles only to a very limited extent, and reduces CSF immune cell infiltration triggered by systemic exposure to a bacterial lipopeptide., Conclusion: The data highlight developmental specificities of the blood-brain barrier organization and of CSF cytokine content. They also indicate that a direct effect of bilirubin on the vascular system organization, brain barriers morphological integrity, and inflammatory response of the choroid plexus-CSF system is not involved in the alteration of brain functions induced by severe neonatal jaundice., (© 2022. The Author(s).)

Purpose: To characterize natural history and early changes of craniovertebral junction stenosis in achondroplasia correlating with clinical and radiological outcome., Methods: Retrospective measures on craniovertebral junction were performed blindly, on sagittal T2-weighted images, in 21 patients with achondroplasia referred from 2008 to 2020. Clinical and polysomnography data were retrospectively collected. Each patient was paired for age and gender with four controls. Wilcoxon means comparison or Student's t-tests were applied., Results: Twenty-one patients (11 females, from 0.1 to 39 years of age) were analyzed and paired with 84 controls. A craniovertebral junction stenosis was found in 11/21 patients (52.4%), all before the age of 2 years. Despite a significant reduction of the foramen magnum diameter (mean ± SD: patients 13.6 ± 6.2 mm, controls 28.5 ± 4.7 mm, p < .001), craniovertebral junction stenosis resulted from the narrowing of C2 dens-opisthion antero-posterior diameter (8.7 ± 3.9 mm vs 24.6 ± 5.1 mm, p < .001). Other significant changes were opisthion anterior placement (-0.4 ± 2.8 mm vs 9.4 ± 2.3 mm, p < .001), posterior tilt of C2 (46.2 ± 13.7° vs 31.6 ± 7.9°, p < .001) and of C1 (15.1 ± 4.3° vs 11.9 ± 5.0°, p = 0.01), and dens thickening (9.4 ± 2.2 mm vs 8.5 ± 2.1 mm, p = 0.03), allowing to define three distinguishable early craniovertebral junction patterns in achondroplasia. All children with C2-opisthion antero-posterior diameter of more than 6 mm had a better clinical and radiological outcome., Conclusion: Craniovertebral junction in achondroplasia results from narrowing between C2 dens and opisthion related to anterior placement of opisthion, thickening of C2 dens, and posterior tilt of C1-C2. A threshold of 6 mm for dens-opisthion sagittal diameter seems to correlate with clinical and radiological outcome., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To characterize a suggestive prenatal imaging pattern of Aicardi syndrome using ultrasound and MR imaging., Methods: Based on a retrospective international series of Aicardi syndrome cases from tertiary centers encountered over a 20-year period (2000-2020), we investigated the frequencies of the imaging features in order to characterize an imaging pattern highly suggestive of the diagnosis., Results: Among 20 cases included, arachnoid cysts associated with a distortion of the interhemispheric fissure were constantly encountered associated with complete or partial agenesis of the corpus callosum (19/20, 95%). This triad in the presence of other CNS disorganization, such as polymicrogyria (16/17, 94%), heterotopias (15/17, 88%), ventriculomegaly (14/20, 70%), cerebral asymmetry [14/20, 70%]) and less frequently extra-CNS anomaly (ocular anomalies [7/11, 64%], costal/vertebral segmentation defect [4/20, 20%]) represent a highly suggestive pattern of Aicardi syndrome in a female patient., Conclusion: Despite absence of genetic test to confirm prenatal diagnosis of AS, this combination of CNS and extra-CNS fetal findings allows delineation of a characteristic imaging pattern of AS, especially when facing dysgenesis of the corpus callosum., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

PIK3CA-related overgrowth spectrum (PROS) includes rare genetic conditions due to gain-of-function mutations in the PIK3CA gene. There is no approved medical therapy for patients with PROS, and alpelisib, an approved PIK3CA inhibitor in oncology, showed promising results in preclinical models and in patients. Here, we report for the first time the outcome of two infants with PROS having life-threatening conditions treated with alpelisib (25 mg) and monitored with pharmacokinetics. Patient 1 was an 8-mo-old girl with voluminous vascular malformation. Patient 2 was a 9-mo-old boy presenting with asymmetrical body overgrowth and right hemimegalencephaly with West syndrome. After 12 mo of follow-up, alpelisib treatment was associated with improvement in signs and symptoms, morphological lesions and vascular anomalies in the two patients. No adverse events were reported during the study. In this case series, pharmacological inhibition of PIK3CA with low-dose alpelisib was feasible and associated with clinical improvements, including a smaller size of associated complex tissue malformations and good tolerability., Competing Interests: Disclosures: F. Dubos reported personal fees from Sanofi-Pasteur, MSD, and Takeda outside the submitted work. T.K. Han reported being an employee at Novartis. F. Branle reported "other" from Novartis.Pharma.AG during the conduct of the study; and is a full-time employee of Novartis.Pharma AG Switzerland. A patent application (“BYL719 [alpelisib] for use in the treatment of PIK3CA-related overgrowth spectrum”; #WO2017140828A1) has been filed by Institut National de la Santé et de la Recherche Médicale, Centre National De La Recherche Scientifique, Université Paris Descartes, and Assistance Publique-Hôpitaux De Paris for the use of BYL719 (alpelisib) in the treatment of PIK3CA-related overgrowth spectrum (PROS/CLOVES syndrome). G. Canaud is the inventor. G. Canaud receives or has received consulting fees from Novartis, Vaderis, Fresenius Medical Care, Alkermes, IPSEN, and BridgeBio. No other disclosures were reported., (© 2022 Morin et al.)