Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cell differentiation.

Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.

Loss-of-function variants in ZEB1 cause dominant anomalies of the corpus callosum with favourable cognitive prognosis.

BACKGROUND: The neurodevelopmental prognosis of anomalies of the corpus callosum (ACC), one of the most frequent brain malformations, varies extremely, ranging from normal development to profound intellectual disability (ID). Numerous genes are known to cause syndromic ACC with ID, whereas the genetics of ACC without ID remains poorly deciphered. METHODS: Through a collaborative work, we describe here ZEB1, a gene previously involved in an ophthalmological condition called type 3 posterior polymorphous corneal dystrophy, as a new dominant gene of ACC. We report a series of nine individuals with ACC (including three fetuses terminated due to ACC) carrying a ZEB1 heterozygous loss-of-function (LoF) variant, identified by exome sequencing. RESULTS: In five cases, the variant was inherited from a parent with a normal corpus callosum, which illustrates the incomplete penetrance of ACC in individuals with an LoF in ZEB1. All patients reported normal schooling and none of them had ID. Neuropsychological assessment in six patients showed either normal functioning or heterogeneous cognition. Moreover, two patients had a bicornuate uterus, three had a cardiovascular anomaly and four had macrocephaly at birth, which suggests a larger spectrum of malformations related to ZEB1. CONCLUSION: This study shows ZEB1 LoF variants cause dominantly inherited ACC without ID and extends the extraocular phenotype related to this gene.

Further characterisation of ARX-related disorders in females due to inherited or de novo variants.

The Aristaless-related homeobox (ARX) gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical spectrum of ARX-related disorders is well described in males, from X linked lissencephaly with abnormal genitalia syndrome to syndromic and non-syndromic intellectual disability (ID), its phenotypic delineation in females is incomplete. Carrier females in ARX families are usually asymptomatic, but ID has been reported in some of them, as well as in others with de novo variants. In this study, we collected the clinical and molecular data of 10 unpublished female patients with de novo ARX pathogenic variants and reviewed the data of 63 females from the literature with either de novo variants (n=10), inherited variants (n=33) or variants of unknown inheritance (n=20). Altogether, the clinical spectrum of females with heterozygous pathogenic ARX variants is broad: 42.5% are asymptomatic, 16.4% have isolated agenesis of the corpus callosum (ACC) or mild symptoms (learning disabilities, autism spectrum disorder, drug-responsive epilepsy) without ID, whereas 41% present with a severe phenotype (ie, ID or developmental and epileptic encephalopathy (DEE)). The ID/DEE phenotype was significantly more prevalent in females carrying de novo variants (75%, n=15/20) versus in those carrying inherited variants (27.3%, n=9/33). ACC was observed in 66.7% (n=24/36) of females who underwent a brain MRI. By refining the clinical spectrum of females carrying ARX pathogenic variants, we show that ID is a frequent sign in females with this X linked condition.

Brain Metabolite Differences in Fetuses With Cytomegalovirus Infection: A Magnetic Resonance Spectroscopy Study.

BACKGROUND: Cytomegalovirus (CMV) is the most common intrauterine infection and may be associated with unfavorable outcomes. While some CMV-infected fetuses may show gross or subtle brain abnormalities on MRI, their clinical significance may be unclear. Conversely, normal development cannot be guaranteed in CMV-infected fetuses with normal MRI. PURPOSE: To assess brain metabolite differences in CMV-infected fetuses using magnetic resonance spectroscopy (MRS). STUDY TYPE: Retrospective. SUBJECTS: Out of a cohort of 149 cases, 44 with maternal CMV infection, amniocentesis results, and good-quality MRS were included. CMV-infected fetuses with positive polymerase chain reaction (PCR) (N = 35) were divided based on MRI results as follows: typical brain abnormalities (gross findings, N = 8), exclusive white matter hyperintense signal (WMHS) on T2-weighted images (subtle findings, N = 7), and normal MRI (N = 20). Uninfected fetuses (negative PCR) with normal MRI were included as controls (N = 9). FIELD STRENGTH: 3 T, T2-weighted half Fourier single-shot turbo spin-echo (HASTE), T2-weighted true fast imaging with steady-state free precession (TrueFISP), T1- and T2*-weighted fast low angle shot (FLASH), and 1H-MRS single-voxel point resolved spectroscopy (PRESS) sequences. ASSESSMENT: MRI findings were assessed by three radiologists, and metabolic ratios within the basal ganglia were calculated using LCModel. STATISTICAL TESTS: Analysis of covariance test with Bonferroni correction for multiple comparisons was used to compare metabolic ratios between groups while accounting for gestational age. A P-value <0.05 was deemed significant. RESULTS: MRS was successfully acquired in 63% of fetuses. Substantial agreement was observed between radiologists (Fleiss' kappa [k] = 0.8). Infected fetuses with gross MRI findings exhibited significantly reduced tNAA/tCr ratios (0.64 ± 0.08) compared with infected fetuses with subtle MRI findings (0.85 ± 0.19), infected fetuses with normal MRI (0.8 ± 0.14) and controls (0.81 ± 0.15). No other significant differences were detected (P ≥ 0.261). CONCLUSION: Reduced tNAA/tCr within the apparently normal brain tissue was detected in CMV-infected fetuses with gross brain abnormalities, suggesting extensive brain damage. In CMV-infected fetuses with isolated WMHS, no damage was detected by MRS. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Proposal for standardized prenatal assessment of fetal open dysraphisms by the European reference network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies (ITHACA) and eUROGEN.

Open dysraphisms, that is, myelomeningocele and myeloschisis, are rare diseases associated with a risk of severe disability, including lower limb motor and sensory deficiency, sphincter deficiency, and potential intellectual deficiency. Open dysraphism is diagnosed in Europe in 93.5% of cases. In case of suspicion of fetal open dysraphism, a detailed fetal morphologic assessment is required to confirm the diagnosis and exclude associated structural anomalies, as well as genetic assessment. In case of isolated fetal open dysraphism, assessment of prognosis is based on fetal imaging including the level of the lesion, the presence or not of a sac, the presence and nature of intra cranial anomalies, and the anatomical and functional evaluation of the lower extremities. Based on these biomarkers, a personalized prognosis as well as comprehensive information about prenatal management alternatives will allow parents to decide on further management options. Standardization of prenatal assessment is essential to compare outcomes with benchmark data and make assessment of surgical innovation possible. Herein, we propose a protocol for the standardized ultrasound assessment of fetuses with isolated open dysraphism.

Prenatal diagnosis of pontocerebellar hypoplasia with postnatal follow-up.

OBJECTIVE: To describe the MR features enabling prenatal diagnosis of pontocerebellar hypoplasia (PCH). METHOD: This was a retrospective single monocentre study. The inclusion criteria were decreased cerebellar biometry on dedicated neurosonography and available fetal Magnetic Resonance Imaging (MRI) with PCH diagnosis later confirmed either genetically or clinically on post-natal MRI or by autopsy. The exclusion criteria were non-available MRI and sonographic features suggestive of a known genetic or other pathologic diagnosis. The collected data were biometric or morphological imaging parameters, clinical outcome, termination of pregnancy (TOP), pathological findings and genetic analysis (karyotyping, chromosomal microarray, DNA sequencing targeted or exome). PCH was classified as classic, non-classic, chromosomal, or unknown type. RESULTS: Forty-two fetuses were diagnosed with PCH, of which 27 were referred for decreased transverse cerebellar diameter at screening ultrasound. Neurosonography and fetal MRI were performed at a mean gestational age of 29 + 4 and 31 + 0 weeks, respectively. Termination of pregnancy occurred. Pregnancy was terminated in 24 cases. Neuropathological examination confirmed the diagnosis in 24 cases and genetic testing identified abnormalities in 29 cases (28 families, 14 chromosomal anomaly). Classic PCH is associated with pontine atrophy and small MR measurements decreasing with advancing gestation. CONCLUSION: This is the first large series of prenatally diagnosed PCHs. Our study shows the essential contribution of fetal MRI to the prenatal diagnosis of PCH. Classic PCHs are particularly severe and are associated with certain MR features.

New insights into CC2D2A-related Joubert syndrome.

PURPOSE: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A. METHODS: We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature. RESULTS: Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype. CONCLUSION: This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.

Reversed cortico-medullary differentiation in the fetal and neonatal kidneys: an indicator of poor prognosis?

BACKGROUND: Bilateral reversed cortico-medullary differentiation is rarely observed on fetal or neonatal renal ultrasound and is therefore a diagnostic challenge. OBJECTIVE: Our purpose was to widen the differential diagnoses of fetal and neonatal nephropathies introducing reversed cortico-medullary differentiation as a clue either on obstetric US or during follow-up of hyperechoic kidneys in order to improve the management of such rare clinical situations. MATERIALS AND METHODS: We retrospectively reviewed the US images of 11 patients showing bilateral reversed cortico-medullary differentiation on prenatal examination or in which this pattern developed postnatally in the follow-up of fetal hyperechoic kidneys. For each patient, a precise diagnosis was established either on clinical assessment or, when available, on histological or genetic findings. RESULTS: Six fetuses displayed bilateral reversed cortico-medullary differentiation on obstetric examination, and the pattern persisted throughout pregnancy. In the five other fetuses, the kidneys appeared initially homogeneously hyperechoic; this evolved into reversed cortico-medullary differentiation during the third trimester in two cases and shortly after birth in three cases. Two pregnancies were terminated because of estimated poor prognosis. In the nine surviving neonates, four died of renal failure in the post-natal period. The clinical evolution was more favorable in the remaining five newborns. CONCLUSIONS: Six different diagnoses were established in patients presenting with a reversed cortico-medullary differentiation renal pattern. This finding was associated with poor outcome in six cases. An acute prenatal diagnosis of reversed cortico-medullary differentiation improves pre- and postnatal work-up and guides counseling and genetic testing.

Standardised and structured reporting in fetal magnetic resonance imaging: recommendations from the Fetal Task Force of the European Society of Paediatric Radiology.

Over the last decades, magnetic resonance imaging (MRI) has emerged as a valuable adjunct to prenatal ultrasound for evaluating fetal malformations. Several radiological societies advocate for standardised and structured reporting practices to enhance the uniformity of imaging language. Compared to narrative formats, standardised and structured reports offer enhanced content quality, minimise reader variability, have the potential to save reporting time, and streamline the communication between specialists by employing a shared lexicon. Structured reporting holds promise for mitigating medico-legal liability, while also facilitating rigorous scientific data analyses and the development of standardised databases. While structured reporting templates for fetal MRI are already in use in some centres, specific recommendations and/or guidelines from international societies are scarce in the literature. The purpose of this paper is to propose a standardised and structured reporting template for fetal MRI to assist radiologists, particularly those with less experience, in delivering systematic reports. Additionally, the paper aims to offer an overview of the anatomical structures that necessitate reporting and the prevalent normative values for fetal biometrics found in current literature.

Prenatal imaging of the normal and abnormal spinal cord: recommendations from the Fetal Task Force of the European Society of Paediatric Radiology (ESPR) and the European Society of Neuroradiology (ESNR) Pediatric Neuroradiology Committee.

Spinal dysraphisms are amenable to diagnosis in utero. The prognosis and the neonatal management of these conditions differ significantly depending on their types, mainly on the distinction between open and closed defects. A detailed evaluation not only of the fetal spine, but also of the brain, skull, and lower limbs is essential in allowing for the right diagnosis. In this article, recommendations from the Fetal Task Force of the European Society of Paediatric Radiology (ESPR) and the European Society of Neuroradiology (ESNR) Pediatric Neuroradiology Committee will be presented. The aim of this paper is to review the imaging features of the normal and abnormal fetal spinal cord, to clarify the prenatal classification of congenital spinal cord anomalies and to provide guidance in their reporting.

Predictive factors for survival in patients with oligohydramnios secondary to antenatal kidney disease.

BACKGROUND: Renal oligohydramnios (ROH) is caused by bilateral congenital abnormalities, either of renal parenchymal or obstructive origin. ROH is a poor prognostic factor of neonatal survival; lung hypoplasia is reported to be the main cause of mortality. We aimed to describe the fetal morbidity and pre- and postnatal mortality in case of ROH due to renal congenital pathologies and to find predictive risk factors for morbidity and mortality. METHODS: All data were collected in Trousseau Hospital in the obstetric, neonatology, and pediatric nephrology units, from 2008 to 2020. RESULTS: We included 66 fetuses with renal parenchymal pathologies posterior urethral valves (PUV) (N = 25), bilateral kidney agenesis (N = 10), hypodysplasia (N = 16), and polycystic kidney disease (N = 10) causing oligohydramnios identified on antenatal ultrasound. Total pre- and postnatal mortality was 76% (50/66). Mortality, excepting termination of pregnancy (TOP), was 65%. The presence of pneumomediastinum and pneumothorax was not different in survivors and non-survivors. Fetuses with kidneys having features of hypodysplasia on ultrasound at T2 and those with oligohydramnios before 32 weeks GA had a higher risk of death. There was a significant difference in plasma creatinine of the surviving patients compared to the deceased patients, from day 3 onwards (183 µmol/L [88; 255] vs. 295 µmol/L [247; 326]; p = 0.038). CONCLUSIONS: The main differences between survivors and non-survivors among patients with "renal oligohydramnios" were oligohydramnios detection before 32 weeks GA, dysplasia detection on the second trimester ultrasound, and increase of serum creatinine from day 3 onwards. A higher resolution version of the Graphical abstract is available as Supplementary information.

Abnormalities of the corpus callosum. Can prenatal imaging predict the genetic status? Correlations between imaging phenotype and genotype.

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.

The fetal brain: migration and gyration anomalies - pre- and postnatal correlations.

The cerebral cortex represents a laminar structure of precisely spatially organized neurons in horizontal layers and vertical columns. Neurogenesis, neuronal migration and neuronal wiring are tightly regulated and coordinated procedures that result in the accurate formation of the human cerebral cortex. Abnormal fetal corticogenesis results in several types of migration and gyration anomalies, known as malformations of cortical development, which have long been a topic of investigation. According to the stage of cortical development that is affected, with diverse genetic and non-genetic etiologies, these malformations can cause abnormal head size, abnormal brain surface and abnormal cortical layering with various degrees of neurodevelopmental delay and epilepsy. The pathogenesis of these malformations is multifactorial and includes genetic mutations or environmental insults, acquired either in utero at varying stages of brain development or during the perinatal period after corticogenesis. In this article, we focus on cortical malformations detected on fetal MRI. We present the main antenatal findings that should raise suspicion for malformations of cortical development, together with findings that might be missed on prenatal imaging and describe the correlations between fetal and postnatal MRI.

Anomalies of the fetal gallbladder: pre-and postnatal correlations.

The gallbladder is not part of the standard survey of a fetus during obstetrical ultrasound. Yet, some anomalies can be detected. Most are clinically benign, but some are features of or associated with more serious complications. Biliary atresia constitutes the diagnosis with the worst prognosis. Its in utero diagnosis is difficult. Still, markers do exist and should be searched for. Knowledge of the normal appearances, variants and abnormalities of the gallbladder contributes to proper management. Any suspicion should lead to meticulous postnatal workup. Pre- or postnatal magnetic resonance imaging can provide additional information in select cases.

Indications for magnetic resonance imaging of the fetal body (extra-central nervous system): recommendations from the European Society of Paediatric Radiology Fetal Task Force.

The indications for fetal body MRI are amplifying because of the expanding possibilities of fetal and perinatal therapy. However, huge heterogeneity regarding the indications for fetal body MRI is seen among different European countries that is mostly related to local use of US, but also to local fetal MRI expertise and legislation on pregnancy termination. The purpose of this article is to summarize the precise indications for fetal MRI, excluding the central nervous system. MRI indications arise from the sonographic findings, based on the operator's experience and the various practices in the countries and institutions represented on the European Society of Paediatric Radiology Fetal Task Force. We also highlight the strengths and weaknesses of fetal US and MRI of the fetal body.

Exploration of the fetal skeleton by ultra-low-dose computed tomography: guidelines from the Fetal Imaging Task Force of the European Society of Paediatric Radiology.

Skeletal anomalies are rare, requiring a systematic ultrasound (US) examination of each skeletal part when there is suspicion of a skeletal dysplasia. Although US examination can provide good evaluation of the fetal bones and cartilage, ultra-low-dose three-dimensional (3-D) multi-detector computed tomography (CT) is a useful complementary tool that can significantly improve prenatal diagnostic accuracy in select cases. Given that ultra-low-dose fetal CT remains an irradiating technique, indications should result from a multidisciplinary consensus, acquisition protocols should be optimized and the reporting standardized. In this paper we discuss guidelines from the Fetal Imaging Task Force of the European Society of Paediatric Radiology for indications, protocols and reporting of ultra-low-dose fetal CT.

Prenatal diagnosis of vermian cyst: a new type of posterior fossa cyst.

BACKGROUND: Prenatal diagnoses of cystic malformations of the posterior fossa mainly encompass arachnoid cysts, Blake's pouch cysts and Dandy-Walker syndrome. To date, vermian cysts have not been reported prenatally. OBJECTIVES: To report a series of fetuses with a vermian cyst. MATERIALS AND METHODS: This was a single-center retrospective study conducted from 2012 to 2021. We included all fetuses presenting with a vermian cyst and excluded all other types of posterior fossa cyst. The cyst was visible at prenatal ultrasound (US) and/or magnetic resonance imaging (MRI). Postnatal imaging and/or clinical outcome data were available. RESULTS: Sixteen fetuses fulfilled the inclusion criteria with a strong female predominance (n=13). US and MRI were performed at a mean gestational age of 29+5 and 33+1 weeks, respectively. In all patients, the cyst was in the vermian horizontal fissure. The mean longest dimension was about 10 mm. The vermis and other posterior fossa structures were otherwise normal. At postnatal imaging, 13 children underwent brain imaging including 11 MRIs with complete regression (n=9), stability (n=1) and increase in size (n=3) of the cyst. Psychomotor development was normal in 14 children. One child (with an inner ear malformation) showed a slight delay in walking and language acquisition. Slight walking ataxia was present in another child. CONCLUSION: We report 16 fetuses with posterior fossa cysts located within the vermis at the level of the horizontal fissure, diagnosed at US and/or MRI and carrying an overall excellent neurological prognosis.

Imaging Factors Affecting Prenatal Counseling in Orofacial Clefts.

INTRODUCTION: We aim to correlate pre- and postnatal data regarding the cleft type and surgical prognostic factors associated to orofacial clefts. METHODS: Retrospective study concerning all cases of orofacial cleft evaluated prenatally (US+/-MRI) between 2015 and 2020 with available postnatal outcomes. We compared prenatal imaging (cleft type and surgical prognostic factors) with postnatal findings. RESULTS: 48 fetuses were included. Median gestational age at first US/MRI examination: 29+2 WG and 31+6 WG, respectively. The prenatal diagnosis was in accordance with postnatal findings with regard to the cleft type in 88% of the cases (n = 42/48) for US and/or MRI, 84% (n = 38/45) for US only, and 90% (n = 37/41) for MRI only. The nasal septum deviation and nostril collapse were underestimated by prenatal US in 48% (n = 12/25) and 44% (n = 11/25) of cases, respectively (Cohen's kappa of 0.22 and 0.32, respectively). Pre- and postnatal examinations were in accordance with 75% of cases (n = 8) regarding evaluation of anteroposterior maxillary shift in case of unilateral alveolar cleft and in 90% and 80% of cases (n = 10) regarding the degree of protrusion/deviation of the premaxillary protrusion in case of bilateral cleft, respectively. CONCLUSION: Prenatal imaging can accurately assess the type of orofacial cleft and evaluate maxillary shift and deviation of the premaxilla. It underestimates the nose deformity.

Neurodevelopmental phenotype in 36 new patients with 8p inverted duplication-deletion: Genotype-phenotype correlation for anomalies of the corpus callosum.

Inverted duplication deletion 8p [invdupdel(8p)] is a complex and rare chromosomal rearrangement that combines a distal deletion and an inverted interstitial duplication of the short arm of chromosome 8. Carrier patients usually have developmental delay and intellectual disability (ID), associated with various cerebral and extra-cerebral malformations. Invdupdel(8p) is the most common recurrent chromosomal rearrangement in ID patients with anomalies of the corpus callosum (AnCC). Only a minority of invdupdel(8p) cases reported in the literature to date had both brain cerebral imaging and chromosomal microarray (CMA) with precise breakpoints of the rearrangements, making genotype-phenotype correlation studies for AnCC difficult. In this study, we report the clinical, radiological, and molecular data from 36 new invdupdel(8p) cases including three fetuses and five individuals from the same family, with breakpoints characterized by CMA. Among those, 97% (n = 32/33) of patients presented with mild to severe developmental delay/ID and 34% had seizures with mean age of onset of 3.9 years (2 months-9 years). Moreover, out of the 24 patients with brain MRI and 3 fetuses with neuropathology analysis, 63% (n = 17/27) had AnCC. We review additional data from 99 previously published patients with invdupdel(8p) and compare data of 17 patients from the literature with both CMA analysis and brain imaging to refine genotype-phenotype correlations for AnCC. This led us to refine a region of 5.1 Mb common to duplications of patients with AnCC and discuss potential candidate genes within this region.

Prenatal bone abnormalities in three cases of familial hypocalciuric hypercalcemia.

INTRODUCTION: Prenatal diagnosis of bone and mineralization anomalies is associated with a wide range of etiologies and prognoses. The improvement of antenatal ultrasound combined with the development of molecular diagnosis in genetics has transformed antenatal medicine into a challenging discipline. Of the various known causes of bone abnormalities and hypomineralization, calcium and phosphate metabolism disorders are exceptional. An accurate diagnosis is crucial for providing appropriate genetic counseling and medical follow-up after birth. CASE: We report on three siblings with severe bone abnormalities diagnosed during the second trimester ultrasound of pregnancy. Postnatal follow-up showed transitory hyperparathyroidism, with hypercalcemia and hypocalciuria. METHODS: Sanger sequencing performed after birth in the three newborns revealed a monoallelic pathogenic variant in the CASR gene, encoding the calcium sensing receptor, confirming the diagnosis of familial hypocalciuric hypercalcemia, paternally inherited. Postnatal evolution was favorable after treatment with a calcimimetic agent. CONCLUSIONS: Previously, prenatal bone abnormalities caused by familial hypocalciuric hypercalcemia had only been described in one patient. This entity should be considered as differential diagnosis of bones abnormalities. Knowing about this unusual etiology is important to guide the diagnosis, the prenatal counseling and to improve medical management.