Molecular and Functional Characterization of Lymphoid Progenitor Subsets Reveals a Bipartite Architecture of Human Lymphopoiesis.

The classical model of hematopoiesis established in the mouse postulates that lymphoid cells originate from a founder population of common lymphoid progenitors. Here, using a modeling approach in humanized mice, we showed that human lymphoid development stemmed from distinct populations of CD127- and CD127+ early lymphoid progenitors (ELPs). Combining molecular analyses with in vitro and in vivo functional assays, we demonstrated that CD127- and CD127+ ELPs emerged independently from lympho-mono-dendritic progenitors, responded differently to Notch1 signals, underwent divergent modes of lineage restriction, and displayed both common and specific differentiation potentials. Whereas CD127- ELPs comprised precursors of T cells, marginal zone B cells, and natural killer (NK) and innate lymphoid cells (ILCs), CD127+ ELPs supported production of all NK cell, ILC, and B cell populations but lacked T potential. On the basis of these results, we propose a "two-family" model of human lymphoid development that differs from the prevailing model of hematopoiesis.

Homozygous MFN2 variants causing severe antenatal encephalopathy with clumped mitochondria.

Pathogenic variants in the MFN2 gene are commonly associated with autosomal dominant (CMT2A2A) or recessive (CMT2A2B) Charcot-Marie-Tooth disease, with possible involvement of the CNS. Here, we present a case of severe antenatal encephalopathy with lissencephaly, polymicrogyria and cerebellar atrophy. Whole genome analysis revealed a homozygous deletion c.1717-274_1734 del (NM_014874.4) in the MFN2 gene, leading to exon 16 skipping and in-frame loss of 50 amino acids (p.Gln574_Val624del), removing the proline-rich domain and the transmembrane domain 1 (TM1). MFN2 is a transmembrane GTPase located on the mitochondrial outer membrane that contributes to mitochondrial fusion, shaping large mitochondrial networks within cells. In silico modelling showed that the loss of the TM1 domain resulted in a drastically altered topological insertion of the protein in the mitochondrial outer membrane. Fetus fibroblasts, investigated by fluorescent cell imaging, electron microscopy and time-lapse recording, showed a sharp alteration of the mitochondrial network, with clumped mitochondria and clusters of tethered mitochondria unable to fuse. Multiple deficiencies of respiratory chain complexes with severe impairment of complex I were also evidenced in patient fibroblasts, without involvement of mitochondrial DNA instability. This is the first reported case of a severe developmental defect due to MFN2 deficiency with clumped mitochondria.

DST variants are responsible for neurogenic arthrogryposis multiplex congenita enlarging the spectrum of type VI hereditary sensory autonomic neuropathy.

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through whole-exome sequencing combined with arrayCGH from DNA of a fetus presenting with early onset AMC, we identified biallelic loss of function variants in Dystonin (DST): a stop gain variant (NM_001144769.5:c.12208G > T:p.(Glu4070Ter)) on the neuronal isoform and a 175 kb microdeletion including exons 25-96 of this isoform on the other allele [NC_000006.11:g.(56212278_56323554)_(56499398_56507586)del]. Transmission electron microscopy of the sciatic nerve revealed abnormal morphology of the peripheral nerve with severe hypomyelination associated with dramatic reduction of fiber density which highlights the critical role of DST in peripheral nerve axonogenesis during development in human. Variants in the neuronal isoforms of DST cause hereditary sensory and autonomic neuropathy which has been reported in several unrelated families with highly variable age of onset from fetal to adult onset. Our data enlarge the disease mechanisms of neurogenic AMC.

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita.

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families. METHODS: Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants. RESULTS: We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%). CONCLUSION: New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

Targeted next-generation sequencing in a large series of fetuses with severe renal diseases.

We report the screening of a large panel of genes in a series of 100 fetuses (98 families) affected with severe renal defects. Causative variants were identified in 22% of cases, greatly improving genetic counseling. The percentage of variants explaining the phenotype was different according to the type of phenotype. The highest diagnostic yield was found in cases affected with the ciliopathy-like phenotype (11/15 families and, in addition, a single heterozygous or a homozygous Class 3 variant in PKHD1 in three unrelated cases with autosomal recessive polycystic kidney disease). The lowest diagnostic yield was observed in cases with congenital anomalies of the kidney and urinary tract (9/78 families and, in addition, Class 3 variants in GREB1L in three unrelated cases with bilateral renal agenesis). Inheritance was autosomal recessive in nine genes (PKHD1, NPHP3, CEP290, TMEM67, DNAJB11, FRAS1, ACE, AGT, and AGTR1), and autosomal dominant in six genes (PKD1, PKD2, PAX2, EYA1, BICC1, and MYOCD). Finally, we developed an original approach of next-generation sequencing targeted RNA sequencing using the custom capture panel used for the sequencing of DNA, to validate one MYOCD heterozygous splicing variant identified in two male siblings with megabladder and inherited from their healthy mother.

Tonate Virus and Fetal Abnormalities, French Guiana, 2019.

We report a case of vertical transmission of Tonate virus in a pregnant woman from French Guiana. The fetus showed severe necrotic and hemorrhagic lesions of the brain and spinal cord. Clinicians should be made aware of possible adverse fetal outcomes in pregnant women infected with Tonate virus.

Evidence of disrupted rhombic lip development in the pathogenesis of Dandy-Walker malformation.

Dandy-Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH.

CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects.

BACKGROUND: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. METHODS: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. RESULTS: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. CONCLUSION: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. TRIAL REGISTRATION NUMBER: NCT01565005.

Finding vacuolated lymphocytes in fetal effusions improves the prenatal diagnosis of lysosomal storage diseases.

OBJECTIVES: There are many causes of fetal effusions, including the rare lysosomal storage diseases (LSDs). Vacuolated lymphocytes (VLs) are found in the blood of infants with LSDs, and their presence in fetal effusion could increase the risk of underlying LSD. METHODS: Between 2006 and 2018, all fetal effusions samples from 43 fetal multidisciplinary centers were referred to a single laboratory. Cells were counted, and, if observed, VLs were categorized and counted. Screening for LSDs was performed by metabolite analyses on amniotic fluid supernatant. The diagnosis of an LSD was confirmed by measuring the activity of the corresponding enzyme and/or mutation analysis. RESULTS: Our laboratory received 614 ascitic fluids and 280 pleural fluids sampled between 22 and 33 weeks of gestation. The final diagnosis was LSD in 16 cases (1.8%). VLs were reported in all these 16 cases, in a mix of lymphocytes with and without vacuoles. Vacuoles in VLs varied in size and number. In most cases, VLs were easy to recognize, with numerous, large, round, well-defined vacuoles, but in three cases of LSDs, VLs were atypical. CONCLUSION: The finding of VLs in fetal effusions is an inexpensive first-line test that may help to prioritize biochemical and genetic tests for LSDs.

Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis.

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through linkage analysis, homozygosity mapping, and exome sequencing in four unrelated families affected by lethal AMC, we identified biallelic mutations in GLDN in the affected individuals. GLDN encodes gliomedin, a secreted cell adhesion molecule involved in the formation of the nodes of Ranvier. Transmission electron microscopy of the sciatic nerve from one of the affected individuals showed a marked lengthening defect of the nodes. The GLDN mutations found in the affected individuals abolish the cell surface localization of gliomedin and its interaction with its axonal partner, neurofascin-186 (NF186), in a cell-based assay. The axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels at developing nodes. These results indicate a major role of gliomedin in node formation and the development of the peripheral nervous system in humans. These data indicate that mutations of GLDN or CNTNAP1 (MIM: 616286), encoding essential components of the nodes of Ranvier and paranodes, respectively, lead to inherited nodopathies, a distinct disease entity among peripheral neuropathies.

Bardet-Biedl syndrome: Antenatal presentation of forty-five fetuses with biallelic pathogenic variants in known Bardet-Biedl syndrome genes.

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.

Sostdc1 is expressed in all major compartments of developing and adult mammalian eyes.

PURPOSE: This study was conducted in order to study Sostdc1 expression in rat and human developing and adult eyes. METHODS: Using the yeast signal sequence trap screening method, we identified the Sostdc1 cDNA encoding a protein secreted by the adult rat retinal pigment epithelium. We determined by in situ hybridization, RT-PCR, immunohistochemistry, and western blot analysis Sostdc1 gene and protein expression in developing and postnatal rat ocular tissue sections. We also investigated Sostdc1 immunohistolocalization in developing and adult human ocular tissues. RESULTS: We demonstrated a prominent Sostdc1 gene expression in the developing rat central nervous system (CNS) and eyes at early developmental stages from E10.5 days postconception (dpc) to E13 dpc. Specific Sostdc1 immunostaining was also detected in most adult cells of rat ocular tissue sections. We also identified the rat ocular embryonic compartments characterized by a specific Sostdc1 immunohistostaining and specific Pax6, Sox2, Otx2, and Vsx2 immunohistostaining from embryonic stages E10.5 to E13 dpc. Furthermore, we determined the localization of SOSTDC1 immunoreactivity in ocular tissue sections of developing and adult human eyes. Indeed, we detected SOSTDC1 immunostaining in developing and adult human retinal pigment epithelium (RPE) and neural retina (NR) as well as in several developing and adult human ocular compartments, including the walls of choroidal and scleral vessels. Of utmost importance, we observed a strong SOSTDC1 expression in a pathological ocular specimen of type 2 Peters' anomaly complicated by retinal neovascularization as well in the walls ofother pathological extra-ocular vessels.  CONCLUSION: As rat Sostdc1 and human SOSTDC1 are dual antagonists of the Wnt/ß-catenin and BMP signaling pathways, these results underscore the potential crucial roles of these pathways and their antagonists, such as Sostdc1 and SOSTDC1, in developing and adult mammalian normal eyes as well as in syndromic and nonsyndromic congenital eye diseases.

Three-Dimensional Modelization of the Female Human Inferior Hypogastric Plexus: Implications for Nerve-Sparing Radical Hysterectomy.

BACKGROUND/AIMS: This study aims to describe the autonomic nervous network of the female pelvis with a 3D model and to provide a safe plane of dissection during radical hysterectomy for cervical cancer. METHODS: Pelvises of 3 human female fetuses were studied by using the computer-assisted anatomic dissection. RESULTS: The superior hypogastric plexus (SHP) was located at the level of the aortic bifurcation in front of the sacral promontory and divided inferiorly and laterally into 2 hypogastric nerves (HN). HN ran postero-medially to the ureter and in the lateral part of the uterosacral ligament until the superior angle of the inferior hypogastric plexus (IHP). IHP extended from the anterolateral face of the rectum, laterally to the cervix and attempted to the base of the bladder. Vesical efferences merged from the crossing point of the ureter and the uterine artery and ran through the posterior layer of the vesico-uterine ligament. CONCLUSIONS: The SHP could be injured during paraaortic lymphadenectomy. Following the ureter and resecting the medial fibrous part of the uterosacral ligament may spare the HN. No dissection should be performed under the crossing point of the ureter and the uterine artery.

Duplicated distal phalanx of thumb or hallux in trisomy 13: A recurrent feature in a series of 42 fetuses.

Trisomy 13 or Patau syndrome (PS) is a well-known aneuploidy characterized by a polymalformative syndrome. We described a large series of fetuses with PS and compared them with cases described in the literature, most of which were live-born. In all, 42 fetuses, aged from 14 to 41 gestational weeks (GW), were examined. The main defects observed were similar to those described in live-born patients: congenital heart defects (76%), holoprosencephaly spectrum anomalies including arhinencephaly and hypotelorism (74%), urinary tract anomalies (71%), ear anomalies (69%), postaxial polydactyly (67%), anogenital anomalies (60%), anophthalmos, and/or microphthalmos (53%), brachycephaly (45%), and oro-facial clefts (45%). A duplication or triplication of at least one distal phalanx of the thumb or hallux was present in 38% of fetuses. This sign has only been reported previously in one patient in the literature. Fetal examination in trisomy 13, is thus, useful to complete the phenotype or to orient diagnosis toward trisomy 13 in the absence of cytogenetic analysis.

Dynamic Expression Patterns of Progenitor and Neuron Layer Markers in the Developing Human Dentate Gyrus and Fimbria.

The molecular mechanisms that orchestrate the development of the human dentate gyrus are not known. In this study, we characterized the formation of human dentate and fimbrial progenitors and postmitotic neurons from 9 gestational weeks (GW9) to GW25. PAX6+ progenitor cells remained proliferative until GW16 in the dentate ventricular zone. By GW11, the secondary dentate matrix had developed in the intermediate zone, surrounding the dentate anlage and streaming toward the subpial layer. This secondary matrix contained proliferating PAX6+ and/or TBR2+ progenitors. In parallel, SOX2+ and PAX6+ fimbrial cells were detected approaching the dentate anlage, representing a possible source of extra-dentate progenitors. By GW16, when the granule cell layer could be delineated, a hilar matrix containing PAX6+ and some TBR2+ progenitors had become identifiable. By GW25, when the 2 limbs of the granule cell layer had formed, the secondary dentate matrix was reduced to a pool of progenitors at the fimbrio-dentate junction. Although human dentate development recapitulates key steps previously described in rodents, differences seemed to emerge in neuron layer markers expression. Further studies are necessary to better elucidate their role in dentate formation and connectivity.

How to Explore Fetal Sacral Agenesis Without Open Dysraphism: Key Prenatal Imaging and Clinical Implications.

The estimated prevalence of fetal caudal dysgenesis is 1 per 100,000 births. The functional prognosis of sacral agenesis is dominated by the large spectrum of associated caudal malformations. Except for cases associated with hydrocephalus secondary to open spinal dysraphism or chromosomal anomalies, association with mental deficiency is rare. We propose a systematic prenatal approach to cases of fetal sacral agenesis based on 9 etiologic items: clinical context, type of sacral dysgenesis, associated spinal cord malformations, mobility of lower limbs, investigation of the presacral region, analysis of the gastrointestinal tract, analysis of the genitourinary tract, associated vertebral defects, and cytogenetic analysis.

TRAP Sequence in Monochorionic/Monoamniotic (MC/MA) Discordant Twins: Two Cases Treated with Fetoscopic Laser Surgery.

INTRODUCTION: Ablation of the acardiac twin umbilical cord in the TRAP protects the normal donor twin. MATERIALS AND METHODS: Two case descriptions, one of interstitial laser photocoagulation and one of laser umbilical cord occlusion (L-UCO) of the acardiac twin in monochorionic monoamniotic pregnancies are reported. RESULTS: L-UCO in two pregnancies with TRAP syndrome in the second trimester resulted in intrauterine fetal death in both cases after 1 month. Case 1 had no detectable cause of fetal death. Case 2 had rupture of the amniotic sac causing anhydramnios and acute chorioamnionitis. A groove on the umbilical cord of the normal twin indicated a cord stricture due to cord entanglement. CONCLUSION: Our experience confirms that the best timing and optimal treatment of MC/MA twins complicated by TRAP sequence still remains a controversial clinical issue. Cord entanglement may continue be a potential clinical risk factor for adverse perinatal outcome even after ablation therapy.

Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome.

Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype-phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype-genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.

Dynamic Expression Patterns of Progenitor and Pyramidal Neuron Layer Markers in the Developing Human Hippocampus.

The molecular mechanisms underlying the formation of hippocampus are unknown in humans. To improve our knowledge of molecules that potentially regulate pyramidal neurogenesis and layering in various hippocampal fields, we investigated the expression of progenitor markers and cell fate molecules from gestational week (GW) 9 to GW 20. At GW 9, the progenitor cell compartment of the hippocampal formation mainly consisted of PAX6(+) cells in the ventricular zone. Between GW 9 and 11, a second germinal area, the subventricular zone (SVZ), was formed, as shown by TBR2 labeling. Postmitotic markers (TBR1, CTIP2, SATB2, and CUX1) might reflect the inside-out layering of the plate from GW 11 onwards. TBR1(+) neurons appeared in the deep plate, whereas CTIP2(+), SATB2(+), and CUX1(+) neurons occupied the upper layers. From GW 16, differences in layer segregation were observed between the ammonic and subicular plates. Moreover, an ammonic-to-subicular maturation gradient was observed in germinal/postmitotic areas. Taken together, these findings demonstrate for the first time the presence of an SVZ in the hippocampus of human fetuses and laminar differences in transcription factor expression in the pyramidal layer of the human ammonic and subicular plate, and provide new information to further investigate the connectivity of the hippocampal formation.

Think of the Conus Medullaris at the Time of Diagnosis of Fetal Sacral Agenesis.

BACKGROUND: There is no precise prenatal indicator to refine an accurate prognosis in case of sacral agenesis and to define the diagnostic approach and outcome criteria in case of fetal sacral agenesis using 3 characteristics of the conus medullaris (CM): its position, its appearance, and associated spinal abnormalities. METHODS: Ten cases of prenatally diagnosed sacral agenesis were included between 1995 and 2014 after collating ultrasound findings and prenatal computed tomography data. RESULTS: Two cases of total sacral agenesis and 8 of partial agenesis were included. There were 1 or more spinal abnormalities in 8/10 cases: 6 lipomas, 4 low-lying tethered cords, 2 diastematomyelias, and 1 syringomyelia. Three situations were distinguished: sacral agenesis with low-lying tethered cord, sacral agenesis with a truncated CM, and sacral agenesis with CM in place. If the sacral agenesis is isolated, a lipoma should be sought. Lipomas of the filum have a good prognosis, whereas lipomas of the CM cause neurological deficits in 1/3 of cases. When there is a low-lying tethered cord, a diastematomyelia or a syringomyelia may be associated. In truncated CM, there may be a severe form suggestive of caudal regression syndrome. Serious ultrasound signs are immobility of the lower limbs, talipes equinovarus, impaired bladder emptying, and dilatation of the upper urinary tract. CONCLUSION: A precise description of the morphology of the CM, its position, and associated spinal malformations are important in defining the neurological, urinary, gastrointestinal, and motor functions prognosis in cases of fetal sacral agenesis.