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Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wide variant calling approach, despite being located in protein coding sequence. More detailed analysis revealed that the position of the variant within exon 5 of TUBB3 was not targeted by the enrichment kit, although consistent high-quality coverage was obtained at this position, resulting from nearby targets that provide off-target coverage. In the initial analysis, variant calling was restricted to the exon targets ± 200 bases, allowing the variant to escape detection by the variant calling algorithm. This phenomenon may potentially occur more often, as we determined that 36 established ID genes have robust off-target coverage in coding sequence. Moreover, within these regions, for 17 genes (likely) pathogenic variants have been identified before. Therefore, this clinical report highlights that, although compute-intensive, performing genome-wide variant calling instead of target-based calling may lead to the detection of diagnostically relevant variants that would otherwise remain unnoticed. This work was financially supported by Aspasia grants of the Dutch Research Council (015.014.036 to TK and 015.014.066 to LELMV) and Netherlands Organization for Health Research and Development (917.183.10 to TK). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. Sí

To date, there is a lack of international guidelines regarding the management of the endocrine features of individuals with Noonan syndrome (NS). The aim was to develop a clinical practice survey to gather information on current treatment and management of these patients across Europe.A group of 10 experts from three clinical specialities involved in the management of NS patients (clinical geneticists, paediatric endocrinologists, and paediatric cardiologists) developed a 60-question clinical practice survey. The questionnaire was implemented in Survey Monkey and sent to physicians from these three specialities via European/national societies. Contingency tables and the Chi-Squared test for independence were used to examine differences between specialities and countries.In total, responses of 364 specialists (paediatric endocrinologists, 40%; geneticists, 30%; paediatric cardiologists, 30%) from 20 European countries were analysed. While endocrinologists mostly referred to national growth charts for the general population, geneticists mostly referred to NS-specific growth charts. Approximately half of the endocrinologists perform growth hormone (GH) stimulation tests in short patients with low IGF1 levels. Two thirds of endocrinologists begin GH treatment for short patients in early childhood (4-6.9 years), and over half of them selected a threshold of -2 standard deviation score (SDS) according to national growth charts. The main concerns about GH treatment appear to be presence of hypertrophic cardiomyopathy (HCM) (59%), increased risk of malignancy (46%), and limited efficacy (31%). When asked if they consider HCM as a contraindication for GH treatment, one third of respondents skipped this question, and among those who replied, two thirds selected 'cannot answer', suggesting a high level of uncertainty. A total of 21 adverse cardiac responses to GH treatment were reported. Although most respondents had not encountered any malignancy during GH treatment, six malignancies were reported. Finally, about half of the endocrinologists expected a typical final height gain of 1-1.5 SDS with GH treatment.This survey describes for the first time the current clinical practice of endocrine aspects of NS across Europe and helps us to identify gaps in the management but also in the knowledge of this genetic disorder.

BACKGROUND The majority of children with Noonan syndrome (NS) or other diseases from the RASopathy spectrum suffer from congenital heart disease. This study aims to survey cardiac care of this patient cohort within Europe. METHODS A cross-sectional exploratory survey assessing the treatment and management of patients with NS by paediatric endocrinologists, cardiologists and clinical geneticists was developed. This report details responses of 110 participating paediatric cardiologists from multiple countries. RESULTS Most paediatric cardiologists responding to the questionnaire were associated with university hospitals, and most treated

International audience; Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.

International audience; Mutations in LZTR1, already known to be causal in familial schwannomatosis type 2, have been recently involved in a small proportion of patients with autosomal dominant and autosomal recessive Noonan syndrome. LZTR1 is also a driver gene in non syndromal glioblastoma. We report a 26-year-old patient with typical Noonan syndrome, and the dominantly transmitted c.850C > T (p.(Arg284Cys)) variant in LZTR1. An oligoastrocytoma was diagnosed in the patient at the age of 22 years; recurrence of the tumor occurred at age 26, as a ganglioblastoma. The patient had been transiently treated with growth hormone between ages 15 and 17. Considering the implication of LZTR1 in sporadic tumors of the nervous system, we hypothesize that gliomas are a possible complication of LZTR1-related Noonan syndrome. This report also supports a possible link between occurrence of a cerebral tumor in Noonan syndrome and a previous treatment with growth hormone.

International audience; The SPECC1L protein plays a role in adherens junctions involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. It modulates PI3K-AKT signaling and controls cranial neural crest cell delamination during facial morphogenesis. SPECC1L causative variants were first identified in individuals with oblique facial clefts. Recently, causative variants in SPECC1L were reported in a pedigree reported in 1988 as atypical Opitz GBBB syndrome. Six families with SPECC1L variants have been reported thus far. We report here eight further pedigrees with SPECC1L variants, including a three-generation family, and a further individual of a previously published family. We discuss the nosology of Teebi and GBBB, and the syndromes related to SPECC1L variants. Although the phenotype of individuals with SPECC1L mutations shows overlap with Opitz syndrome in its craniofacial anomalies, the canonical laryngeal malformations and male genital anomalies are not observed. Instead, individuals with SPECCL1 variants have branchial fistulae, omphalocele, diaphragmatic hernias, and uterus didelphis. We also point to the clinical overlap of SPECC1L syndrome with mild Baraitser-Winter craniofrontofacial syndrome: they share similar dysmorphic features (wide, short nose with a large tip, cleft lip and palate, blepharoptosis, retrognathia, and craniosynostosis), although intellectual disability, neuronal migration defect, and muscular problems remain largely specific to Baraitser-Winter syndrome. In conclusion, we suggest that patients with pathogenic variants in SPECC1L should not be described as "dominant (or type 2) Opitz GBBB syndrome", and instead should be referred to as "SPECC1L syndrome" as both disorders show distinctive, non overlapping developmental anomalies beyond facial communalities.

Donnai-Barrow syndrome (DBS; MIM 222448) is characterized by typical craniofacial anomalies (major hypertelorism with bulging eyes), high grade myopia, deafness and low molecular weight proteinuria. The disorder results from mutations in the low density lipoprotein receptor-related protein 2 gene LRP2 that maps to chromosome 2q31.1. LRP2 encodes megalin, a multi-ligand endocytic receptor. Herein, we describe the clinical presentation of 4 patients from 2 unrelated Saudi families. Two novel LRP2 mutations, a homozygous nonsense mutation (c.4968C>G; p.Tyr1656*) and a missense mutation (c.12062G>A; p.Cys4021Tyr), were detected in the first and second family respectively. Interestingly, intrafamilial phenotypic variability was observed in one family, while DBS features were atypical in the second family. Differential diagnosis of DBS includes several syndromes associating hypertelorism with high grade myopia, and several syndromal forms of CDH, which are briefly summarized in this study.

We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann–Rautenstrauch syndrome. The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome. A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1. We show that this mutation leads to exon 64 skipping and to the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered. FBN1 mutations associated with a similar phenotype have only been reported in four other patients. We confirm the correlation between marfanoid phenotype with congenital lipodystrophy and neonatal progeroid features (marfanoid–progeroid–lipodystrophy syndrome) and frameshift mutations at the 3′ end of FBN1. This syndrome should be considered in differential diagnosis of neonatal progeroid syndromes.

International audience; We report two male sibs, born from unrelated French Caribbean parents, presenting with an unclassifiable storage disorder. Pregnancy and delivery were uneventful. Stunted growth was noted during the first year of life. Both children have short stature (below - 4SD) with short trunk, barrel chest, micromelia with rhizomelic shortening, severe kyphoscoliosis, pectus carinatum, short hands and feet with metatarsus adductus, and excessive joint laxity of the small joints. Learning difficulties with borderline intelligence quotient (IQ) were noted in one of them. They had no hepatomegaly, no splenomegaly, and no dysmorphism. Skeletal X-rays survey demonstrated generalized platyspondyly with tongue-like deformity of the anterior part of the vertebral bodies, hypoplasia of the odontoid process, generalized epiphyseal dysplasia and abnormally shaped metaphyses. The acetabular roofs had a trident aspect. Ophthalmologic and cardiac examinations were normal. Spine deformity required surgical correction in one of the patient at age 4 years. Lysosomal enzymes assays including N-acetylgalactosamine-6-sulfate sulfatase and β-galactosidase were normal, excluding mucopolysaccharidoses type IV A and IV B (Morquio syndrome), respectively. Qualitative analysis found traces of dermatan and chondroitin-sulfates in urine, but quantitative glycosaminoglycan excretion fell within normal limits. They were no vacuolated lymphocytes. Abnormal coarse inclusions were present in eosinophils. Mild Alder anomaly was observed in polymorphonuclears. Granulations were discretely metachromatic with toluidine blue. Those morphological anomalies are in favor of a lysosomal storage disease. No inclusions were found in skin fibroblasts. We hypothesize that these two boys have a distinct autosomal recessive or X-linked lysosomal storage disorder of unknown origin that shares clinical and radiological features with Morquio disease.

Omphalocele is a relatively common developmental anomaly of the abdominal wall. Isolated omphalocele is generally regarded as a sporadic malformation with a negligible recurrence risk, although rare familial occurrences have been reported, compatible with AD, AR and XLR inheritance. Omphaloceles occurring in a syndromal context are strongly correlated with various types of chromosomal anomalies. Few monogenic syndromes have a high frequency of omphalocele. We report a family with facial dysmorphism somewhat reminiscent of Robinow syndrome (flat face, very short, upturned nose, very long and unusually wide philtrum, and flattened maxillary arch), observed in 3 generations. Four sibs in the second generations had large omphaloceles. One child had ectrodactyly. Genomic rearrangements, and WNT5A or ROR2 mutations were excluded in this family. At this point, we feel reasonable to consider this family as expressing a "new" syndrome related but different from Robinow syndrome, associating facial dysmorphism and abdominal wall defect, and compatible with dominant inheritance with variable expressivity, although recessively inherited omphalocele occurring in a family showing independently some dominant craniofacial peculiarities cannot be ruled out.

Background The 17p13.3 deletion syndrome (or Miller-Dieker syndrome, MDS, MIM 247200) is characterized by lissencephaly, mental retardation and facial dysmorphism. The phenotype is attributed to haploinsufficiency of two genes present in the minimal critical region of MDS: PAFAH1B1 (formerly referred to as LIS1) and YWHAE. Whereas isolated PAFAH1B1 deletion causes lissencephaly, YWHAE is a candidate for the dysmorphic phenotype associated with MDS. Objective We describe clinical, neuroradiological and molecular data in four patients with a 17p13.3 deletion distal to PAFAH1B1 involving YWHAE. Results All patients presented with mild or moderate developmental delay and pre and/or post-natal growth retardation. Patients A, B and C had neuro-imaging anomalies: leucoencephalopathy with macrocephaly (patients A and C), Chiari type 1 malformation (patient A) and paraventricular cysts (patient C). Patient B had patent ductus arteriosus and pulmonary arterial hypertension. Patient C had unilateral club foot. Patient D had enlarged Virchow Robin spaces, microcornea, and chorioretinal and lens coloboma. Array-CGH revealed de novo terminal 17p13.3 deletions for patient A and B, and showed interstitial 17p13.3 deletions of 1.4 Mb for patient C and of 0.5 Mb for patient D. In all patients, PAFAH1B1 was not deleted. Conclusion Our patients confirm that 17p deletion distal to PAFAH1B1 have a distinctive phenotype : mild mental retardation, moderate to severe growth restriction, white matter abnormalities and developmental defects including Chiari type 1 malformation and coloboma. Our patients contribute to the delineation and clinical characterization of 17p13.3 deletion distal to PAFAH1B1 and highlight the role of the region containing YWHAE in brain and eye development and in somatic growth.

Polyvalvular heart disease has been reported in a handful of "private" syndromes that have been recently suggested to represent a single dominantly inherited condition, the polyvalvular heart disease syndrome. We report five cases in two unrelated families (one sporadic case in the first family and three siblings and their father in the second family) with the same association of polyvalvular heart disease, distinctive facial appearance, and, except the father in family 2, major joint hypermobility. Interestingly, in three of our patients (2 siblings and the sporadic case), electron microscopy revealed characteristic ultrastructural skin abnormalities with abnormal amorphous or microfibrillar deposits under the capillary basal membrane in the papillary dermis, suggestive of a connective tissue disorder, but different from Marfan syndrome or Ehlers-Danlos syndrome. Moreover, in family 2, three others sibs died in early infancy of their heart defect. Our two families and the other published cases might illustrate intrafamilial and interfamilial variability within a single condition. However, our two families disclose major joint hypermobility, normal stature, and ultrastructural skin abnormalities that were not described in the previous reports. These discrepancies let us to consider them as affected by a distinct disorder of the connective tissue.

The genetic control of dental development represents a complex series of events, which can very schematically be divided in two pathways: specification of type, size and position of each dental organ, and specific processes for the formation of enamel and dentin. Several genes linked with early tooth positioning and development, belong to signalling pathways and have morphogenesis regulatory functions in morphogenesis of other organs where they are associated with the signalling pathways. Their mutations often show pleiotropic effects beyond dental morphogenesis resulting in syndromic developmental disorders. Some genes affecting early tooth development (MSX1, AXIN2) are associated with tooth agenesis and systemic features (cleft palate, colorectal cancer). By contrast, genes involved in enamel (AMELX, ENAM, MMP20, and KLK4) and dentin (DSPP) structures are highly specific for tooth. Mutations in these genes have been identified as causes of amelogenesis imperfecta, dentinogenesis imperfecta, dentin dysplasias and anomalies of teeth number (hypo-, oligo and anodontia), which only partially overlap with the classical phenotypic classifications of dental disorders. This review of genetic basis of inherited anomalies describes, in this first paper, the molecular bases and clinical features of inherited non-syndromic teeth disorders. And in a second part, the review focus on genetic syndromes with dental involvement.

We report paternally inherited duplication of 1q12q21.2 of 5.8 Mb associated with maternally inherited deletion of 16p11.2 of 545 Kb, this latter first identified in a fetus exhibiting an absent nasal bone detected during pregnancy. During the neonatal period, the young boy presented developmental delay, epilepsy, congenital anomalies and overweight. The clinical features of the proband with two rearrangements were more severe than in either of the parents carrying only one or the other mutation. Thus our data support a two-hit model in which the concomitant presence of these two copy-number variations exacerbates the neurodevelopmental phenotype.

We report a boy with severe developmental delay, microcephaly and characteristic facial dysmorphism consisting in round face, hypertelorism, upslanted palpebral fissures, small nose, large mouth, micrognathia, sparse hair and eyelashes. Array-CGH revealed a de novo duplication of 103 kb within 17q21.2 not reported to date. The duplication includes 8 genes: DHX58, KAT2A, HSPB9, RAB5C, KCNH4, HCRT, GHDC and STAT5B. Three genes (KATA2, KCNH4, and STAT5B) may contribute to intellectual deficiency. Further observations will be necessary to confirm the specificity of the facial Gestalt.

Congenital absence of the left pericardium (allowing communication between pericardial and pleural cavities) is a rare developmental defect that results from faulty partitioning of the pleuropericardic cavity during the 5th week of development. It occurs sporadically in most instances, and may be associated with other malformations of the thoracic viscera. We report here two sibs born to consanguineous parents with absent left fibrous pericardium and developmental defects of the septum transversum: left posterolateral diaphragmatic hernia in one child, left diaphragmatic eventration in the other sib. This appears to be the first familial report of this rare association.

Background 15q11-q13 region is an area of well-known susceptibility to genomic rearrangements, in which several breakpoints have been identified (BP1–BP5). Duplication of this region is observed in two instances: presence of a supernumerary marker chromosome (SMC) derived of chromosome 15, or interstitial tandem duplication. Duplications are clinically characterized by a variable phenotype that includes central hypotonia, developmental delay, speech delay, seizure, minor dysmorphic features and autism. Methods Retrospective clinical and molecular study of 30 unrelated patients who were identified among the patients seen at the genetic clinics of Robert DEBRE hospital with microduplication of the 15q11-q13 region. Results Fifteen patients presented with a supernumerary marker derived from chromosome 15. In fourteen cases the SMC was of large size, encompassing the Prader–Willi/Angelman critical region. All but one was maternal in origin. One patient had a PWS-like phenotype in absence of maternal UPD. In one case, the marker had a smaller size and contained only the BP1–BP2 region. Fifteen patients presented with interstitial duplication. Four cases were inherited from phenotypically normal parents (3 maternal and 1 paternal). Phenotypic features were somewhat variable and 57% presented with autism. Twelve patients showed cerebral anomalies and 18 patients had an abnormal EEG with a typical, recognizable pattern of excessive diffuse rapid spikes in the waking record, similar to the pattern observed after benzodiazepine exposure. Duplication of paternally expressed genes MKRN3 , MAGEL2 and NDN in two autistic patients without extra material of a neighboring region enhances their likelihood to be genes related to autism.

The CHARGE syndrome is a multiple congenital malformation syndrome that usually results from deletion or heterozygous loss of function mutations of the chromodomain helicase DNA-binding protein 7 (CHD7) gene at 8q12.1. Besides CHD7-related cases, some patients with CHARGE-like phenotype have been reported with chromosomal imbalances. We describe a patient with a pattern of malformations reminiscent of CHARGE syndrome: choanal atresia, facial dysmorphism (micrognathia, hypertelorism, epicanthic folds, and depressed, broad nasal bridge), cardiovascular malformations, cryptorchidism, and developmental delay. He had duplication 8q and deletion 4q derived from paternal translocation t(4;8)(q34;q22.1). CHD7 mutation or deletion was excluded. The present report to the best of our knowledge is the only one describing an unbalanced translocation t(4;8) and CHARGE-like phenotype.

Uncommon features of rare genetic disorders are often poorly known, as the likelihood of having them reported is low. We describe a 7-year-old boy with clinical and radiological diagnosis of pycnodysostosis, and c.436G>C (p.G146R) mutation in CSTK). He developed intracranial hypertension that required surgical decompression. Despite patent fontanels, the cause of the intracranial hypertension was identified to be a combination of coronal and metopic craniosynostoses. Intracranial hypertension and craniosynostosis have only been reported once in pycnodysostosis, which is on the contrary characterized by delayed closure of the sutures and persistence of open fontanels. Our observation confirms that intracranial hypertension represents a rare but life-threatening complication of pycnodysostosis. We strongly suggest including systematic examination of fundus oculi and monitoring of OFC in the systematic clinical follow-up of these patients.

Background The 22q13.3 deletion syndrome (or Phelan-McDermid syndrome, MIM 606232) is characterized by developmental delay, absent or severely delayed speech, neonatal hypotonia, autistic behavior, normal to accelerated growth, and minor dysmorphic facial features. Among the three genes in the minimal critical region (from the centromere to the telomere: SHANK3 , ACR and RABL2B ), the defect in the SHANK3 gene is considered to be the cause of the neurobehavioral symptoms. Objective We describe the molecular characterization of a de novo interstitial del(22)(q13.3q13.3) disrupting the SHANK3 gene in a child with a phenotype compatible with the 22q13.3 deletion syndrome. Methods Clinical work-up included clinical histories, physical, neurological, and ophthalmological examinations, and imaging of the brain. Commercially available MLPA for subtelomeric analysis, FISH specific probes and quantitative real-time PCR were used to characterize the rearrangement. Results Subtelomere analysis by MLPA showed a discrepancy between P036B and P070 kits (MCR Holland ® ): the P070 MLPA 22q probe (targeting the ARSA gene) showed a deletion but the P036B one (targeting the RABL2B gene) showed a normal result. FISH analysis using LSI TUPLE1/LSI ARSA (Vysis ® ) probes confirmed deletion of ARSA , whereas FISH with N25/N85A3 (Cytocell ® ) probes, targeting the SHANK3 locus was normal. Supplemented FISH analysis using BAC clones allowed us to specify the centromeric breakpoint region of the interstitial deletion between clones RP11-354I12 and RP11-232E17, at less than 2 Mb from the telomere. Quantitative real-time PCR of exon 5, 22 and 24 and intron 9 of SHANK3 showed that the telomeric breakpoint occurred between intron 9 and exon 22. Conclusions These data highlight the difficulty of performing an appropriate test aimed at looking for cryptic 22q13.3 deletion. Furthermore, the molecular characterization of this interstitial 22q13.3 deletion contributes to the clinical and genetic delineation of the 22q13.3 deletion syndrome.

Teeth are specialized structural components of the craniofacial skeleton. Developmental defects occur either alone or in combination with other birth defects. In this paper, we review the dental anomalies in several multiple congenital anomaly (MCA) syndromes, in which the dental component is pivotal in the recognition of the phenotype and/or the molecular basis of the disorder is known. We will consider successively syndromic forms of amelogenesis imperfecta or enamel defects, dentinogenesis imperfecta (i.e. osteogenesis imperfecta) and other dentine anomalies. Focusing on dental aspects, we will review a selection of MCA syndromes associated with teeth number and/or shape anomalies. A better knowledge of the dental phenotype may contribute to an earlier diagnosis of some MCA syndromes involving teeth anomalies. They may serve as a diagnostic indicator or help confirm a syndrome diagnosis.

The genetic control of dental development represents a complex series of events, which can very schematically be divided in two pathways: specification of type, size and position of each dental organ, and specific processes for the formation of enamel and dentin. Several genes linked with early tooth positioning and development, belong to signalling pathways and have morphogenesis regulatory functions in morphogenesis of other organs where they are associated with the signalling pathways. Their mutations often show pleïotropic effects beyond dental morphogenesis resulting in syndromic developmental disorders. Some genes affecting early tooth development (MSX1, AXIN2) are associated with tooth agenesis and systemic features (cleft palate, colorectal cancer). By contrast, genes involved in enamel (AMELX, ENAM, MMP20, and KLK4) and dentin (DSPP) structures are highly specific for tooth. Mutations in these genes have been identified as causes of amelogenesis imperfecta, dentinogenesis imperfecta, dentin dysplasias and anomalies of teeth number (hypo-, oligo and anodontia), which only partially overlap with the classical phenotypic classifications of dental disorders. This review of genetic basis of inherited anomalies describes, in this first paper, the molecular bases and clinical features of inherited non-syndromic teeth disorders. And in a second part, the review focus on genetic syndromes with dental involvement.

Syndromes with smooth muscle dysmotility are uncommon, and may be related either to smooth muscle myopathy, or to neuropathy. In most instances, neuropathic visceral dysmotility is an isolated finding leading to chronic intestinal pseudo-obstruction syndrome (CIPO). We report here on two sibs, born to consanguineous parents, with neuropathic visceral dysmotility and CNS anomalies. They share facial dysmorphia, neurogenic megacystis, intracerebral calcifications, and developmental delay. The elder one, a girl, has microcephaly and multicystic kidneys, and her brother has a more extensive neuropathic visceral disorder leading clinically to CIPO. CIPO associated with megacystis is relatively frequent but is rarely associated with mental retardation. The cases reported in the literature are different from those described here, clinically and histologically. A recessively inherited form of CIPO associated with widespread intra-cerebral calcifications, malabsorption is known as Cockel syndrome. Severity of Cockel syndrome, absence of urinary tract involvement and neuropathologic discrepancies allow distinction with the disorder reported here. In conclusion, the two siblings described here have facial dysmorphia, vesical and (in one of them) intestinal neurogenic dysmotility, intracerebral calcifications and developmental delay that could represent a specific, recessively inherited form of CIPO.