Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials.

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability.

PURPOSE: Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects. METHODS: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic. RESULTS: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes. CONCLUSION: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10-4) and genes regulated by the fragile X mental retardation protein (p=3×10-8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.

Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum.

PURPOSE: PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. METHODS: Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. RESULTS: Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. CONCLUSION: This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.

Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome.

Cohen Syndrome (CS) is a rare autosomal recessive disorder, with defective glycosylation secondary to mutations in the VPS13B gene, which encodes a protein of the Golgi apparatus. Besides congenital neutropenia, retinopathy and intellectual deficiency, CS patients are faced with truncal obesity. Metabolism investigations showed abnormal glucose tolerance tests and low HDL values in some patients, and these could be risk factors for the development of diabetes mellitus and/or cardiovascular complications. To understand the mechanisms involved in CS fat storage, we used two models of adipogenesis differentiation: (i) SGBS pre-adipocytes with VPS13B invalidation thanks to siRNA delivery and (ii) CS primary fibroblasts. In both models, VPS13B invalidation led to accelerated differentiation into fat cells, which was confirmed by the earlier and increased expression of specific adipogenic genes, consequent to the increased response of cells to insulin stimulation. At the end of the differentiation protocol, these fat cells exhibited decreased AKT2 phosphorylation after insulin stimulation, which suggests insulin resistance. This study, in association with the in-depth analysis of the metabolic status of the patients, thus allowed us to recommend appropriate nutritional education to prevent the occurrence of diabetes mellitus and to put forward recommendations for the follow-up of CS patients, in particular with regard to the development of metabolic syndrome. We also suggest replacing the term obesity by abnormal fat distribution in CS, which should reduce the number of inappropriate diagnoses in patients who are referred only on the basis of intellectual deficiency associated with obesity.

Application of whole-exome sequencing to unravel the molecular basis of undiagnosed syndromic congenital neutropenia with intellectual disability.

Neutropenia can be qualified as congenital when of neonatal onset or when associated with extra-hematopoietic manifestations. Overall, 30% of patients with congenital neutropenia (CN) remain without a molecular diagnosis after a multidisciplinary consultation and tedious diagnostic strategy. In the rare situations when neutropenia is identified and associated with intellectual disability (ID), there are few diagnostic hypotheses to test. This retrospective multicenter study reports on a clinically heterogeneous cohort of 10 unrelated patients with CN associated with ID and no molecular diagnosis prior to whole-exome sequencing (WES). WES provided a diagnostic yield of 40% (4/10). The results suggested that in many cases neutropenia and syndromic manifestations could not be assigned to the same molecular alteration. Three sub-groups of patients were highlighted: (i) severe, symptomatic chronic neutropenia, detected early in life, and related to a known mutation in the CN spectrum (ELANE); (ii) mild to moderate benign intermittent neutropenia, detected later, and associated with mutations in genes implicated in neurodevelopmental disorders (CHD2, HUWE1); and (iii) moderate to severe intermittent neutropenia as a probably undiagnosed feature of a newly reported syndrome (KAT6A). Unlike KAT6A, which seems to be associated with a syndromic form of CN, the other reported mutations may not explain the entire clinical picture. Although targeted gene sequencing can be discussed for the primary diagnosis of severe CN, we suggest that performing WES for the diagnosis of disorders associating CN with ID will not only provide the etiological diagnosis but will also pave the way towards personalized care and follow-up. © 2016 Wiley Periodicals, Inc.

High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations.

AIMS: Mutations in PRKAG2, the gene encoding for the γ2 subunit of 5'-AMP-activated protein kinase (AMPK), are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block. The aim of this study was to perform a retrospective time-to-event study of the clinical manifestations associated with PRKAG2 mutations. METHODS AND RESULTS: A cohort of 34 patients from 9 families was recruited between 2001 and 2010. DNA were sequenced on all exons and flanking sequences of the PRKAG2 gene using Sanger sequencing. Overall, four families carried the recurrent p.Arg302Gln mutation, and the five others carried private mutations among which three had never been reported. In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%. The global survival at 60 years of age was 66%. Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant. Only one patient presented with significant skeletal muscle symptoms. No significant differences regarding the occurrence of VPE, ablation complications, or death incidence were observed between different mutations. CONCLUSION: This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications. Early recognition of this disease appears important to allow an appropriate management.

Zac1 Regulates the Differentiation and Migration of Neocortical Neurons via Pac1.

Imprinted genes are dosage sensitive, and their dysregulated expression is linked to disorders of growth and proliferation, including fetal and postnatal growth restriction. Common sequelae of growth disorders include neurodevelopmental defects, some of which are indirectly related to placental insufficiency. However, several growth-associated imprinted genes are also expressed in the embryonic CNS, in which their aberrant expression may more directly affect neurodevelopment. To test whether growth-associated genes influence neural lineage progression, we focused on the maternally imprinted gene Zac1. In humans, either loss or gain of ZAC1 expression is associated with reduced growth rates and intellectual disability. To test whether increased Zac1 expression directly perturbs neurodevelopment, we misexpressed Zac1 in murine neocortical progenitors. The effects were striking: Zac1 delayed the transition of apical radial glial cells to basal intermediate neuronal progenitors and postponed their subsequent differentiation into neurons. Zac1 misexpression also blocked neuronal migration, with Zac1-overexpressing neurons pausing more frequently and forming fewer neurite branches during the period when locomoting neurons undergo dynamic morphological transitions. Similar, albeit less striking, neuronal migration and morphological defects were observed on Zac1 knockdown, indicating that Zac1 levels must be regulated precisely. Finally, Zac1 controlled neuronal migration by regulating Pac1 transcription, a receptor for the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP). Pac1 and Zac1 loss- and gain-of-function presented as phenocopies, and overexpression of Pac1 rescued the Zac1 knockdown neuronal migration phenotype. Thus, dysregulated Zac1 expression has striking consequences on neocortical development, suggesting that misexpression of this transcription factor in the brain in certain growth disorders may contribute to neurocognitive deficits. Significance statement: Altered expression of imprinted genes is linked to cognitive dysfunction and neuropsychological disorders, such as Angelman and Prader-Willi syndromes, and autism spectrum disorder. Mouse models have also revealed the importance of imprinting for brain development, with chimeras generated with parthenogenetic (two maternal chromosomes) or androgenetic (two paternal chromosomes) cells displaying altered brain sizes and cellular defects. Despite these striking phenotypes, only a handful of imprinted genes are known or suspected to regulate brain development (e.g., Dlk1, Peg3, Ube3a, necdin, and Grb10). Herein we show that the maternally imprinted gene Zac1 is a critical regulator of neocortical development. Our studies are relevant because loss of 6q24 maternal imprinting in humans results in elevated ZAC1 expression, which has been associated with neurocognitive defects.

CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders.

BACKGROUND: The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma. METHODS: Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics. RESULTS: 97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. 89% patients were male, with CBAVD being the reason for referral in 76%. In 166/179 patients with available detailed clinical features, final diagnoses were: four late-onset marked pulmonary disease, 83 isolated CBAVD, 67 other CFTR-related phenotypes, including 44 CBAVD with pulmonary and/or pancreatic symptoms and 12 asymptomatic cases. Respiratory symptoms were observed in 30% of the patients, but the overall phenotype was mild. No correlation was observed between sweat chloride concentrations and disease severity. Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation genetic diagnoses (PND or PGD). Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation. CONCLUSIONS: Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Depending on the CBAVD patients' genotype, a CFTR analysis should be considered in their partners in order to identify CF carrier couples and offer PND or PGD.

Expectations, needs and mid-term outcomes in people accessing to secondary findings from ES: 1st French mixed study (FIND Study).

Generation and subsequently accessibility of secondary findings (SF) in diagnostic practice is a subject of debate around the world and particularly in Europe. The French FIND study has been set up to assess patient/parent expectations regarding SF from exome sequencing (ES) and to collect their real-life experience until 1 year after the delivery of results. 340 patients who had ES for undiagnosed developmental disorders were included in this multicenter mixed study (quantitative N = 340; qualitative N = 26). Three groups of actionable SF were rendered: predisposition to late-onset actionable diseases; genetic counseling; pharmacogenomics. Participants expressed strong interest in obtaining SF and a high satisfaction level when a SF is reported. The medical actionability of the SF reinforced parents' sense of taking action for their child and was seen as an opportunity. While we observed no serious psychological concerns, we showed that these results could have psychological consequences, in particular for late-onset actionable diseases SF, within families already dealing with rare diseases. This study shows that participants remain in favor of accessing SF despite the potential psychological, care, and lifestyle impacts, which are difficult to anticipate. The establishment of a management protocol, including the support of a multidisciplinary team, would be necessary if national policy allows the reporting of these data.

Quantification of belatacept by liquid chromatography-tandem mass spectrometry in human plasma: Application to a pharmacokinetic study in renal transplant recipients.

Therapeutic drug monitoring is the cornerstone of immunosuppressive treatment in transplantation. The immunosuppressive drugs used in kidney transplant patients are mostly comprised of biologics, including therapeutic monoclonal antibodies (mAbs) and fusion proteins. Therefore, a specific and sensitive analytical technique that can universally quantify mAbs, as well as fusion proteins, is essential for clinical pharmacokinetics studies. In this short communication, we describe the validation of a liquid chromatography tandem mass-spectrometry (LC-MS/MS) method for quantification of the fusion protein belatacept in the plasma of kidney-transplant patients. Sample preparation was based on our previously published and implementable electrospray ionization LC-MS/MS method that allows the simultaneous quantification of seven mAbs. Immunocapture was made possible by the Fc domain of belatacept and identification/quantification by the choice of MRM transitions of peptides. The temporal evolution of the belatacept concentration after intravenous infusion and inter-individual variability of trough concentrations were assessed in 17 human plasma samples. The belatacept calibration curves were linear from 1 to 200 mg.L-1 and within-day and between-day accuracy and precision fulfilled Food and Drug Administration validation criteria. Residual belatacept concentrations (n = 8) ranged from 5.1 to 15.0 mg.L-1, with a median of 8.9 mg.L-1 and an inter-individual CV of 33.0%. Our generic LC-MS/MS method allows the quantification of fusion proteins, such as belatacept, and could be used for therapeutic drug monitoring. This method provides a useful tool to study the intra-patient variability of belatacept and the association between belatacept exposure and its therapeutic effects.

Advancing precision oncology through systematic germline and tumor genetic analysis: The oncogenetic point of view on findings from a prospective multicenter clinical trial of 666 patients.

INTRODUCTION: With the emergence of targeted therapies, there is a need to accurately identify more tumor biomarkers. The EXOMA trial was designed to offer tumor and germline exome sequencing (ES) to patients with solid malignant tumors and facing therapeutic failure. As hereditary cancer predispositions could be identified, with genetic counseling and health management implications, a genetic consultation was systematically established. This design needs to be discussed as genetic human resources are limited and indication of theranostic tests will increase. METHODS: Genetic counseling was conducted within 15 days following inclusion in the study for patients recruited between December 2015 and July 2019. In silico analyses from theranostic ES were limited to 317 genes involved in oncogenesis, from both tumor and blood DNA. RESULTS: Six hundred and sixty six patients had a genetic consultation before ES. In 65/666 patients, 66 germline pathogenic or likely pathogenic (P/LP) variants were identified in 16 actionable genes and seven non-actionable genes according to French guidelines. 24/65 patients had previously received genetic analysis for diagnostic purposes, and for 17 of them, a P/LP variant had already been identified. Among the 48/65 remaining cases for which the EXOMA protocol revealed a previously unknown P/LP variant, only 19 met the criteria for genetic testing for inherited cancer risk after familial survey. These criteria had not been identified by the oncologist in 10 cases. In 21/65 cases, the variant was considered incidental. DISCUSSION: In 7.4% of patients, an undiagnosed hereditary genetic predisposition was identified, whether or not related to the clinical presentation, and germline analysis impacted oncological management for only 6.3% of the cohort. This low percentage should be weighed against the burden of systematic genetic consultation and urgent circuits. Information or training tools to form oncologists to the prescription of germline genetic analyses should be explored, as well as information supports and patient preferences.

Patient satisfaction, experience and preferences in the implementation of genetics teleconsultations in the North-eastern region of France.

INTRODUCTION: In France, few centres per region offer genetics consultations. Consequently, each centre covers a large area, often requiring patients to take a day off to travel long distances. In certain situations, genetic counselling in particular, a physical exam is not required. In these cases, teleconsultations between medical professional and patients, at the patient's location of choice, are an interesting offer. The COVID-19 pandemic has accelerated the implementation and the use of this type of consultation. With the aim of developing teleconsultation for certain types of referrals, a study of patient satisfaction, experience and preferences has been set up in our region. METHODS: 2307 patients who had a teleconsultation by phone or videoconferencing with professionals from one of five genetic centres in North-eastern France between March and December 2020 were asked by e-mail or by post to answer an online survey. RESULTS: 20% of the patients (n = 465) responded to the survey (80% women, 55% over 40 years old). In 64% of the cases (n = 299), the teleconsultation replaced a physical consultation due to the pandemic. In 56% of cases (n = 217), the consultations were conducted by videoconference. The teleconsultation involved the disclosure of results in 56% of cases (n = 260), a first consultation in 30% of cases (n = 138), and a follow-up consultation in 14% of cases (n = 67). The satisfaction rate was 96% (n = 447), with a rating of "excellent" in 72% of responses (n = 290) and "good" in 24% of responses (n = 157). Only 22% of the patients (n = 103), particularly patients who lived near the hospital or who were older than 70 years, would have preferred a physical consultation. Half of respondents (n = 232) declared that they avoided more than 1.5 h of transport, and 69% (n = 321) avoided taking a work day off. Patients were less often accompanied by a relative than if the consultation had taken place face-to-face (43%; n = 201 vs. 61%; n = 285). There was no change in responses during or after lock-down. CONCLUSION: This collection of feedback and analysis of patients' preferences has validated the long-term implementation of medical genetics teleconsultations in certain circumstances and indications, for patients who prefer this approach.

Forced G1-phase reduction alters mode of division, neuron number, and laminar phenotype in the cerebral cortex.

The link between cortical precursors G1 duration (TG1) and their mode of division remains a major unresolved issue of potential importance for regulating corticogenesis. Here, we induced a 25% reduction in TG1 in mouse cortical precursors via forced expression of cyclin D1 and cyclin E1. We found that in utero electroporation-mediated gene transfer transfects a cohort of synchronously cycling precursors, necessitating alternative methods of measuring cell-cycle phases to those classical used. TG1 reduction promotes cell-cycle reentry at the expense of differentiation and increases the self-renewal capacities of Pax6 precursors as well as of Tbr2 basal precursors (BPs). A population level analysis reveals sequential and lineage-specific effects, showing that TG1 reduction: (i) promotes Pax6 self-renewing proliferative divisions before promoting divisions wherein Pax6 precursors generate Tbr2 BPs and (ii) promotes self-renewing proliferative divisions of Tbr2 precursors at the expense of neurogenesis, thus leading to an amplification of the BPs pool in the subventricular zone and the dispersed mitotic compartment of the intermediate zone. These results point to the G1 mode of division relationship as an essential control mechanism of corticogenesis. This is further supported by long-term studies showing that TG1 reduction results in cytoarchitectural modifications including supernumerary supragranular neuron production. Modeling confirms that the TG1-induced changes in neuron production and laminar fate are mediated via the changes in the mode of division. These findings also have implications for understanding the mechanisms that have contributed to brain enlargement and complexity during evolution.

Prognosis factors in probands with an FBN1 mutation diagnosed before the age of 1 year.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder. Diagnostic criteria of neonatal MFS (nMFS), the most severe form, are still debated. The aim of our study was to search for clinical and molecular prognostic factors that could be associated with length of survival. Probands ascertained via the framework of the Universal Marfan database-FBN1, diagnosed before the age of 1 y and presenting with cardiovascular features (aortic root dilatation or valvular insufficiency) were included in this study. Clinical and molecular data were correlated to survival. Among the 60 individuals, 38 had died, 82% died before the age of 1 y, mostly because of congestive heart failure. Three probands reached adulthood. Valvular insufficiencies and diaphragmatic hernia were predictive of shorter life expectancy. Two FBN1 mutations were found outside of the exon 24-32 region (in exons 4 and 21). Mutations in exons 25-26 were overrepresented and were associated with shorter survival (p = 0.03). We report the largest genotyped series of probands with MFS diagnosed before 1 y of life. In this population, factors significantly associated with shorter survival are presence of valvular insufficiencies or diaphragmatic hernia in addition to a mutation in exons 25 or 26.

Cardiovascular manifestations in men and women carrying a FBN1 mutation.

AIMS: In patients with Marfan syndrome and other type-1 fibrillinopathies, genetic testing is becoming more easily available, leading to the identification of mutations early in the course of the disease. This study evaluates the cardiovascular (CV) risk associated with the discovery of a fibrillin-1 (FBN1) mutation. METHODS AND RESULTS: A total of 1,013 probands with pathogenic FBN1 mutations were included, among whom 965 patients [median age: 22 years (11-34), male gender 53%] had data suitable for analysis. The percentage of patients with an ascending aortic (AA) dilatation increased steadily with increasing age and reached 96% (95% CI: 94-97%) by 60 years. The presence of aortic events (dissection or prophylactic surgery) was rare before 20 years and then increased progressively, reaching 74% (95% CI: 67-81%) by 60 years. Compared with women, men were at higher risk for AA dilatation [≤ 30 years: 57% (95% CI: 52-63) vs. 50% (95% CI: 45-55), P = 0.0076] and aortic events [≤ 30 years: 21% (95% CI: 17-26) vs. 11% (95% CI: 8-16), P < 0.0001; adjusted HR: 1.4 (1.1-1.8), P = 0.005]. The prevalence of mitral valve (MV) prolapse [≤ 60 years: 77% (95% CI: 72-82)] and MV regurgitation [≤ 60 years: 61% (95% CI: 53-69)] also increased steadily with age, but surgery limited to the MV remained rare [≤ 60 years: 13% (95% CI: 8-21)]. No difference between genders was observed (for all P> 0.20). From 1985 to 2005 the prevalence of AA dilatation remained stable (P for trend = 0.88), whereas the percentage of patients with AA dissection significantly decreased (P for trend = 0.01). CONCLUSION: The CV risk remains important in patients with an FBN1 gene mutation and is present throughout life, justifying regular aortic monitoring. Aortic dilatation or dissection should always trigger suspicion of a genetic background leading to thorough examination for extra-aortic features and comprehensive pedigree investigation.

Periodontal disorders in a cohort of patients with Cohen syndrome.

AIMS: Cohen syndrome (CS) is an uncommon autosomal recessive disorder due to mutations in vacuolar protein sorting 13B, with an intermittent presence of neutropenia. Contrary to other clinical phenotypic features, oral health has been little investigated in CS. We described oral health and dental hygiene in a cohort of CS patients. METHODS AND RESULTS: Twelve CS patients with neutropenia (<1500/mm3 ) were recruited in the dental department of Dijon University Hospital (France). Patients underwent oral examination, and blood samples were collected. Oral health markers were described and compared between patients with moderate and severe neutropenia (<500/mm3 ). In 12 patients (mean age = 21.1 years, SD = 13.7, six females), 45.5% brushed at least twice daily their teeth, and the same percentage annually visited a dentist. Dental plaque index was high (mean = 1.7, SD = 1.4). So was the number of lost teeth per patient, notably among adults (mean = 13.8, SD = 9.8). Elevated markers of periodontitis were noted as percentage of bleeding dental sites (mean = 70.2%, SD = 45.2%) or Gingival Index (mean = 2.2, SD = 1.0). The severity of neutropenia was correlated to the level of tooth-loss (P = .03). CONCLUSION: This study highlighted in CS patients worrisome oral health and dental follow-up in the context of intellectual disability with behavioural anomalies. More attention is needed by care-givers on oral condition in CS.

Care management in a French cohort with Down syndrome from the AnDDI-Rares/CNSA study.

Down syndrome (DS) is a genetic neurodevelopmental disorder. In individuals with DS, a multidisciplinary approach to care is required to prevent multiple medical complications. The aim of this study was to describe the rehabilitation, medical care, and educational and social support provided to school-aged French DS patients with varying neuropsychological profiles. A mixed study was conducted. Quantitative data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Qualitative data were collected by semi-structured face-to-face interviews and focus groups. Ninety-five DS subjects with a mean age of 10.9 years were included. Sixty-six per cent had a moderate intellectual disability (ID) and 18.9% had a severe ID. Medical supervision was generally multidisciplinary but access to medical specialists was often difficult. In terms of education, 94% of children under the age of six were in typical classes. After the age of 15, 75% were in medico-social institutions. Analysis of multidisciplinary rehabilitation conducted in the public and private sectors revealed failure to access physiotherapy, psychomotor therapy and occupational therapy, but not speech therapy. The main barrier encountered by patients was the difficulty accessing appropriate facilities due to a lack of space and long waiting lists. In conclusion, children and adolescents with DS generally received appropriate care. Though the management of children with DS has been improved considerably, access to health facilities remains inadequate.

Radial Migration Dynamics Is Modulated in a Laminar and Area-Specific Manner During Primate Corticogenesis.

The orderly radial migration of cortical neurons from their birthplace in the germinal zones to their final destination in the cortical plate is a prerequisite for the functional assembly of microcircuits in the neocortex. Rodent and primate corticogenesis differ both quantitatively and qualitatively, particularly with respect to the generation of neurons of the supragranular layers. Marked area differences in the outer subventricular zone progenitor cell density impact the radial glia scaffold compactness which is likely to induce area differences in radial migration strategy. Here, we describe specific features of radial migration in the non-human primate, including the absence of the premigratory multipolar stage found in rodents. Ex vivo approaches in the embryonic macaque monkey visual cortex, show that migrating neurons destined for supragranular and infragranular layers exhibit significant differences in morphology and velocity. Migrating neurons destined for the supragranular layers show a more complex bipolar morphology and higher motility rates than do infragranular neurons. There are area differences in the gross morphology and membrane growth behavior of the tip of the leading process. In the subplate compartment migrating neurons destined for the supragranular layers of presumptive area 17 exhibit radial constrained trajectories and leading processes with filopodia, which contrast with the meandering trajectories and leading processes capped by lamellipodia observed in the migrating neurons destined for presumptive area 18. Together these results present evidence that migrating neurons may exhibit autonomy and in addition show marked area-specific differences. We hypothesize that the low motility and high radial trajectory of area 17 migrating neurons contribute to the unique structural features of this area.

Associations between cognitive performance and the rehabilitation, medical care and social support provided to French children with Prader-Willi syndrome.

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.

Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20.

Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.