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Pathogenic variants in the cohesin genes, NIPBL and SMC1A, both cause Cornelia de Lange syndrome (CdLS), a rare genetic disorder associated with developmental delay and intellectual disability. This study aimed to compare sleep behaviors across individuals with CdLS caused by a variant in NIPBL or SMC1A, and identify relationships between sleep and behavior functioning. A total of 31 caregivers of individuals with a variant in NIPBL (N = 22) or SMC1A (N = 9) completed questionnaires regarding their child's sleep behaviors, behavior regulation, attention, and autistic features (repetitive behaviors and social communication difficulties) as part of the Coordination of Rare Diseases (CoRDS) registry. Findings showed a trend of increased behavior regulation difficulties and repetitive behaviors in the NIPBL compared to the SMC1A participants. Both groups presented with a similar degree of attention, social communication, and sleep challenges. In the whole sample, sleep disturbance was strongly correlated with more behavior regulation difficulties, a relationship that was more robust in the NIPBL sample. In brief, study results support our prior observations of greater behavior difficulties among those with a variant in NIPBL as compared to SMC1A. Preliminary findings point to unique associations between sleep and behavior regulation in the NIPBL group, suggesting sleep interventions may yield differential effects on behavior management across variants., (© 2024 Wiley Periodicals LLC.) more...

The aim of this study was to expand knowledge about endocrine disorders in individuals with Cornelia de Lange syndrome (CdLS), a rare developmental genetic disorder with anomalies in multiple organs and systems. Hormone levels, clinical scores, anthropometric measurements, and molecular analysis were assessed in 24 individuals with CdLS. Hyperprolactinemia was the most common endocrine disorder. Three patients showed subclinical hypothyroidism. Concerning the gonadotropic axis, mildly delayed puberty was observed, as well as genital anomalies, such as cryptorchidism. Despite short stature, levels of insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 tended to be normal. Three prepubertal individuals without risk factors had higher than normal values for the homeostatic model assessment of insulin resistance (HOMA-IR) and for insulinemia, suggesting insulin resistance. Furthermore, two adults had elevated body mass indexes associated with HOMA-IR values over the cut-off values. CdLS may lead to dysregulation of the endocrine system, particularly in patients with high HOMA-IR values and insulinemia who are at risk of insulin resistance. Therefore, clinical follow-up with comprehensive hormonal assessment appears warranted in individuals with CdLS., (©Copyright 2024 by Turkish Society for Pediatric Endocrinology and Diabetes / The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.) more...

Cornelia de Lange syndrome (CdLS) is a genetic disease that exemplifies the evolution of knowledge in the field of rare genetic disorders. Originally described as a unique pattern of major and minor anomalies, over time this syndrome has been shown to be characterized by a significant variability of clinical expression. By increasing the number of patients described, knowledge of the natural history of the condition has been enriched with the demonstration of the relative frequency of various potential comorbidities. Since 2006, the discovery of CdLS's molecular basis has shown an equally vast genetic heterogeneity linked to the presence of variants in genes encoding for the cohesin complex pathway. The most recent clinical-genetic data led to the classification of the "original syndrome" into a "clinical spectrum" that foresees the presence of classic patients, of non-classic forms, and of conditions that show a modest phenotypic overlapping with the original disease. Finally, the knowledge of the molecular basis of the disease has allowed the development of basic research projects that could lay the foundations for the development of possible innovative pharmacological treatments. more...

Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder, which causes a range of physical, cognitive, and medical challenges. To retrospectively analyze the clinical characteristics and genetic variations of Chinese patients, and to provide experience for further diagnosis and treatment of CdLS in Chinese children, we identified 15 unrelated Chinese children who presented with unusual facial features, short stature, developmental delay, limb abnormalities, and a wide range of health conditions. In this study, targeted-next generation sequencing was used to screen for causal variants and the clinically relevant variants were subsequently verified using Sanger sequencing. DNA sequencing identified 15 genetic variations, including 11 NIPBL gene variants, two SMC1A gene variants, one RAD21 gene variant, and one HDAC8 variant. The phenotype of these patients was summarized and differences between this cohort and another four groups were compared. The clinical manifestations of the patients in this cohort were mostly consistent with other ethnicities, but several clinical features in our cohort had different frequencies compared with other groups. We identified 15 deleterious variants of which 11 were novel. Variants in the NIPBL gene were the most common cause in our cohort. Our study not only expands upon the spectrum of genetic variations in CdLS, but also broadens our understanding of the clinical features of CdLS. more...

Chromothripsis is a type of chaotic complex genomic rearrangement caused by a single event of chromosomal shattering and repair processes. Chromothripsis is known to cause rare congenital diseases when it occurs in germline cells, however, current genome analysis technologies have difficulty in detecting and deciphering chromothripsis. It is possible that this type of complex rearrangement may be overlooked in rare-disease patients whose genetic diagnosis is unsolved. We applied long read nanopore sequencing and our recently developed analysis pipeline dnarrange to a patient who has a reciprocal chromosomal translocation t(8;18)(q22;q21) as a result of chromothripsis between the two chromosomes, and fully characterize the complex rearrangements at the translocation site. The patient genome was evidently shattered into 19 fragments, and rejoined into derivative chromosomes in a random order and orientation. The reconstructed patient genome indicates loss of five genomic regions, which all overlap with microarray-detected copy number losses. We found that two disease-related genes RAD21 and EXT1 were lost by chromothripsis. These two genes could fully explain the disease phenotype with facial dysmorphisms and bone abnormality, which is likely a contiguous gene syndrome, Cornelia de Lange syndrome type IV (CdLs-4) and atypical Langer-Giedion syndrome (LGS), also known as trichorhinophalangeal syndrome type II (TRPSII). This provides evidence that our approach based on long read sequencing can fully characterize chromothripsis in a patient's genome, which is important for understanding the phenotype of disease caused by complex genomic rearrangement. more...

Psychomotor delay and intellectual disability are potential limitations in psoriasis management, due to low compliance, and strict dependence from caregivers intervention. We report our successful experience with a 58-year-old woman, who was genetically affected by Cornelia De Lange syndrome, which causes intellectual disability and psychomotor disorders. The patient had been already treated with topical and traditional therapies, without any clinical benefits. Eventually, she adhered to guselkumab treatment. The compliance was excellent, significant improvements were observed after only 3 months of treatment, without adverse effects. During follow-up, the COVID-19 pandemic address concern on the possible increased risk of infection due to immunosuppression. In agreement with current Italian recommendations, risk and benefits profile was discussed with the patient's legal tutor and the decision to continue the treatment was taken. Psoriasis complete clarification was maintained during the most difficult period of the Italian outbreak, allowing the patient to remain safely at home., (© 2020 Wiley Periodicals LLC.) more...

Cornelia de Lange Syndrome (CdLS) is a rare congenital genetic disease causing abnormal unique facial phenotypes, several defects in organs and body parts, and mental disorder or intellectual disorder traits. Main causes of CdLS have been reported as variants in cohesin complex genes, in which mutations in the NIPBL gene have been estimated to account for up to 80%. Our study included three Vietnamese patients with typical CdLS phenotypes. Whole exome sequencing revealed two known heterozygous mutations c.6697G>A (p.Val2233Met) and c.2602C>T (p.Arg868X), and a novel heterozygous mutation c.4504delG (p.Val1502fsX87) in the NIPBL gene of the three patients. In silico analyses of the identified mutations predicted possible damaging and truncating effects on the NIPBL protein. Inherited analyses in the patients' families showed that all of the mutations are de novo. Our results lead a definitive diagnosis of patients with CdLS and expand the spectrum of mutations in the NIPBL gene. These findings also confirm whole exome sequencing is an efficient tool for genetic screening of CdLS. more...

Background: There is growing evidence to suggest that children with neurodevelopmental disorders may evidence differences in their sensory processing. The aim of this study was to compare sensory processing patterns in three genetic syndromes associated with sensory difference., Methods: Sensory processing in Angelman syndrome (n = 91), Cornelia de Lange syndrome (n = 28) and Fragile X syndrome (n = 40) was examined using the informant report measure the Sensory Experiences Questionnaire (SEQ)., Results: All three groups were associated with a heightened prevalence of unusual sensory processing in comparison with normative data, evidenced in over 80% of all participants. Cross-syndrome comparisons highlighted syndrome-specific sensory processing profiles, with heightened hypo responsivity in Cornelia de Lange syndrome and sensory seeking in Angelman syndrome., Conclusions: The results have important implications for the understanding of sensory processing in genetic syndromes and the development of tailored behavioural interventions., (© 2019 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.) more...

Background: Pitt-Hopkins syndrome (PTHS) is a genetic neurodevelopmental disorder associated with intellectual disability. Although the genetic mechanisms underlying the disorder have been identified, description of its behavioural phenotype is in its infancy. In this study, reported behavioural and psychological characteristics of individuals with PTHS were investigated in comparison with the reported behaviour of age-matched individuals with Angelman syndrome (AS) and Cornelia de Lange syndrome (CdLS)., Methods: Questionnaire data were collected from parents/caregivers of individuals with PTHS (n = 24), assessing behaviours associated with autism spectrum disorder (ASD), sociability, mood, repetitive behaviour, sensory processing, challenging behaviours and overactivity and impulsivity. For most measures, data were compared to data for people with AS (n = 24) and CdLS (n = 24) individually matched by adaptive ability, age and sex., Results: Individuals with PTHS evidenced significantly higher levels of difficulties with social communication and reciprocal social interaction than individuals with AS, with 21 of 22 participants with PTHS meeting criteria indicative of ASD on a screening instrument. Individuals with PTHS were reported to be less sociable with familiar and unfamiliar people than individuals with AS, but more sociable with unfamiliar people than individuals with CdLS. Data also suggested areas of atypicality in sensory experiences. Challenging behaviours were reported frequently in PTHS, with self-injury (70.8%) occurring at significantly higher rates than in AS (41.7%) and aggression (54.2%) occurring at significantly higher rates than in CdLS (25%). Individuals with PTHS also evidenced lower reported mood than individuals with AS., Conclusions: Behaviours which may be characteristic of PTHS include those associated with ASD, including deficits in social communication and reciprocal social interaction. High rates of aggression and self-injurious behaviour compared to other genetic syndrome groups are of potential clinical significance and warrant further investigation. An atypical sensory profile may also be evident in PTHS. The specific aetiology of and relationships between different behavioural and psychological atypicalities in PTHS, and effective clinical management of these, present potential topics for future research. more...

Background: Depressive symptomology and low affect are comparatively common in individuals with genetic disorders such as Cornelia de Lange syndrome. However, lifespan trajectories and associated person characteristics have not been examined. In this study, the trajectories for affect and associated behavioural characteristics were investigated in individuals with Cornelia de Lange syndrome with individuals with fragile X syndrome (FXS) comparable for chronological age and total number of behavioural indicators of ASD included for the purpose of contrast., Methods: A 7-year longitudinal study of affect (mood, interest and pleasure) was conducted in individuals with CdLS (n = 44) and FXS (n = 95). The trajectories of low affect were explored, as well as associations between Time 1 behavioural characteristics and affect at Time 1 and Time 3 (7 years later)., Results: The CdLS group were lower in mood than the FXS group overall (p < .001). Interest and pleasure scores showed a significant decline over the lifespan for individuals with CdLS (p < .001) but not the FXS group. Lower level of ability at Time 1 was associated with lower mood at Time 1 and Time 3 in the FXS group only. Higher levels of ASD symptomology at Time 1 were associated with low mood and interest and pleasure in both syndrome groups at Time 1 and Time 3. Greater insistence on sameness at Time 1 was associated with lower mood at Time 1 in the FXS group and lower interest and pleasure at Time 1 and Time 3 in the CdLS group., Conclusions: Low affect in specific genetic syndromes may be associated with differing lifespan trajectories and behavioural profiles. Specifically, individuals with CdLS appear at risk for experiencing declines in levels of interest and pleasure whereas individuals with FXS show no significant change in the level of affect with age. more...

Introduction: Development and behaviour in Cornelia de Lange Syndrome (CdLS), including autism characteristics, have been described infrequently stratified to genetic cause and only a few studies have considered behavioural characteristics in relation to developmental level. Here, we describe the behavioural phenotype in individuals with CdLS with SMC1A variants., Methods: We performed an international, interdisciplinary study on 51 individuals with SMC1A variants. Results of questionnaire studies are compared to those in individuals with Down Syndrome and with Autism Spectrum Disorder. Results on cognition and self-injurious behaviour (SIB) are compared to those in individuals with CdLS caused by NIPBL variants. For Dutch participants with SMC1A variants we performed direct in-person assessments of cognition, autism, and added an interview and questionnaire on adaptive behaviour and sensory processing., Results: Individuals with SMC1A variants show a higher cognitive level and less SIB than individuals with NIPBL variants. Individuals with SMC1A variants without classic CdLS phenotype but with a Rett-like phenotype show more severe intellectual disability and more SIB compared to those with a CdLS phenotype. Autism is less present if outcomes in direct in-person assessments are evaluated taking developmental level into account compared to results based on a questionnaire., Conclusions: Behaviour in individuals with CdLS should be evaluated taking genetic cause into account. Detailed interdisciplinary approaches are of clinical importance to inform tailored care and may eventually improve quality of life of patients and families., (© 2018 Association for Child and Adolescent Mental Health.) more...

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide., (© 2019 Wiley Periodicals, Inc.) more...

Cornelia de Lange syndrome (CdLS), which is reported to affect ∼1 in 10 000 to 30 000 newborns, is a multisystem organ developmental disorder with relatively mild to severe effects. Among others, intellectual disability represents an important feature of this condition. CdLS can result from mutations in at least five genes: nipped-B-like protein, structural maintenance of chromosomes 1A, structural maintenance of chromosomes 3, RAD21 cohesin complex component and histone deacetylase 8 (HDAC8). It is believed that mutations in these genes cause CdLS by impairing the function of the cohesin complex (to which all the aforementioned genes contribute to the structure or function), disrupting gene regulation during critical stages of early development. Since intellectual disorder might result from alterations in neural development, in this work, we studied the role of Hdac8 gene in mouse neural stem cells (NSCs) and in vertebrate (Danio rerio) brain development by knockdown and chemical inhibition experiments. Underlying features of Hdac8 deficiency is an increased cell death in the developing neural tissues, either in mouse NSCs or in zebrafish embryos. more...

Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder caused by mutations in genes that encode for either structural (SMC1A, SMC3, RAD21) or regulatory (NIPBL, HDAC8) subunits of the cohesin complex. NIPBL represents the major gene of the syndrome and heterozygous mutations can be identified in more than 65% of patients. Interestingly, large portions of these variants were described as somatic mosaicism and often escape standard molecular diagnostics using lymphocyte DNA. Here we discuss the role of somatic mosaicism in CdLS and describe two additional patients with NIPBL mosaicism detected by targeted gene panel or exome sequencing. In order to verify the next generation sequencing data, Sanger sequencing or pyrosequencing on DNA extracted from different tissues were applied. None of the pathogenic variants was originally detected by Sanger sequencing on blood DNA. Patient 1 displays an unusual combination of clinical features: he is cognitively only mildly affected, but shows severe limb reduction defects. Patient 2 presents with a moderate phenotype. Interestingly, Sanger sequencing analysis on fibroblast DNA of this patient did not detect the disease-causing variant previously observed on the same DNA sample by exome sequencing. Subsequent analyses could confirm the variants by Sanger sequencing on buccal mucosa DNA. Notably, this is the first report of a higher mutational load in buccal mucosa than in fibroblast cells of a CdLS patient. Detection of low-level mosaicism is of utmost importance for an accurate molecular diagnosis and a proper genetic counseling of patients with a clinical diagnosis of CdLS. Next-generation sequencing technologies greatly facilitate the detection of low-level mosaicism, which might otherwise remain undetected by conventional sequencing approaches., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.) more...

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning. more...

Background: Catatonia-like presentations in people with autism have been increasingly recognised within research and diagnostic guidelines. The recently developed Attenuated Behaviour Questionnaire has identified that attenuated behaviour [autistic catatonia] is very prevalent in people with autism spectrum disorders (ASDs) and associated with repetitive behaviour. In the current study, we investigated attenuated behaviour within two genetic syndromes associated with ASD and examined ASD and repetitive behaviour as longitudinal predictors of attenuated behaviour., Method: The Attenuated Behaviour Questionnaire was completed by parents/carers of 33 individuals with Cornelia de Lange syndrome (CdLS) and 69 with fragile X syndrome (FXS). Information collected from the same informants 4 years previously was utilised to examine ASD and repetitive behaviour as predictors of later attenuated behaviour, controlling for age, gender and ability., Results: Catatonia-like attenuated behaviour was reported for individuals with CdLS (30.3%) and FXS (11.6%). Slowed movement was more prevalent in people with CdLS. No other phenotypic differences were observed. Across the two groups, repetitive behaviour predicted the presence of attenuated behaviour 4 years later, after controlling for age, gender and ability., Conclusions: Attenuated behaviour can be identified in individuals with CdLS and FXS and may have an effect on both adaptive behaviour and quality of life. Repetitive behaviours predicted subsequent risk within both groups and should be assessed by services as part of a pro-active strategy of support., (© 2018 The Authors. Journal of Intellectual Disability Research published by MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disibilities and John Wiley & Sons Ltd.) more...

It is well documented that mothers of children with challenging behavior (CB) experience elevated levels of stress and that this persists over time, but less is known about the experience of mothers of children with rare genetic syndromes. This article describes 2 studies, 1 cross-sectional and 1 longitudinal, comparing well-being in mothers of children with Angelman, Cornelia de Lange and Cri du Chat syndrome who have either shown chronic CB ( n = 18) or low/no CB ( n = 26) in the preceding 7 years. The presence of chronic, long-term CB increased maternal stress but not depression or anxiety, and did not influence positive well-being. Stress relating specifically to their child's genetic syndrome reduced with age, highlighting the need for further exploration in this area. more...

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes., (© 2017 Wiley Periodicals, Inc.) more...

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder associated with unusual facial features, limb abnormalities, a wide range of health conditions, and intellectual disability. Mutations in five genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex have been identified in up to 70% of individuals. Genetic cause remains unknown for a proportion of individuals. There is substantial heterogeneity in all aspects of CdLS but very little is known about what predicts phenotypic heterogeneity. In this study, we evaluated genotype-phenotype associations in 34 individuals with CdLS. Participants with NIPBL mutations had significantly lower self help skills and were less likely to have verbal skills relative to those who were negative for the NIPBL mutation. No significant differences were identified between the groups in relation to repetitive behavior, mood, interest and pleasure, challenging behavior, activity, impulsivity, and characteristics of autism spectrum disorder whilst controlling differences in self help skills. Significant correlations indicating lower mood, interest and pleasure, and increased insistence on sameness with older age were identified for those who were NIPBL mutation positive. The findings suggest similarities in the behavioral phenotype between those with and without the NIPBL mutation once differences in self help skills are controlled for. However, there may be subtle differences in the developmental trajectory of these behaviors according to genetic mutation status in CdLS., (© 2017 Wiley Periodicals, Inc.) more...

De novo missense mutations and in-frame coding deletions in the X-linked gene SMC1A (structural maintenance of chromosomes 1A), encoding part of the cohesin complex, are known to cause Cornelia de Lange syndrome in both males and females. For a long time, loss-of-function (LoF) mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male nor female patients. However, recently, the authors and others reported LoF mutations in females with intellectual disability (ID) and epilepsy. Here we present the detailed phenotype of two females with de novo LoF mutations in SMC1A, including a de novo mutation of single base deletion [c.2364del, p.(Asn788Lysfs*10)], predicted to result in a frameshift, and a de novo deletion of exon 16, resulting in an out-of-frame mRNA splice product [p.(Leu808Argfs*6)]. By combining our patients with the other recently reported females carrying SMC1A LoF mutations, we ascertained a phenotypic spectrum of (severe) ID, therapy-resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet. Our data show the existence of a novel phenotypic entity - distinct from CdLS - and caused by de novo SMC1A LoF mutations., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.) more...

Objectives: Patients with Cornelia de Lange Syndrome (CdLS) are reported to have conductive (CHL) and sensorineural hearing loss (SNHL), but there is little information pertaining to the progression of hearing loss over time. The goal of this study was to examine the prevalence of CHL and SNHL in adults and children with CdLS and look for changes in SNHL over time., Methods: Retrospective chart review of patients with CdLS presenting to a CdLS clinic was conducted. Also, a written survey of clinical concerns was collected from additional patients/families seen in the clinic and through the Cornelia de Lange Foundation., Results: Seventy-eight patients (50% female) were included in the chart review. Mean age was 16.8 ± 11.4 years (range-0.6-50 years) and mean age at diagnosis of hearing loss was 4.6 ± 10.6 years (n = 26). Five patients (6.4%) had severe to profound SNHL that improved with time, including 2 who had complete normalization of audiogram results. Thirty-five families/patients completed the clinical survey, and 45.5% of the families reported a noticeable improvement of hearing over time., Conclusions: Conductive hearing loss and SNHL are common in CdLS. More than 50% of the patients seen in an adult CdLS clinic reported improvement in hearing loss over time, and a subset of patients had an improvement in SNHL. In light of these findings, we recommend longitudinal evaluations of hearing loss in these patients with both auditory brainstem response and otoacoustic emissions testing if SNHL is identified., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.) more...

Background: Recent research has identified differences in relative attention to competing social versus non-social video stimuli in individuals with autism spectrum disorder (ASD). Whether attentional allocation is influenced by the potential threat of stimuli has yet to be investigated. This is manipulated in the current study by the extent to which the stimuli are moving towards or moving past the viewer. Furthermore, little is known about whether such differences exist across other neurodevelopmental disorders. This study aims to determine if adolescents with ASD demonstrate differences in attentional allocation to competing pairs of social and non-social video stimuli, where the actor or object either moves towards or moves past the viewer, in comparison to individuals without ASD, and to determine if individuals with three genetic syndromes associated with differing social phenotypes demonstrate differences in attentional allocation to the same stimuli., Methods: In study 1, adolescents with ASD and control participants were presented with social and non-social video stimuli in two formats (moving towards or moving past the viewer) whilst their eye movements were recorded. This paradigm was then employed with groups of individuals with fragile X, Cornelia de Lange, and Rubinstein-Taybi syndromes who were matched with one another on chronological age, global adaptive behaviour, and verbal adaptive behaviour (study 2)., Results: Adolescents with ASD demonstrated reduced looking-time to social versus non-social videos only when stimuli were moving towards them. Individuals in the three genetic syndrome groups showed similar looking-time but differences in fixation latency for social stimuli moving towards them. Across both studies, we observed within- and between-group differences in attention to social stimuli that were moving towards versus moving past the viewer., Conclusions: Taken together, these results provide strong evidence to suggest differential visual attention to competing social versus non-social video stimuli in populations with clinically relevant, genetically mediated differences in socio-behavioural phenotypes. more...

Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder caused by mutations in the cohesion complex and its regulators. The syndrome is characterized by multiple organ system abnormalities, pre- and post-natal growth retardation and typical facial features. Thrombocytopenia is a reduction in platelet count to <150 × 10(9)  L. It can be caused by congenital or acquired decreased production, increased destruction, or sequestration of platelets. In recent years, several papers reported thrombocytopenia and immune thrombocytopenia in patients affected by CdLS. In 2011, Lambert et al. estimated the risk of idiopathic thrombocytopenia purpura in CdLS patients to be 31-633 times greater than in the general population. We describe the incidence of thrombocytopenia in 127 Italian CdLS patients, identifying patients with transient or persistent thrombocytopenia, but a lower incidence of true idiopathic thrombocytopenic purpura (ITP)., (© 2015 Wiley Periodicals, Inc.) more...

Little is known about the way in which the characteristics of autism spectrum disorder (ASD) develop and manifest across the age span in individuals with genetic syndromes. In this study we present findings from a two and a half year follow-up of the characteristics associated with ASD in three syndromes: Cornelia de Lange (CdLS), Fragile X (FXS), and Cri du Chat (CdCS). Parents and carers of 251 individuals (CdLS=67, CdCS=42, and FXS=142) completed the Social Communication Questionnaire (SCQ) at Time 1 (T1) and again two and a half years later (T2). The FXS and CdLS groups were more likely to meet the cut-offs for both autism and ASD and show greater severity of ASD related behaviors, at both T1 and T2, compared to the CdCS group. Older individuals (>15yrs) with CdLS were more likely to meet the cut off for ASD than younger individuals (≤15 yrs) with the syndrome and more likely to show greater severity of social impairments. In FXS repetitive behaviors were found to become less prominent with age and in CdCS social impairments were reported to be more severe with age. There were no significant changes between T1 and T2 in the severity of ASD characteristics in the CdCS and CdLS groups. The FXS group showed significantly fewer repetitive behaviors and less severe impairments in social interaction over this time frame. The findings suggest that while there may be similarities in overall severity and presentation of ASD characteristics in CdLS and FXS, these characteristics have divergent patterns of development within these groups., (© 2015 Wiley Periodicals, Inc.) more...

Studies of individuals with Cornelia de Lange syndrome (CdLS) have described changes in mood and behavior with age, although no empirical or longitudinal studies have been conducted. Caregivers of individuals with CdLS (N  =  67), cri du chat syndrome (CdCS; N  =  42), and Fragile X syndrome (FXS; N  =  142) completed the Mood, Interest and Pleasure Questionnaire (MIPQ) at Time 1 and 2 years later (Time 2). Scores on the MIPQ were significantly lower in the CdLS group compared with the CdCS and FXS groups at Time 1 and Time 2. Lower MIPQ scores were characteristic of older adolescents (> 15 years) and adults with CdLS. However, there were no significant differences in MIPQ scores between Time 1 and Time 2. Age and insistence on sameness predicted MIPQ scores in CdLS. more...

The disorders caused by mutations in genes encoding subunits and accessory proteins of cohesin complex are collectively termed as cohesinopathies. The best known cohesinopathy is Cornelia de Lange Syndrome (CdLS), which is a multisystem developmental disorder characterized by facial dysmorphism, limb malformations, growth and cognitive impairment. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), are responsible for ∼ 70% of CdLS cases. We describe a 16-year-old boy with facial dysmorphism, growth retardation, intellectual disability, hirsutism and small hands, who has a small Supernumerary Marker Chromosome (sSMC) present in mosaic form. sSMC is composed of two duplicated segments encompassing 17 genes including SMC1A gene, at the regions Xp11.22 and Xp11.21q11.1. Clinical comparison between our patient with a previously reported individual with a SMC1A duplication and four male carriers of similar sSMC reported in databases, suggest that they all share clinical features related to cohesinopathies. Although our patient does not have the classical CdLS craniofacial phenotype, he has pre and postnatal growth retardation, intellectual disability and mild musculoskeletal anomalies, features commonly seen in patients with cohesinopathies., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.) more...

We evaluated autism spectrum disorder (ASD) characteristics and social behavior in Angelman (AS; n  =  19; mean age  = 10.35 years), Cornelia de Lange (CdLS; n  =  15; mean age  = 12.40 years), and Cri du Chat (CdCS, also known as 5 p-syndrome; n  =  19; mean age  =  8.80 years) syndromes. The proportion of individuals meeting the ASD cutoff on the Social Communication Questionnaire was significantly higher in the AS and CdLS groups than in the CdCS group (p < .01). The groups demonstrated divergent social behavior profiles during social conditions in which adult availability, adult familiarity, and social demand were manipulated. Social enjoyment was significantly heightened in AS, whereas social approaches were heightened in individuals with CdCS. Social motivation, social communication, and enjoyment were significantly lower in CdLS. The findings highlight the importance of detailed observation when evaluating ASD and social behavior in genetic syndromes. more...

Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder characterized by growth retardation, cognitive impairment, external and internal structural malformations, and characteristic facial features. Currently, there are no definitive prenatal screening measures that lead to the diagnosis of CdLS. In this study, documented prenatal findings in CdLS syndrome were analyzed towards the development of a prenatal profile predictive of CdLS. We reviewed 53 cases of CdLS (29 previously reported and 24 unreported) in which prenatal observations/findings were available. The review of these cases revealed a pattern of sonographic findings, including obvious associated structural defects, growth restriction, as well as a more subtle, but strikingly characteristic, facial profile, and suggestive of a recognizable prenatal ultrasonographic profile for CdLS. In addition, the maternal serum marker, PAPP-A, may be reduced and fetal nuchal translucency (NT) may be increased in some pregnancies when measured at an appropriate gestational age. In conclusion, CdLS can be prenatally diagnosed or readily ruled out in a family with a known mutation in a CdLS gene. The characteristic ultrasonographic profile may allow for prenatal diagnosis of CdLS in (1) subsequent pregnancies to a couple with a prior child with CdLS in whom a mutation has not been identified or (2) when there are unexplained pregnancy signs of fetal abnormality, such as oligo- or polyhydramnios, a low maternal serum PAPP-A level and/or increased NT, fetal growth retardation, or structural anomalies consistent with CdLS., (Copyright © 2012 Wiley Periodicals, Inc.) more...

Cohesin is responsible for sister chromatid cohesion, ensuring the correct chromosome segregation. Beyond this role, cohesin and regulatory cohesin genes seem to play a role in preserving genome stability and gene transcription regulation. DNA damage is thought to be a major culprit for many human diseases, including cancer. Our present knowledge of the molecular basis underlying genome instability is extremely limited. Mutations in cohesin genes cause human diseases such as Cornelia de Lange syndrome and Roberts syndrome/SC phocomelia, and all the cell lines derived from affected patients show genome instability. Cohesin mutations have also been identified in colorectal cancer. Here, we will discuss the human disorders caused by alterations of cohesin function, with emphasis on the emerging role of cohesin as a genome stability caretaker. more...

Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75-80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only approximately 30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/- mice and in individuals with CdLS., Competing Interests: The authors have declared that no competing interests exist. more...

Cornelia de Lange syndrome is a congenital disease, basically characterized by psychomotor retardation associated with a series of malformations, including mainly skeletal, craniofacial deformities together with gastrointestinal and cardiac malformations. There is no definitive biochemical or chromosomal marker for the prenatal diagnosis of this syndrome. We actually want to present the case of a 10-year-old patient, who was admitted to our clinic for dental pain. The patient had the symptoms of Cornelia de Lange syndrome. During the oral examination of this patient, the patient was found to have the typical symptoms of Cornelia de Lange syndrome, such as micrognathia and delayed eruption in conjunction with the symptoms of the Hutchinson's syndrome, which had never been reported before. more...

The cohesin complex, discovered through its role in sister chromatid cohesion, also plays roles in gene expression and development in organisms from yeast to human. This review highlights what has been learned about the gene control and developmental functions of cohesin and the Nipped-B (NIPBL/Scc2) cohesin loading factor in Drosophila. The Drosophila studies have provided unique insights into the aetiology of Cornelia de Lange syndrome (CdLS), which is caused by mutations affecting sister chromatid cohesion proteins in humans. In vivo experiments with Drosophila show that cohesin and Nipped-B have dosage-sensitive effects on the functions of many evolutionarily conserved genes and developmental pathways. Genome-wide studies with Drosophila cultured cells show that Nipped-B and cohesin co-localize on chromosomes, and bind preferentially, but not exclusively, to many actively transcribed genes and their regulatory sequences, including many of the proposed in vivo target genes. In contrast, the cohesion factors are largely excluded from genes silenced by Polycomb group (PcG) proteins. Combined, the in vivo genetic data and the binding patterns of cohesin and Nipped-B in cultured cells are consistent with the hypothesis that they control the action of gene regulatory sequences, including transcriptional enhancers and insulators, and suggest that they might also help define active chromatin domains and influence transcriptional elongation. more...

The development of children who have syndromes with mental retardation and/or language delay can be worsened by sensorineural or conductive hearing loss (HL). Given the existing scarcity of data, we investigated the prevalence of otitis media with effusion and/or HL in 50 children with Cornelia de Lange syndrome (CdLS) aged 1-18 years, and its impact on the children's performance. The children underwent otological and audiological examinations in order to ascertain the relative frequencies of otitis media with effusion and/or hearing impairment; their demographic and clinical data were obtained by questionnaires and from information in their medical charts. Otitis media with effusion was diagnosed in 94%, and its prevalence was similar in all age groups; HL was detected in 40 children (80%). Conductive HL due to middle ear effusion was the main cause of hearing impairment alone (60%) or in combination with sensorineural deficit (20%). HL had a negative impact on performance regardless of the type. A history of routine audiological and/or otological assessments was reported by a minority of parents. Our findings indicate that otitis media with effusion and/or HL is an important feature of children with CdLS and may negatively affect their performance. Careful follow-up throughout childhood is necessary to detect and treat any hearing loss in children with CdLS in order to minimize its impact on performance. more...

Objectives: Cornelia de Lange syndrome (CdLS) is a dominantly inherited disorder characterized by growth and mental retardation, abnormalities of the upper limbs, gastroesophageal dysfunction, cardiac, ophthalmologic and genitourinary anomalies, hirsutism and characteristic facial features. Growth retardation, behavioural disturbances and gastro-intestinal manifestations can mimic coeliac disease (CD). Genetic conditions like Down, Williams and Turner syndromes can be associated to CD., Aim: To establish if gastro-intestinal signs and symptoms in CdLS patients are due to CD., Methods: Multiple duodenal biopsies were performed in 24 CdLS patients (mean age 12 years) during the endoscopic follow-up for gastro-esophageal reflux disease (GERD). Histological assessment was performed. Anthropometric parameters were recorded and plotted on the growth charts specific for CdLS patients. Antiendomysium and antitransglutaminase antibodies and HLA-DQ2/DQ8 were tested in all patients., Results: All CdLS patients were growth retarded, although weight and height were within the normal limits using the specific growth charts for CdLS. No histological abnormalities were noted in the intestinal biopsy specimens. Serum levels of antiendomysium and antitransglutaminase antibodies were always normal. The HLA-DQ2/DQ8 was absent in all patients., Conclusions: While a high prevalence of gastro-intestinal disorders has been described in CdLS children, no association with CdLS has been found. more...

Background: Cornelia-de-Lange syndrome is a rare congenital syndrome with poor social relatedness as one of several characteristics of its behavioural phenotype., Methods: Video observations were collected from seven children in their first year of life and again with age 2-4 years. Data were analysed for distribution of object-related and social attention and for relationships between early and later observations., Results: The findings suggest some inter-individual stability for social relatedness., Conclusions: Low frequency of eye-contact in early interaction may serve as a risk factor. Intensive early interaction is recommended in early stimulation programmes. more...

Observations about the natural history of aging in Cornelia de Lange syndrome (CdLS) are made, based on 49 patients from a multidisciplinary clinic for adolescents and adults. The mean age was 17 years. Although most patients remain small, obesity may develop. Gastroesophageal reflux persists or worsens, and there are early long-term sequelae, including Barrett esophagus in 10%; other gastrointestinal findings include risk for volvulus, rumination, and chronic constipation. Submucous cleft palate was found in 14%, most undetected before our evaluation. Chronic sinusitis was noted in 39%, often with nasal polyps. Blepharitis improves with age; cataracts and detached retina may occur. Decreased bone density is observed, with occasional fractures. One quarter have leg length discrepancy and 39% scoliosis. Most females have delayed or irregular menses but normal gynecologic exams and pap smears. Benign prostatic hypertrophy occurred in one male prior to 40 years. The phenotype is variable, but there is a distinct pattern of facial changes with aging. Premature gray hair is frequent; two patients had cutis verticis gyrata. Behavioral issues and specific psychiatric diagnoses, including self-injury, anxiety, attention-deficit disorder, autistic features, depression, and obsessive-compulsive behavior, often worsen with age. This work presents some evidence for accelerated aging in CdLS. Of 53% with mutation analysis, 55% demonstrate a detectable mutation in NIPBL or SMC1A. Although no specific genotype-phenotype correlations have been firmly established, individuals with missense mutations in NIPBL and SMC1A appear milder than those with other mutations. Based on these observations, recommendations for clinical management of adults with CdLS are made., ((c) 2007 Wiley-Liss, Inc.) more...

A 3-year-old girl with facial dysmorphic features suggestive of Cornelia de Lange syndrome was seen in the ophthalmology unit for a right leukocoria. The leukocoria was found to be caused by a large retinoblastoma and the right eye was enucleated. Chromosomal analysis revealed partial chromosome 13q deletion involving band 14 which is associated with a high risk of retinoblastoma. This case shows that patient with chromosome 13q deletion syndrome cannot be diagnosed based on dysmorphic features only. Chromosomal analysis is warranted in all infants with facial dysmorphism suggestive of Cornelia de Lange syndrome so that those with chromosome 13q deletion can be referred early for early detection of retinoblastoma. more...

The Cornelia de Lange syndrome is a multiple congenital anomaly syndrome characterised by dysmorphic facial features, hirsutism, severe growth and developmental delays, and malformed upper limbs. The prevalence is estimated to be one per 10,000. Recently, several independent groups proved that Cornelia de Lange syndrome is caused by mutations in the NIPBL gene, the human homologue of the Drosophila Nipped-B gene. Here, we present the first clinical case report of a Malay child, a 9-year-old boy with the Cornelia de Lange syndrome. We also report the molecular investigation of the NIPBL gene in this patient. more...

The Aim: The aim of the research work is the evaluation of auditory function in children with rare, genetically determined Brachmann-de Lange syndrome., Methods: Test material came from 18 children (7 girls and 11 boys) between 11 months and 18 years of age with Brachmann-de Lange syndrome who have been diagnosed and treated at ENT Department and Department of Paediatrics, Haematology, Oncology and Endocrinology Medical University of Gdansk with support of Cornelia de Lange Association - Poland. In all children examinations of brainstem auditory evoked potential have been carried out as well as tympanometric examination in case of finding hearing loss. All these examinations were carried out in ENT Department of Medical University of Gdansk, using Racia-Alvar Centor C apparatus and Madsen-Zodiak 901., Results: 9 (50%) of patients demonstrated hearing loss. In 3 (16.7%) cases the conduction hearing loss was connected with the chronic diseases of middle ear which required medical treatment. In remaining 6 (33.3%) cases due to sensorineural hearing loss children had hearing aids applied and underwent rehabilitation., Conclusion: The results indicate that all children with Brachmann-de Lange syndrome should undergo examinations of brainstem auditory evoked potential. It enables to detect hypoacusis and initiate proper treatment. Lack of the opportunity of having a hearing aid applied and further rehabilitation deepens the social isolation of the little patients and inhibits their natural progress in communication. In such cases mental retardation may subsequently occur. more...

Cornelia De Lange syndrome is a relatively uncommon, multiple congenital anomaly / mental retardation disorder of unknown etiology. Its incidence has been reported to vary from 1 : 30,000 to 1 : 50,000 of live births, without any known racial predilection. However, it has been considered to be due to a new dominant mutation. Main clinical features of this syndrome include growth retardation, developmental delay, hirsutism, structural limb abnormalities, mental retardation and facial growth discrepancies. Main causes of death in such patients include pneumonia along with cardiac, respiratory and GI abnormalities. more...

Introduction: Cornelia de Lange syndrome is a rare polimalformative association that shows an expresivity of unknown etiology being most cases sporadic. The diagnosis is clinical., Case Reports: Two female newborns without remarkable antecedents affected of intrauterine growth retardation were born by cesarean section due to risk of perinatal asphyxia. Both cases had a harmonic hypotrophy and a very similar clinical phenotype, especially the craniofacial anomalies, with typical facial features and limb alterations. Besides, the evolution confirms the diagnosis because in both cases the delay of somatic development and microcephaly, as well as moderate-severe psychomotor delay and behavior alterations were present. Likewise, both cases have developed typical medical complications of the condition. The complementary study showed in both patients an important dysfunction of the auditory ways and a atrial septal defect. They were soon included in sensory and motor program of rehabilitation., Conclusion: We present two cases of Cornelia de Lange syndrome of neonatal diagnosis that we consider of interest due to the importance of an early recognition of the clinical condition for the family advice and the medical aid and for an appropriate development. more...

Objective: To examine auditory brainstem evoked responses (ABRs) of children with Cornelia de Lange syndrome (CDLS) to evaluate hearing and the utility of hearing aids in hearing impaired cases., Subjects and Methods: Thirteen Japanese infants and children with CDLS were studied. Behavioral observation audiometry and ABR were used to evaluate hearing., Result: Four different ABR patterns at 85 dB clicks were observed: no response in either ear (6 patients); clear ABRs in both ears (2 patients); no response in one ear but ABRs recorded in the other ear (3 patients); and no peaks after wave III in one ear and ABRs recorded in the other ear (2 patients). However, in 2 patients with no response in either ear at the first measurement, ABRs were recorded in one ear within 2 years. Three out of 13 patients exhibited better responses to sound through the use of hearing aids and auditory training., Conclusions: The fitting of hearing aids and early consistent training have a significant effect on auditory development in CDLS children in terms of making them aware of sound localization and the different types of environmental sound. more...

Cornelia de Lange syndrome (CdLS) is a rare dysmorphogenic disorder characterized by growth retardation, severe cognitive limitations, distinctive facial features, and limb reduction anomalies recognizable at birth. Currently, no single criterion is diagnostic for CdLS, and misdiagnosis is not uncommon. Long-term management of the infant with CdLS requires a coordinated effort among many different specialists. This article presents a general overview of Cornelia de Lange syndrome. It concludes with a case study illustrating the many problems infants with CdLS may have and the great amount of teaching and support that is needed by families affected by CdLS. more...

An analysis of seven infants with Brachmann-de Lange syndrome, of whom two identical twin sisters: Brachmann-de Lange syndrome (BDLS) is characterized by typical facial features, intrauterine growth retardation, short stature, microbrachycephaly, hirsutism and limb anomalies. Here, we reviewed the findings of seven infants with BDLS, of whom two were identical twin sisters of normal parents. All of the infants' parents were normal, and no consanguinity between the parents was noted although the ratio of consanguineous marriages is very high (21.1%) in Turkey. It is well known that most cases of BDLS are sporadic, some cases of this disorder are inherited in an autosomal dominant trait. Our findings suggested that familial cases of BDLS were infrequent, and vast majority of cases appeared to be sporadic and the occurrence of the syndrome in the identical twin sisters of normal parents was also thought a heterogeneity in this condition, overlapping with other conditions and syndromes as mentioned by Fryns et al. more...

Auditory brainstem evoked responses (ABRs) were recorded in 10 Japanese infants and children with Cornelia de Lange syndrome to determine the level of the lesion causing their poor response to sound. Behavioral audiometry showed severe threshold elevation compared to an age-matched control group. ABR thresholds, peak latencies of wave I and IV and the peak interval latency of waves I-V were measured. ABR abnormalities of 4 types: no ABRs following 85 dB clicks in both ears (4 cases), no ABRs in one ear but normal ABR in the other (2 cases), mild wave V threshold elevation of ABR with a markedly prolonged wave V (2 cases) and normal ABR pattern in the one side and abnormal ABR pattern in the opposite side suggesting brainstem immaturity for age (2 cases). Our results demonstrate a high prevalence of peripheral sensorineural hearing loss in Cornelia de Lange syndrome, but brainstem immaturity was not ruled out in 2 cases. more...