Age-related hallmarks of psychopathology in Cornelia de Lange and Rubinstein-Taybi syndromes.

BACKGROUND AND AIM: There is mounting evidence highlighting that Cornelia de Lange Syndrome (CdLS) and Rubinstein-Taybi Syndrome's (RSTS) behavioral phenotypes are not stable over individual developmental trajectories and that several psychiatric disorders might arise with age. Our study aims to examine the specific hallmarks of psychopathology and behavioral phenotypes in four different age ranges: infancy and toddlerhood, early childhood, middle childhood, and adolescence, in both genetic syndromes. METHOD: The sample included 44 patients with CdLS (48% boys, age = 6.67 ± 4.36) and 31 with RSTS (48% boys, age = 6.89 ± 4.58) recruited through follow-ups. Cognitive, behavioral, and autism assessments were carried out with Griffith's scales or the Leiter-R, the Child Behavior Checklist, and the Child Autism Rating Scales 2. Multiple ANOVA 2 × 4 were run to outline behavioral phenotypic age-related syndromic markers and ANCOVA to value the weight of IQ and ASD-related traits on the psychopathological outcome. RESULTS: Findings showed that anxiety is a crucial phenotypic hallmark, independent of IQ but associated with autistic traits, that increases from infancy to adolescence in both CdLS and RSTS. CONCLUSION AND IMPLICATIONS: Being aware of the developmental challenges that growing children are called to face is essential for drawing up proper standards of assessment turning into target age-related interventions, ensuring these patients personalized healthcare and improvement in life quality.

The development of early social cognitive skills in neurogenetic syndromes associated with autism: Cornelia de Lange, fragile X and Rubinstein-Taybi syndromes.

BACKGROUND: Cornelia de Lange (CdLS), Fragile X (FXS) and Rubinstein-Taybi syndromes (RTS) evidence unique profiles of autistic characteristics. To delineate these profiles further, the development of early social cognitive abilities in children with CdLS, FXS and RTS was compared to that observed in typically developing (TD) and autistic (AUT) children. METHODS: Children with CdLS (N = 22), FXS (N = 19) and RTS (N = 18), completed the Early Social Cognition Scale (ESCogS). Extant data from AUT (N = 19) and TD (N = 86) children were used for comparison. RESULTS: Similar to AUT children, children with CdLS, FXS and RTS showed an overall delay in passing ESCogS tasks. Children with CdLS showed a similar degree of delay to AUT children and greater delay than children with FXS and RTS. The CdLS, FXS and RTS groups did not pass tasks in the same sequence observed in TD and AUT children. Children with CdLS (p = 0.04), FXS (p = 0.02) and RTS (p = 0.04) performed better on tasks requiring understanding simple intentions in others significantly more than tasks requiring joint attention skills. CONCLUSIONS: An underlying mechanism other than general cognitive delay may be disrupting early social cognitive development in children with CdLS, FXS and RTS. Factors that may disrupt early social cognitive development within these syndromes are discussed.

Repetitive and Self-injurious Behaviors in Children with Cornelia de Lange Syndrome.

Cornelia de Lange syndrome (CdLS) is associated with repetitive and self-injurious behaviors (RBs, SIB). Evaluating children with CdLS, this study: (1) characterizes the spectrum of RBs; (2) characterizes the impact and severity of RBs including SIB; (3) describes how age and adaptive functioning relate to RBs including SIB. Fifty children (5-17 years) with CdLS were assessed with Children's Yale-Brown Obsessive Compulsive Scale Modified for PDD; Aberrant Behavior Checklist (ABC); Vineland Adaptive Behaviors Scales (VABS). All children had ≥ 1 type of RB; 44% had some form of SIB. 64% spent > 1 h/day displaying RBs. Lower VABS adaptive functioning was associated with higher stereotypy and SIB scores (ABC). In children with CdLS, RBs including SIB are common, impactful, and associated with lower adaptive functioning.

Behaviour across the lifespan in Cornelia de Lange syndrome.

PURPOSE OF REVIEW: While previous reviews have extended descriptions of the behavioural phenotype of Cornelia de Lange syndrome (CdLS) significantly, potential changes with age across the lifespan have been neglected. Age-related difference in the behavioural phenotype constitutes preliminary evidence of change with age. Documenting and understanding the developmental trajectories of behaviours is informative as it enables identification of risk periods for behavioural challenges and compromised mental health. RECENT FINDINGS: Recent cross sectional, longitudinal and mixed design studies report differing presentations of the behavioural phenotype across the lifespan. Of particular interest are autistic characteristics and behaviours consistent with compromised mental health, particularly anxiety and negative affect, which are reported to be more common and severe in older individuals. Preliminary evidence for identified causal pathways with consideration of biological, cognitive and environmental factors are discussed. SUMMARY: Older individuals with CdLS appear to be at greater risk of poorer psychological wellbeing than younger peers with significant implications for risk informed preventive and early interventions. Further work is required to document the behavioural phenotype across the lifespan with consideration of multiple factors that may influence the trajectory and extent of negative outcomes.

An Observational Study of Social Interaction Skills and Behaviors in Cornelia de Lange, Fragile X and Rubinstein-Taybi Syndromes.

We directly assessed the broader aspects of sociability (social enjoyment, social motivation, social interaction skills and social discomfort) in individuals with Cornelia de Lange (CdLS), fragile X (FXS) and Rubinstein-Taybi syndromes (RTS), and their association with autism characteristics and chronological age in these groups. Individuals with FXS (p < 0.01) and RTS (p < 0.01) showed poorer quality of eye contact compared to individuals with CdLS. Individuals with FXS showed less person and more object attention than individuals with CdLS (p < 0.01). Associations between sociability and autism characteristics and chronological age differed between groups, which may indicate divergence in the development and aetiology of different components of sociability across these groups. Findings indicate that individuals with CdLS, FXS and RTS show unique profiles of sociability.

Branding of subjects affected with genetic syndromes of severe short stature in developing countries.

In Ecuador, a developing South American country, subjects affected with genetic syndromes of severe short stature are commonly referred to as dwarfs or midgets. Furthermore, and because in earlier studies some patients had evidenced mental retardation, such abnormality is assumed to exist in all affected subjects. Herein, we present two discrete instances in which this type of branding occurs. The first is that of individuals with Laron syndrome who are still called 'dwarfs' and considered as having a degree of mental retardation despite evidence showing otherwise. A similar problem, that of a girl affected with a genetic syndrome of short stature, which might include mental retardation, is also discussed. Considering that stigmatising is a form of discrimination, it concerns us all. Hence, the use of derogatory terms such as midget, dwarf or cretin, that might unintentionally occur even when delivering the best and most devoted medical care, must be eliminated.

A Behavioural Assessment of Social Anxiety and Social Motivation in Fragile X, Cornelia de Lange and Rubinstein-Taybi Syndromes.

Unique socio-behavioural phenotypes are reported for individuals with different neurodevelopmental disorders. Here, the effects of adult familiarity and nature of interaction on social anxiety and social motivation were investigated in individuals with fragile X (FXS; n = 20), Cornelia de Lange (CdLS; n = 20) and Rubinstein-Taybi (RTS; n = 20) syndromes, compared to individuals with Down syndrome (DS; n = 20). The Social Anxiety and Motivation Rating Scale was employed whilst participants completed four social tasks, each administered separately by a familiar adult, and also by an unfamiliar adult. Compared to participants with DS, those with FXS and RTS exhibited high levels of social anxiety but similar levels of social motivation. Participants with CdLS showed heightened social anxiety and reduced social motivation only during interactions with an unfamiliar adult when active participation was voluntary.

Behavioural and psychological characteristics in Pitt-Hopkins syndrome: a comparison with Angelman and Cornelia de Lange syndromes.

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.

Mental Health and Well-Being in Mothers of Children With Rare Genetic Syndromes Showing Chronic Challenging Behavior: A Cross-Sectional and Longitudinal Study.

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.

Integrating molecular and structural findings: Wnt as a possible actor in shaping cognitive impairment in Cornelia de Lange syndrome.

Cornelia de Lange Syndrome (CdLS) is a choesinopathy: a severe genetic disorder caused by mutations in the cohesin complex genes. The phenotype is characterized by typical facial dysmorphism, growth impairment and multiorgan abnormalities including brain alterations. Wnt pathway is known to play a fundamental role in central nervous system development and it has been shown that Wnt pathway is disrupted in CdLS animal models and patients cells. In this review we investigate the possible link between Wnt pathway disruption and brain abnormalities in Cornelia de Lange Syndrome as such molecular impairment could lead to an abnormal embryonic development resulting in brain abnormalities (i.e. microcephaly, cerebellar hypoplasia, abnormal cortical development) in patients with Cornelia de Lange Syndrome.

Tratamiento rehabilitador a un paciente con síndrome de Cornelia de Lange / Rehabilitation Treatment to a Patient with Cornelia de Lange Syndrome

Se presentó un paciente de un año de edad con síndrome Cornelia de Lange, único recibido en el Servicio de Rehabilitación del Policlínico Docente René Vallejo Ortiz del municipio Manzanillo, provincia Granma, con signos evidentes de retraso del desarrollo psicomotor, remitido al servicio por su médico de familia cuando tenía seis meses de nacido. Para su tratamiento se emplearon técnicas específicas de la estimulación temprana, se lograron pequeños avances en su desarrollo motor y cognitivo, aunque no solo depende de la rehabilitación, sino también del entorno familiar en el cual se va desarrollando el niño. Se lograron pequeños avances motores en el paciente como: sostén cefálico, abertura de las manos y seguimiento de los objetos con la mirada, el paciente continúa rehabilitándose en el servicio de fisiatría.(AU)

A one –year-old patient with Cornelia de Lange syndrome (SCdL) was presented in this article, who was the only one attended in the service of rehabilitation of the René Vallejo Ortiz teaching polyclinic of Manzanillo municipality, Granma province. The patient had evident signs of late psychomotor development, so he was referred to this service by the family doctor when he was six months of age. For the treatment, specific techniques of early stimulation were used; small advances have been achieved regarding motor and cognitive development, although it not only depends on the rehabilitation, but also depends on the family environment, in which the infant is developing. Not many motors progresses were achieved in the patient such as: cephalic support, opening of the hands and objects pursuit followed by the eyes. The patient continues rehabilitating in the physiotherapy service.(AU)

Diverse Profiles of Anxiety Related Disorders in Fragile X, Cornelia de Lange and Rubinstein-Taybi Syndromes.

Anxiety disorders are heightened in specific genetic syndromes in comparison to intellectual disability of heterogeneous aetiology. In this study, we described and contrasted anxiety symptomatology in fragile X (FXS), Cornelia de Lange (CdLS) and Rubinstein-Taybi syndromes (RTS), and compared the symptomatology to normative data for typically-developing children and children diagnosed with an anxiety disorder. Scores did not differ between children diagnosed with an anxiety disorder and (a) participants with FXS on social phobia, panic/agoraphobia, physical injury fears, and obsessive-compulsive subscales (b) participants with CdLS on separation anxiety, generalized anxiety, panic/agoraphobia, physical injury fears and obsessive-compulsive subscales, and (c) participants with RTS on panic/agoraphobia and obsessive-compulsive subscales. The results highlight divergent profiles of anxiety symptomatology between these groups.

Behavioral and psychiatric manifestations in Cornelia de Lange syndrome.

PURPOSE OF REVIEW: Cornelia de Lange syndrome (CdLS) is a rare genetic syndrome with clinical manifestations due to multiple affected organ systems including limbs, gastrointestinal, skin, and central nervous systems. Although the genetic basis of CdLS is now uncovered, how behavioral manifestations are associated with genetic and brain differences are less well understood. The current focused review systematically describes the main behavioral observations to date in individuals with CdLS, which have a significant impact on quality of life and adaptive functioning. RECENT FINDINGS: The CdLS behavioral phenotype includes autistic traits as a prominent feature; however, brain imaging studies, required to understand gene-brain-behavior connections in CdLS, are scarce. Moreover, autistic features in CdLS have a greater emphasis on repetitive behaviors, including self-injurious behaviors (SIB) and expressive communication deficits, different that the core social deficit seen in idiopathic autism. Current data strongly support the use of CdLS as a model disease for repetitive behaviors and associated developmental delay manifestations. SUMMARY: Behavioral phenotype characteristics in CdLS point to a preponderance of repetitive clinical phenomena as well as expressive verbal deficits that ought to inform specific treatment approaches in CdLS. In particular, repetitive behaviors associated with self-injury are of high negative impact on the quality of life for individuals with CdLS and their families. Treatment approaches geared to manage repetitive behaviors and self-injurious behaviors in CdLS are required in this developmental condition.

Behaviour in Cornelia de Lange syndrome: a systematic review.

AIM: Careful study and accurate description of behaviour are important to understand developmental challenges for individuals with Cornelia de Lange syndrome (CdLS). Here we present a systematic review of current understanding of behaviour in CdLS. METHOD: A systematic search was performed for articles published between January 1946 and December 2015 evaluating autism, self-injury, and/or cognition in CdLS. After study-selection, 43 papers were included. The Cochrane quality criteria were adjusted to assign quality scores to the included studies. RESULTS: Participants were mostly categorized in the severe/profound developmental level. Methodology and quality were very heterogeneous, as well as reporting occurrence of autism. Self-injurious behaviour was reported in 15 papers. Physical conditions were reported in 21 studies, mostly related to hearing and vision. Only nine studies mentioned details about medication. INTERPRETATION: Comparison of presented results was hindered by heterogeneous assessment methods. Improving our understanding of behavioural characteristics in CdLS requires more uniform methodology. We propose a criterion standard of instruments that can ideally be used in assessment of behaviour and development. This will improve understanding of behaviour in the context of developmental level and daily functioning.

A Comparative Study of Sociability in Angelman, Cornelia de Lange, Fragile X, Down and Rubinstein Taybi Syndromes and Autism Spectrum Disorder.

Few comparative studies have evaluated the heterogeneity of sociability across a range of neurodevelopmental disorders. The Sociability Questionnaire for People with Intellectual Disability (SQID) was completed by caregivers of individuals with Cornelia de Lange (n = 98), Angelman (n = 66), Fragile X (n = 142), Down (n = 117) and Rubinstein Taybi (n = 88) syndromes and autism spectrum disorder (ASD; n = 107). Between groups and age-band (<12yrs; 12-18yrs; >18yrs) comparisons of SQID scores were conducted. Rates of behaviors indicative of selective mutism were also examined. Fragile X syndrome achieved the lowest SQID scores. Cornelia de Lange, ASD, and Fragile X groups scored significantly lower than Angelman, Down and Rubinstein Taybi groups. Selective mutism characteristics were highest in Cornelia de Lange (40%) followed by Fragile X (17.8%) and ASD (18.2%). Age-band differences were identified in Cornelia de Lange and Down syndrome.

Attitudes about the use of internet support groups and the impact among parents of children with Cornelia de Lange syndrome.

There is an abundance of information in the literature on patient experiences with Internet support groups (ISGs). However, studies exploring these experiences in a rare disease population are scarce, even though these families are often at a disadvantage for resources, reliable information, and support. The aim of the current study was to explore the experiences with ISGs for parents of children with Cornelia de Lange syndrome (CdLS), a rare genetic diagnosis, in order to better understand the impact on emotional support and their child's medical care. Focus groups were conducted to inform the design of a large-scale internet survey. The survey asked parents closed- and open-ended questions regarding experiences with ISGs, with a focus on the psychosocial, medical, and logistical aspects. The survey found that 141/170 (82.6%) respondents have visited an Internet-based support group to find support or information about their child's CdLS diagnosis. The majority of respondents (71.7%) reported that ISGs have been helpful in finding emotional support, with the most common areas impacted as a result of ISG participation being behavior toward their children and family dynamic. Regarding medical care, most respondents (63.9%) reported that ISGs have been helpful in finding medical information and support, with the most commonly impacted areas of their child's care including day-to-day management, diet, therapy interventions, and healthcare providers. These findings provide a greater understanding of the role of Internet networking in healthcare and may inform future approaches to medical care and psychosocial support for rare, complex genetic diagnoses. © 2016 Wiley Periodicals, Inc.

Cornelia de Lange and Ehlers-Danlos: comorbidity of two rare syndromes.

We present a case of a young adult with both Cornelia de Lange syndrome and Ehlers-Danlos syndrome. The patient showed non-verbal autism, intellectual disability and severe/intractable self-harming behaviours that led to a life-threatening complication (ie, septicaemia). A significant reduction in the self-harming behaviours was attained in a multidisciplinary neurobehavioural inpatient unit after addressing all causes of somatic pains, managing pain using level II and III analgesics, stabilising the patient's mood, limiting the iatrogenic effects of multiple prescriptions and offering a specific psychoeducational approach.

Functional Brain Imaging in Cornelia de Lange Syndrome: Case Report and Literature review.

Functional brain imaging with brain single photon emission computer tomography (Brain SPECT) has been used for many years in the evaluation of multiple neuro-degenerative and neuro-developmental disorders. Brain SPECT is a nuclear medicine tomographic study performed with a lipophilic radiopharmaceutical labeled with 99mTc-pertechnetate. It is a cerebral perfusion agent that depicts the global and regional perfusion patterns in the cortical gray matter and subcortical structures. Cornelia de Lange syndrome (CdLS) is a rare neuro-developmental and genetic condition, associated to several malformations. There are a limited number of cases reported in the medical literature and few of them report neuro-radiological and/or neuro-pathologic abnormalities. We report a case of a 15 year old patient, clinically diagnosed at birth with CdLS, who presents limited anatomical findings on Computed Tomography and Magnetic Resonance Imaging. To the best of our knowledge, this is the first report of the Brain SPECT findings in this syndrome.

Contrasting age related changes in autism spectrum disorder phenomenology in Cornelia de Lange, Fragile X, and Cri du Chat syndromes: Results from a 2.5 year follow-up.

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.

Communication, cognitive development and behavior in children with Cornelia de Lange Syndrome (CdLS): preliminary results.

In this study, we present preliminary data on cognitive, behavioral and communication domains of individuals with Cornelia de Lange Syndrome (CdLS), collected through a specific protocol combining direct and indirect tools. Seventeen subjects with CdLS were assessed, 2.5- to 13.4-year-old. Cognitive level of the subjects differed from what previously described in literature, showing more patients with normal or borderline cognitive abilities. We found a relation between severe autistic behavior and comprehension impairments: all children with high CARS score have severe receptive language disability. A correlation was also found between CARS score and ID: high CARS score occurred only in patients with profound levels of ID. Results of this study support the need for a specific assessment protocol tailored for the characteristics of subjects with multiple disabilities, to be able to identify their strengths avoiding the avalanche effect of weaknesses. Most tests on neuropsychological functions have been developed and standardized for typically developing children, and require the integrity of other functions aside the one that is evaluated, determining an underestimation of the level of functioning. This study could be a starting point to develop new models applicable to other genetic syndromes and complex situations; new and wider studies are needed in order to allow a more complete and accurate assessment, thereby ensuring more efficient and family-centered treatment plans.