Endocrine manifestations in adults with 22q11.2 deletion syndrome: a retrospective single-center cohort study.

INTRODUCTION AND OBJECTIVE: Patients with the 22q11.2 deletion syndrome (22q11DS) frequently display cardiological and psychiatric diseases, but are also at increased risk for endocrine manifestations. The aim of this study was to evaluate the screening, prevalence, and management of hypoparathyroidism and thyroid disease in patients with 22q11DS, to evaluate the metabolic profile, and to compare these results with current literature and guidelines. DESIGN: We performed a retrospective study of patients with genetically confirmed 22q11DS, followed at the center for human genetics of the University Hospitals Leuven, resulting in a cohort of 75 patients. Medical history, medication, and laboratory results concerning hypoparathyroidism, thyroid dysfunction, and the metabolic profile were collected. RESULTS: Of the total cohort, 26 patients (35%) had at least one hypocalcaemic episode. During hypocalcaemia, parathyroid hormone (PTH) was measured in only 12 patients with 11 having normal or low PTH, confirming a diagnosis of hypoparathyroidism. Recurrent episodes of hypocalcaemia occurred in seventeen patients (23%). Adherence to the guidelines was low, with 13% of patients having a yearly serum calcium evaluation, 12% receiving daily calcium supplements, and 20% receiving non-active vitamin D. Hypothyroidism was present in 31 patients (44%) and hyperthyroidism in 6 patients (8%). Information on body mass index (BMI) was available in 52 patients (69%), of which 38% were obese (BMI ≥ 30 kg/m2). CONCLUSION: Hypoparathyroidism, hypothyroidism, and obesity are common endocrine manifestations in patients with 22q11DS but are probably underdiagnosed and undertreated, indicating the need for multidisciplinary follow-up including an endocrinologist.

Association of behavioural and social-communicative profiles in children with 16p11.2 copy number variants: a multi-site study.

BACKGROUND: Despite the established knowledge that recurrent copy number variants (CNVs) at the 16p11.2 locus BP4-BP5 confer risk for behavioural and language difficulties, limited research has been conducted on the association between behavioural and social-communicative profiles. The current study aims to further delineate the prevalence, nature and severity of, and the association between, behavioural and social-communicative features of school-aged children with 16p11.2 deletion syndrome (16p11.2DS) and 16p11.2 duplication (16p11.2Dup). METHODS: A total of 68 individuals (n = 47 16p11.2DS and n = 21 16p11.2Dup) aged 6-17 years participated. Standardised intelligence tests were administered, and behavioural and social-communicative skills were assessed by standardised questionnaires. Scores of both groups were compared with population norms and across CNVs. The influence of confounding factors was investigated, and correlation analyses were performed. RESULTS: Compared with the normative sample, children with 16p11.2DS showed high rates of social responsiveness (67%) and communicative problems (69%), while approximately half (52%) of the patients displayed behavioural problems. Children with 16p11.2Dup demonstrated even higher rates of social-communicative problems (80-90%) with statistically significantly more externalising and overall behavioural challenges (89%). In both CNV groups, there was a strong positive correlation between behavioural and social-communicative skills. CONCLUSIONS: School-aged children with 16p11.2 CNVs show high rates of behavioural, social responsiveness and communicative problems compared with the normative sample. These findings point to the high prevalence of autistic traits and diagnoses in these CNV populations. Moreover, there is a high comorbidity between behavioural and social-communicative problems. Patients with difficulties in both domains are vulnerable and need closer clinical follow-up and care.

An online survey to understand the needs of caregivers of family members with 22q11 deletion syndrome.

BACKGROUND: Most individuals with 22q11.2 deletion syndrome (22q11DS) have multi-system and lifelong needs requiring substantial support. Their primary caregivers are usually family members who dedicate lifelong time and effort to their role. The pressures of their roles can negatively impact caregivers' psychosocial well-being, suggesting a need for additional support for this community who currently have no specialised interventions available. METHOD: This online study surveyed 103 caregivers of family members with 22q11DS to determine the barriers to accessing support that they faced, the kind of support they would value and whether an online intervention could meet their needs. RESULTS: The caregivers indicated that a brief online intervention focused on teaching practical skills and connecting them with a peer network of support would be most valuable. CONCLUSIONS: Future studies are planned that will build on these results by designing and testing online interventions tailored to this community.

The COVID-19 pandemic's impact on worry and medical disruptions reported by individuals with chromosome 22q11.2 copy number variants and their caregivers.

BACKGROUND: The world has suffered immeasurably during the COVID-19 pandemic. Increased distress and mental and medical health concerns are collateral consequences to the disease itself. The Genes to Mental Health (G2MH) Network consortium sought to understand how individuals affected by the rare copy number variations of 22q11.2 deletion and duplication syndrome, associated with neurodevelopmental/neuropsychiatric conditions, were coping. The article focuses on worry and disruptions in medical care caused by the pandemic. METHODS: The University of Pennsylvania COVID-19 Stressor List and care disruption questions were circulated by 22 advocacy groups in English and 11 other languages. RESULTS: A total of 512 people from 23 countries completed the survey; most were caregivers of affected individuals. Worry about family members acquiring COVID-19 had the highest average endorsed worry, whilst currently having COVID-19 had the lowest rated worry. Total COVID-19 worries were higher in individuals completing the survey towards the end of the study (later pandemic wave); 36% (n = 186) of the sample reported a significant effect on health due to care interruption during the pandemic; 44% of individuals (n = 111) receiving care for their genetic syndrome in a hospital setting reported delaying appointments due to COVID-19 fears; 12% (n = 59) of the sample reported disruptions to treatments; and of those reporting no current disruptions, 59% (n = 269) worried about future disruptions if the pandemic continued. Higher levels of care disruptions were related to higher COVID-19 worries (Ps < 0.005). Minimal differences by respondent type or copy number variation type emerged. CONCLUSIONS: Widespread medical care disruptions and pandemic-related worries were reported by individuals with 22q11.2 syndrome and their family members. Reported worries were broadly consistent with research results from prior reports in the general population. The long-term effects of COVID-19 worries, interruptions to care and hospital avoidance require further study.

[Monogenetic causes of psychiatric disorders: a review]. / Monogenetische oorzaken van psychiatrische aandoeningen: een overzicht.

BACKGROUND: Because of rapid developments in genetic technology, more underlying genetic causes of psychiatric disorders can be detected which may contribute to better monitoring and treatment of co-morbidities than previously. AIM: Review of monogenetic causes of psychiatric disorders. METHODE: Review of the literature. RESULTATS: Research in people with monogenetic disorders will generate new knowledge and insights on psychopathology and cognitive function in general and pave the way to new treatment targets. In this article we discuss four monogenetic disorders that are relevant for clinical psychiatry and (educational) psychology: fragile X syndrome, tuberous sclerosis, Rett Syndrome, and Huntington’s disease. CONCLUSION: Given the multisystem nature of these genetic disorders, a well-coordinated, multidisciplinary approach by specialized expert centers is highly recommended.

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium.

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole-genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.

Developmental trajectories of structural and pragmatic language skills in school-aged children with Williams syndrome.

BACKGROUND: This study aimed to compare developmental courses of structural and pragmatic language skills in school-aged children with Williams syndrome (WS) and children with idiopathic intellectual disability (IID). Comparison of these language trajectories could highlight syndrome-specific developmental features. METHOD: Twelve monolingual Dutch-speaking children with WS aged 5.10 to 13.3 years were assessed by means of standardised structural language tests measuring receptive and expressive vocabulary and sentence comprehension and production. Pragmatic language was evaluated by means of an expressive referential communication task and a retelling test. All of these language abilities were re-evaluated with the same measures after a period of 18 to 24 months. Performance was compared to 12 children with IID pairwise matched for chronological age (CA) and non-verbal fluid reasoning (Gf) at Time 1. Non-verbal mental age (NVMA) was taken into account when delineating developmental trajectories. RESULTS: Children with WS outperformed children with IID on expressive vocabulary development. In contrast, sentence comprehension was significantly poorer than in children with IID at the second time point. Increased variability and rather poor performance on pragmatic language tasks were demonstrated in the WS group. Irrelevant and off-topic extraneous information transfer continued to be a syndrome-specific characteristic of children with WS. CONCLUSION: The data provide new insights into diverging developmental trajectories across language domains. Expressive structural language skills tend to progress more rapidly than receptive language skills in children with WS causing more distinctive language profiles over time. Some children with WS seem to benefit from the growth in expressive structural language abilities to enhance their expressive pragmatic language skills, while in some others these abilities remain challenging. This study highlights the need for continued follow-up of language challenges in WS and for a dynamic and individualised interventional approach.

[Adaptive skills, cognitive functioning and behavioural problems in adolescents with 22q11.2 deletion syndrome]. / Adaptieve vaardigheden, cognitief functioneren en gedragsproblemen bij adolescenten met het 22q11.2-deletiesyndroom.

BACKGROUND: The 22q11.2 deletion syndrome (22q11.2DS) has a highly variable phenotype with a multitude of somatic and psychiatric features. Little is known about the adaptive skills of adolescents with 22q11.2DS. AIM: To investigate adaptive functioning, intelligence and behavioural problems and their interrelationship in adolescents with 22q11.2DS. METHOD: We interviewed the parents of 37 adolescents with 22q11.2DS using the Vineland Adaptive Behavior Scales. We assessed the intelligence of the adolescents by means of the Wechsler Intelligence Scales. Parents, adolescents and teachers were required to complete the Achenbach behavioural questionnaire. RESULTS: We found that adolescents with 22q11.2DS had impaired adaptive skills; these skills were significantly more impaired than the adolescents' overall intelligence, i.e. their I.Q. Socialisation was a relatively well-developed domain compared to daily living skills. All respondents reported that the number of internalising problems exceeded the number of externalising problems. There was no correlation between adaptive functioning and behavioural problems, age or gender. CONCLUSION: The evaluation of adaptive skills in these adolescents is a first step on the road to the development of measures aimed at improving their functioning in society.

Microduplication 22q11.2: a description of the clinical, developmental and behavioral characteristics during childhood.

Microduplication 22q11.2 is a recently discovered genomic disorder. So far, targeted research on the cognitive and behavioral characteristics of individuals with this microduplication is limited. Therefore, 11 Flemish children (3-13 years old) with a microduplication 22q 1.2 were investigated in order to describe their clinical, developmental and behavioral characteristics. We measured their general intelligence, visual-motor capacities, attention, behavioral problems and characteristics of autism. In addition, there was an interview with the parents on developmental history and we reviewed available information from other specialists. The results show that the cognitive and behavioral phenotype of the children with microduplication 22q.11.2 is very wide and heterogeneous. Some of the children have a cognitively nearly normal development whereas others are more severely affected. All children had some degree of developmental delay and some of them have an intellectual disability. The most common clinical features include congenital malformations such as heart defects and cleft lip, feeding problems, hearing impairment and facial dysmorphism. The most common non-medical problems are learning difficulties, motor impairment, attention deficits, social problems and behavioral problems. There is no correlation between the size of the duplication and the phenotype.

Cognitive correlates of mathematical disabilities in children with velo-cardio-facial syndrome.

Children with Velo-Cardio-Facial Syndrome (VCFS) consistently show mathematical disabilities (MD). At the neuropsychological level, it is important to know which general cognitive deficits underlie these MD. Therefore, we examined various mathematical abilities, working memory, rapid automatized naming and processing speed in 25 children with VCFS and 25 carefully selected matched controls. Children with VCFS showed a reduced ability to solve addition and subtraction problems and performed less accurately on multidigit arithmetic and word problem solving. There were no group differences on the general cognitive measures, except that children with VCFS performed higher than controls on the phonological loop tasks. To conclude, the administered general cognitive competencies could not give a satisfactory account of the MD in VCFS.

Mathematical disabilities in children with velo-cardio-facial syndrome.

Current neurocognitive theories of number processing [Dehaene, S., Piazza, M., Pinel, P., & Cohen, L. (2003). Three parietal circuits for number processing. Cognitive Neuropsychology, 20, 487-506] state that mathematical performance is made possible by two functionally and anatomically distinct subsystems of number processing: a verbal system located in the angular gyrus, which underlies the retrieval of arithmetic facts, and a quantity system located in the intraparietal sulcus, which subserves operations that involve semantic manipulations of quantity. According to this model, subtypes of math disability (MD) should be traceable to differential impairments in these subsystems. The present study investigated MD in children with velo-cardio-facial syndrome (VCFS) and aimed to verify which of these subsystems of number processing is impaired in these children. Eleven children with VCFS and 11 individually matched controls, selected from the same classes, completed a large battery of mathematical tests. Our data revealed that children with VCFS had preserved number reading abilities and preserved retrieval of arithmetic facts, both of which indicate that the verbal subsystem is not impaired in VCFS. By contrast, children with VCFS showed difficulties in number comparison, the execution of a calculation strategy and word problem solving, all of which involve the semantic manipulation of quantities. This provides evidence for a specific deficit in the quantity subsystem in children with VCFS, suggesting underlying abnormalities in the intraparietal sulcus.

A Comprehensive Craniofacial Study of 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is one of the most frequent microdeletion syndromes and presents with a highly variable phenotype. In most affected individuals, specific but subtle facial features can be seen. In this observational study, we aim to investigate the craniofacial and dental features of 20 children with a confirmed diagnosis of 22q11.2DS by analyzing 3-dimensional (3D) facial surface scans, 2-dimensional (2D) clinical photographs, panoramic and cephalometric radiographs, and dental casts. The 3D facial scans were compared to scans of a healthy control group and analyzed using a spatially dense geometric morphometric approach. Cephalometric radiographs were digitally traced, and measurements were compared to existing standards. Occlusal and dental features were studied on dental casts and panoramic radiographs. Interestingly, a general trend of facial hypoplasia in the lower part of the face could be evidenced with the 3D facial analysis in children with 22q11.2DS compared to controls. Cephalometric analysis confirmed a dorsal position of the mandible to the maxilla in 2D and showed an enlarged cranial base angle. Measurements for occlusion did not differ significantly from standards. Despite individual variability, we observed a retruded lower part of the face as a common feature, and we also found a significantly higher prevalence of tooth agenesis in our cohort of 20 children with 22q11.2DS (20%). Furthermore, 3D facial surface scanning proved to be an important noninvasive, diagnostic tool to investigate external features and the underlying skeletal pattern.

Mathematical disabilities in young primary school children with velo-cardio-facial syndrome.

The aim of the present study was to examine the previously reported mathematical disabilities (MD) of children with Velo-Cardio-Facial Syndrome (VCFS) in children of a younger age range. Fourteen children with VCFS (aged 6-10 years) participated in this study. These children were individually matched on sex, IQ, age and parental educational level to a control group of peers, selected from the same classes. A broad range of mathematical abilities were assessed, comprising number reading and writing, number comparison, counting, single-digit arithmetic, multidigit arithmetic and word problem solving. Consistent with previous reports, children with VCFS were significantly slower in counting numerosities and they tended to perform more poorly on number comparison. These results indicate that difficulties in low-level number processing in children with VCFS occur already at a very young age. Furthermore, children with VCFS demonstrated preserved retrieval of arithmetic facts, but, in contrast to older children with VCFS, no procedural difficulties in mathematics were observed. Finally, word problem solving appeared to be an important area of weakness, starting already at this young age.

Chromosome 22q11 deletion syndrome: update and review of the clinical features, cognitive-behavioral spectrum, and psychiatric complications.

In this contribution we review current knowledge of the chromosome 22q11 deletion syndrome, with special emphasis on the clinical characteristics, including physical features, cognitive-behavioral spectrum, and psychiatric complications.

PTEN mutation in a family with Cowden syndrome and autism.

We report on a mother and son with Cowden syndrome and a PTEN mutation. The boy also exhibits autistic behavior and mental retardation, while his mother has a normal intelligence and social interaction pattern. We review the scanty literature data on the association of Cowden syndrome and autism and emphasize that the association of progressive macrocephaly and pervasive developmental disorder seems to be an indication for screening for PTEN mutations.

Neuropsychological, learning and psychosocial profile of primary school aged children with the velo-cardio-facial syndrome (22q11 deletion): evidence for a nonverbal learning disability?

In this exploratory study, the neuropsychological and learning profile of nine primary school age children with velo-cardio-facial syndrome (VCFS) was studied by systematic neuropsychological testing. In five out of nine children, the following profile was found: a VIQ-PIQ discrepancy (in favor of the VIQ), significantly better scores (.05 level) for reading (decoding) and spelling compared to arithmetic, deficient tactile-perceptual skills (difficulties mainly on the left side of the body), weak but not deficient visual-perceptual abilities, deficient visual-spatial skills, extremely poor psychomotor skills (gross motor skills more deficient than fine motor skills), problems with processing of new and complex material, poor visual attention, good auditory memory and relatively good language skills. These findings correspond to the pattern of neuropsychological assets and deficits that has been described for the syndrome of nonverbal learning disabilities (NLD) (Rourke, 1987, 1988, 1989, 1995). The psychosocial profile of all nine children with VCFS also correspond to that of children with NLD. Further studies on the relationship between cognitive function, behavior, psychiatric disorder and abnormalities in brain anatomy in young people with VCFS will be needed. In clinical practice, it is worthwhile exploring in greater depth the neuropsychological functions of children with VCFS to rule out NLD, since they may benefit from specific remediation following the learning principles of the NLD-treatment.

Fragile X boys: evolution of the mental age in childhood. Preliminary data on 10 prepubertal boys.

In this report we present data on the longitudinal evolution of the mental versus the chronological age in 10 fragile X boys diagnosed before the age of 6 years and compare these findings to the longitudinal evolution in children with Down syndrome (6 patients) and Williams syndrome (4 patients). The present findings suggest that the evolution of the velocity of development is more decreased in fra(x) boys compared to the two other groups.

Children with a 22q11 deletion versus children with a speech-language impairment and learning disability: behavior during primary school age.

Children with a 22q11 deletion versus children with a speech-language impairment and learning disability: behavior during primary school age: Common behavioral features described in children with the Velo-Cardio-Facial syndrome (VCFS) (del 22q11) are problems with attention and concentration, extremes in behavior and social problems, especially in relationship with peers. At present, it is unclear whether these behavioral manifestations are directly related to the chromosomal anomaly or related to other manifestations of the syndrome such as developmental delay and speech-language delay. This study describes for the first time the behavior of young primary school aged children with a del22q11 compared to a control group of children matched for age, sex and mental level, with similar developmental problems (speech-language impairment plus learning disability: SLI + LD) but without a del22q11 or any other known genetic condition. Parents and teachers evaluated the children's behavior with standardized questionnaires (CBCL; TRF). Results indicate that most of the behaviors are similar across both groups. The only differences found are in the field of <> and <>. Children with a del22q11 have a stronger tendency to withdraw from others, whereas children with a SLI+LD seem to be more aggressive.

Turner syndrome patients as adults: a study of their cognitive profile, psychosocial functioning and psychopathological findings.

In this study we collected data on the cognitive abilities, psychosocial adjustment and psychopathology of 20 non-institutionalized adult Turner syndrome patients. The majority of them had a normal intelligence, most were socially well adapted and no high prevalence of psychopathology was noted. In only one patient evidence of a serious bipolar hypomanic disorder and antisocial personality was found, and in one other an episode of anorexia nervosa. Nevertheless, 50% of the women expressed feelings of low self-confidence, depression and social insecurity i.e. achieving a mature level of psycho-social functioning remains a problem for a number of Turner individuals. In the counseling process of adult Turner patients special attention should be given to the social and psychological functioning so that intervention can be made if social awkwardness and psychological well-being becomes a problem.

Intelligence, behaviour and psychosocial development in Turner syndrome. A cross-sectional study of 50 pre-adolescent and adolescent girls (4-20 years).

In this paper we report the findings and data on a cross-sectional study of 50 pre-adolescent and adolescent girls with Turner syndrome. We confirm the presence of a typical cognitive profile in the different age groups with normal verbal intelligence contrasting with lower results on performal IQ subtests, related to relative weaknesses on visuospatial subtests i.e. "Block Design" and "Object Assembly". 5% of the girls with a "classical" Turner syndrome karyotype (i.e. 2/40) were mentally retarded versus 30% (i.e. 3/10) in the group with "rare" karyotypic anomalies. We noted a positive influence of hormonal therapy on the visuospatial functioning. No evidence was found for a high risk for behavioural problems. Hyperactive behaviour was seen in the youngest patients contrasting with a tendency to hypoactivity around the age of normal puberty. Problems in social development were noted from the age of primary school on resulting in social immaturity and even isolation. A proposal for guidance of Turner girls during the different developmental periods is given.