Psychiatric Features in Children with Genetic Syndromes: Toward Functional Phenotypes

doi:10.1016/j.pcl.2011.06.010

Pediatric Clinics of North America

Volume 58, Issue 4, August 2011, Pages 833-864

https://doi.org/10.1016/j.pcl.2011.06.010 Get rights and content

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Genetic testing

Significant advances have been made in methods and availability of genetic testing in the past decade, allowing for increased precision in establishing a diagnosis for many individuals. In fact, the long-honored chromosome analysis (or karyotype), once the mainstay of genetic testing, is now often replaced as a first-line test with molecular methods, including fluorescent in situ hybridization (FISH), comparative genomic hybridization (CGH) microarray, and gene sequencing. A good analogy for

Genetics, Etiology, and Epidemiology

Initially described by John Langdon Down in 1866, the condition known eponymously as Down syndrome (DS) was determined to be caused by trisomy of chromosome 21 in the 1950s. Whereas the vast majority of individuals (more than 95%) with trisomy 21 have an entire additional chromosome 21 secondary to nondisjunction during gametogenesis, a smaller percentage of individuals will have trisomy 21 related to a chromosome translocation. An even smaller percentage of affected individuals will have

Genetics, Etiology, and Epidemiology

Fragile X syndrome (FXS) is recognized as the most common inherited form of mental retardation, with an incidence of approximately 1 in 3000, including affected males and females. The premutation/intermediate length mutation carrier frequency is much higher, approximately 1% in females²⁶ and 1 in 800 males.

FXS is one of several “triplet repeat” neurologic disorders caused by expansion of a disease-specific trinucleotide repeat within a disease-specific gene. In FXS this trinucleotide repeat,

Genetics, Etiology, and Epidemiology

Classic Rett syndrome has a prevalence of approximately 1 in 10,000 females,⁵⁷ although emerging information regarding the range of phenotypes associated with MECP2 alterations in both males and females will expand the clinical impact of this gene over time. MECP2 is located at Xq28 and encodes the MeCP2 protein responsible for decreasing transcription, and thus expression, of other genes. Loss of this inhibition in the brain probably results in overexpression of normally tightly regulated

Genetics, Etiology, and Epidemiology

The genes within the proximal region of the long arm of chromosome 15 demonstrate tightly regulated, specific parent-of-origin expression. This differential expression is controlled by imprinting, by which methylation of the DNA causes the selective silencing of genes from either the paternal or the maternal homolog. The genes within this region are variably expressed, with some genes expressed only when inherited paternally and others only when inherited maternally.

Loss of the paternally

Genetics, Etiology, and Epidemiology

Within the 15q11-q13 region are genes with specific parent of origin expression; some genes are exclusively expressed from the paternal allele and others are expressed only from the maternal allele. When there is loss of the normal expression of maternal alleles, Angelman syndrome (AS) results.⁹⁶ This loss of expression can result from several molecular mechanisms including a deletion within the maternal chromosome homolog (70%–75%), paternal UPD of chromosome 15 (2%–5%), and imprinting defects

Genetics, Etiology, and Epidemiology

The co-occurrence of idiopathic hypercalcemia and supravalvar aortic stenosis was initially described in the 1960s106, 107, 108 and the full syndrome was eponymously named after cardiologists Williams and Buren. WS is primarily a sporadic condition with an approximate incidence of 1 in 10,000. A common chromosome microdeletion of 1.5 Mb at 7q11.23 is responsible for the full phenotype¹⁰⁹; absence of the ELN gene is associated with the cardiac and connective tissue features, and loss of the LIMK1

Genetics, Etiology, and Epidemiology

Encompassing a wide range of physical phenotypes, including several eponymous syndromes, this microdeletion is thought to be the most common contiguous gene deletion, with general population estimates ranging from 1 in 3800 to 1 in 6000.¹²⁶ The deletion is found in much higher frequency within populations selected for cardinal physical features including cleft lip/palate/bifid uvula and conotruncal cardiac malformations.

The classic 3-Mb deletion includes 30 genes, several of which appear to

Genetics, Etiology, and Epidemiology

Smith-Magenis syndrome (SMS) has been recognized since the 1980s152, 153, 154 and is caused by a deletion of chromosome 17p11.2.155, 156 The phenotype changes significantly over the life span, and diagnosis is largely dependent on the presence of structural malformations or recognition of the behavioral phenotype.

The critical region for SMS is a 1-Mb region157, 158 within the classic deletion of approximately 4 Mb.159, 160 Several genes within this region have been implicated in the features of

Genetics, Etiology, and Epidemiology

By definition, Turner syndrome (TS) occurs only in females and has an incidence of approximately 1 in 3000 live-born infant girls. At the most basic level, TS results when there is a single functioning X chromosome as a result of loss of the second sex chromosome in its entirety or more specifically, portions of the short arm of either the second X chromosome or the Y. Half of affected individuals will have a 45,X karyotype; a wide range of other structural X-chromosome malformations and mosaic

Genetics, Etiology, Epidemiology, Physical Features, and Medical Issues

Lesch-Nyhan syndrome is an X-linked disorder of purine metabolism resulting from decreased activity of hypoxanthine-guanine phosphoribosyltransferase. This diagnosis is often suspected because of the specific physical and behavioral phenotype seen in childhood; choreoathetosis, seizures, dystonia, and dysarthria are also frequently present. The diagnosis is established by measuring plasma or urine uric acid levels, which are markedly elevated. Medical treatment is primarily symptomatic, and

Common inborn errors of metabolism

Several other inborn errors of metabolism are associated with marked behavioral or psychiatric manifestations. Not all of these diagnoses are established in infancy through newborn screening, and many may not be diagnosed until the behavioral phenotype is well established. Although in general these diagnoses are rare, consideration should be given to a metabolic evaluation in individuals with suggestive medical and psychological features.

Phenylketonuria (PKU), resulting from a deficiency of

Summary

The identification of specific genetic diagnoses, including genotype-specific variations, presents the unique opportunity to study genotype/phenotype connections in child psychiatry. Multiple investigators have spent the last 2 decades characterizing the psychopathologic features associated with specific diagnoses, and the latest research seeks to connect specific facets of behavioral functioning, such as social gaze processing in TS, with genetic variance. These advances have implications for

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Practice Parameter for the Assessment and Treatment of Psychiatric Disorders in Children and Adolescents With Intellectual Disability (Intellectual Developmental Disorder)
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Certain genetic syndromes are associated with increased rates of psychiatric and behavioral disorders. Table 119 lists behavioral phenotypes and psychiatric features in certain genetic syndromes associated with ID/IDD. Clinical consensus and existing guidelines from the Social Security Act, the Individuals with Disabilities Education Improvement Act (IDEA) of 2004, and the American Academy of Pediatrics (AAP)20,21 consistently recommend standardized developmental screening and support a variety of validated, parent-report screening tools for the early identification of developmental delays.
Intellectual disability (intellectual developmental disorder) (ID/IDD) is both a psychiatric disorder and a risk factor for co-occurring psychiatric disorders in children and adolescents. DSM-5 introduced important changes in the conceptualization and diagnosis of ID/IDD, and current research studies clarify assessment and treatment of co-occurring psychiatric disorders in this population. Optimal assessment and treatment of psychiatric illness in children and adolescents with ID/IDD includes modifications in diagnostic and treatment techniques, appreciation of variations in the clinical presentation of psychiatric disorders, an understanding of the spectrum of etiologies of behavioral disturbance, and knowledge of psychosocial and medical interventions.
Association between CANCA1C gene rs1034936 polymorphism and alcohol dependence in bipolar disorder
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BD has a strong genetic component, as evidenced by high disease concordance among monozygotic vs. dizygotic twins (Edvardsen et al., 2008; Van Der Schot et al., 2009). Heritability estimates for BD have typically been reported to be about 75% (Lescai et al., 2017; Siegel and Smith, 2011), while evidence for genetic heterogeneity between clinical subtypes of BD has also been reported (Charney et al., 2017). Genome-wide association studies (GWAS) have indicated an association between BD and single nucleotide polymorphisms (SNPs) in a variety of genes including monoaminergic neurotransmitter systems, GABAergic, voltage depended ion channel, regulation of neuroplasticity and structural proteins (Calabrò et al., 2016; Gurung and Prata, 2017; Stahl et al., 2019).
Bipolar disorder (BD) is a highly heritable and disabling mental illness, commonly associated with substance abuse, being alcohol abuse the most frequent. Comorbid BD and substance abuse disorders are often associated with high levels of health service utilization and destabilization of the course of illness resulting in poor treatment outcomes. Although recent genome-wide association studies have detected a number of risk genes for BD, the data is still sparse and inconclusive for those genes that may contribute to the increased risk of comorbid alcohol abuse (AA) in BD. The primary aim of the present study was to investigate the effects of 46 single-nucleotide polymorphisms (SNPs) within eight genes on different phenotypes of BD patients, such as comorbid alcohol abuse. We further assessed clinical variables associated with AA.
One-hundred fifty-eight BD I and II patients were enrolled in a naturalistic cohort study. Genomic DNA of 92 patients was extracted from whole blood using standard procedures and 46 tag SNPs in eight genes of interest (ANK, CACNA1C, CACNB2, FKBP5, GRM7, ITIH3, SYNE1 and TCF4) were genotyped.
Seventy-one patients out of 158 (45%) satisfied diagnostic criteria for comorbid AA.
Among 46 SNPs analyzed, the only SNP associated with comorbid AA was rs1034936 polymorphism in the CANCA1C gene. This polymorphism was also associated with lifetime cocaine abuse, manic switch and current atypical antipsychotics.
Our findings suggest a role of rs1034936 CACNA1C gene variant in BD-AA group. Despite their preliminary nature, the present results may provide new insight on mechanisms underlying AA in BD.
Negative subthreshold psychotic symptoms distinguish 22q11.2 deletion syndrome from other neurodevelopmental disorders: A two-site study
2017, Schizophrenia Research
Citation Excerpt :
Both syndromes have overlapping phenotypic manifestations, including cardiovascular anomalies, calcium dysregulation, cognitive deficits, and high rates of psychiatric comorbidities (Campbell et al., 2009). As a group, individuals with neurodevelopmental disabilities (e.g., 22q11DS, WS, fragile X, or Turner syndrome) have higher rates of neuropsychiatric, cognitive, and social–behavioral deficits including nonverbal learning disorder, visuospatial deficits, attention deficit/hyperactivity disorder (ADHD), anxiety disorders, and affective disorders, compared to typically developing (TD) individuals (Schneider et al., 2014; Siegel and Smith, 2011; Weisman et al., 2015; Zarchi et al., 2014). Additionally, individuals with 22q11.2DS have a 30-fold increased risk of developing psychosis compared to TD individuals and individuals with other neurodevelopmental disabilities (10-fold) (Schneider et al., 2014).
About one third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop schizophrenia. Notably, a full-blown psychotic disorder is usually preceded by subthreshold symptoms. Therefore, it is important to identify early signs of psychosis in this population, a task that is complicated by the intellectual disabilities typically seen in 22q11.2DS. We aimed to identify subthreshold psychotic symptoms that distinguish 22q11.2DS from other neurodevelopmental disorders. The study included two independent cohorts from Tel Aviv and Philadelphia. 22q11.2DS (N = 171) and typically developing (TD; N = 832) individuals were enrolled at both sites and further compared to two groups with intellectual disabilities: Williams syndrome (WS; N = 21) in the Tel Aviv cohort and idiopathic developmental disabilities (IDD; N = 129) in the Philadelphia cohort. Participants and their primary caregivers were interviewed with the Structured Interview for Prodromal Symptoms (SIPS) and psychopathologies were assessed using standardized tools; general cognitive abilities were assessed with the Computerized Neurocognitive Battery. Negative/disorganized subthreshold syndrome was significantly more common in the 22q11.2DS group than in the WS (OR = 3.90, 95% CI = 1.34–11.34) or IDD (OR = 5.05, 95% CI = 3.01–10.08) groups. The 22q11.2DS group had higher scores than the two intellectual disabilities groups on several SIPS negative items, including avolition and decreased expression of emotion. Overall, there were few significant correlations between level of cognitive deficits and severity of negative symptoms in 22q11.2DS and only in the Tel Aviv cohort. Our findings suggest that 22q11.2DS individuals at the age of risk for developing psychosis should be closely monitored for negative symptoms.
Parental perspectives on the quality of life of children with Down syndrome
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: A version of this article was previously published in the Child and Adolescent Psychiatric Clinics of North America, 19:2.

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Psychiatric Features in Children with Genetic Syndromes: Toward Functional Phenotypes

Section snippets

Genetic testing

Genetics, Etiology, and Epidemiology

Genetics, Etiology, and Epidemiology

Genetics, Etiology, and Epidemiology

Genetics, Etiology, and Epidemiology

Genetics, Etiology, and Epidemiology

Genetics, Etiology, and Epidemiology

Genetics, Etiology, and Epidemiology

Genetics, Etiology, and Epidemiology

Genetics, Etiology, and Epidemiology

Genetics, Etiology, Epidemiology, Physical Features, and Medical Issues

Common inborn errors of metabolism

Summary

First page preview

Genet Med

Brain Dev

Res Dev Disabil

Genet Med

Genet Med

J Pediatr

Curr Opin Genet Dev

Psychiatry Res

Brain Cogn

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

J Pediatr

Europ J Paediatr Neurol

Genet Med

Growth Horm IGF Res

Child Adolesc Psychiatr Clin N Am

Lancet

Pediatr Neurol

J Am Acad Child Adolesc Psychiatry

Pediatr Neurol

Childhood developmental disorders: an academic and clinical convergence point for psychiatry, neurology, psychology and pediatrics

J Child Psychol Psychiatry

Behavioural phenotypes: what do they teach us?

Arch Dis Child

Emotional disturbance and mental retardation: diagnostic overshadowing

Am J Ment Defic

Psychopathology in persons with Williams-Beuren syndrome

Social phenotypes in neurogenetic syndromes

Child Adolesc Psychiatr Clin N Am

Prevalence of Down syndrome among children and adolescents in metropolitan Atlanta

Birth Defects Res A Clin Mol Teratol

Clinical, social, and ethical implications of changing life expectancy in Down syndrome

Dev Med Child Neurol

Anomalies in Down syndrome individuals in a large population based registry

Am J Med Genet

Down syndrome and thyroid disorders: a review

Downs Syndr Res Pract

Guidelines for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

J Pediatr Gastroenterol

Health supervision for children with Down syndrome

Pediatrics

Individual differences in vocabulary acquisition in children with Down syndrome

Prog Clin Biol Res

Psychiatric disorders in persons with Down syndrome

J Nerv Ment Dis

Environmental and temperament assessments of children with Down's syndrome

J Intellect Disabil Res

Mental retardation: a review of the past 10 years. Part II

J Am Acad Child Adolesc Psychiatry

Neurobehavioral disorders in children, adolescents, and young adults with Down syndrome

Am J Med Genet

Maladaptive behavior in children and adolescents with Down's syndrome

J Intellect Disabil Res

Compulsive-like behavior in individuals with Down syndrome: its relation to mental age level, adaptive, and maladaptive behavior

Child Dev

Clinical features and diagnostic criteria of depression in Down's syndrome

Br J Psychiatry

Mood disorders and down syndrome

Semin Clin Neuropsychiatry

Autism in Down's syndrome: a family history study

J Intellect Disabil Res

Safety and efficacy of rivastigimine in adolescents with Down syndrome: a preliminary 20-week, open-label study

J Child Adolesc Psychopharmacol

Health supervision for children with Fragile X syndrome