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BJPsych Advances (2017), vol. 23, 149–157 doi: 10.1192/apt.bp.114.012864

Microdeletion syndromes and ARTICLE : an update Melvyn W. B. Zhang, Nikki Fong, Ying Hui Quek, Cyrus S. H. Ho, Beng Yeong Ng & Roger C. M. Ho

Microdeletions are alterations of the chromo­ Melvyn Zhang is an associate SUMMARY somes that cannot be detected by conventional light consultant at the National Addictions Management Service is an important topic microscopy or other conventional methodologies, in intellectual , associated with various at the Institute of Mental Health and are usually approximately 1–3 Mb long. in Singapore. He is also an psychiatric symptoms, such as autism, attention Although the site and size of the may adjunct research scientist with deficit, hyperactivity, obsession and compulsion, vary for a particular syndrome, it should be noted the Biomedical Institute for Global and . In this article, we provide a Health Research & Technology clinical update on the following syndromes and that a particular area of a critical gene is usually (BIGHEART). He has multiple their associated psychiatric disorders: Prader– involved. Given that critical areas of gene are publications in high impact factor Willi syndrome, , Williams affected, the deletion often results in characteristic psychiatry journals, and he has a syndrome, Wolf–Hirschhorn syndrome, cri du chat phenotypic changes due to the lack of expression special interest in the application of information technologies in syndrome, DiGeorge syndrome and Rubinstein– of particular segments of genes. To date, the psychiatry. Nikki Fong is currently Taybi syndrome. visualisation of these deletions has only been a medical officer/trainee with the Ministry of Health Holdings, LEARNING OBJECTIVES possible via methods such as comparative genomic Singapore. Ying Hui Quek is a hybridisation or fluorescence in situ hybridisation • Gain an up-to-date understanding of the micro­ final-year medical undergraduate deletion syndromes commonly seen in daily (FISH). Such consistent alterations in DNA content student at the Yong Loo Lin School practice have been associated with some well-established of Medicine, National University of malformation syndromes (Schinzel 1988). In Singapore. Cyrus Ho is an associate • Appreciate the association between underlying consultant at the National University chromosomal abnormalities and the resultant in- circumstances in which psychiatrists suspect the Hospital, Singapore. He has special tellectual in microdeletion syndromes presence of an underlying genetic disorder, it is interests in neuropsychiatry, neuro- thus recommended for the individual to undergo rehabilitation and the interface • Gain up-to-date knowledge about the treatment . Visualisation of the deletions would between medicine and psychiatry. options for the various microdeletion syndromes Beng Yeong Ng is a psychiatrist commonly seen in daily practice be done using the methodologies described above. at the Singapore General Hospital. The most common microdeletion syndromes Roger Ho is an associate professor DECLARATION OF INTEREST are listed in Box 1, together with the other and consultant psychiatrist at None known microdeletion syndromes. Table 1 gives the National University Hospital, Singapore. He has a special interest an overview of the common syndromes. The latest in psychoneuroimmunology and the microdeletion syndrome to be discovered is the interface between medicine and Microdeletion syndromes have been found to be 8p23.1 syndrome, which involves the duplication psychiatry. associated with various psychiatric comorbidities, of a region of . The phenotypic Correspondence Dr Melvyn Zhang, Associate Consultant and such as hyperkinetic disorder, autism spectrum changes include changes in speech, developmental Adjunct Research Scientist, MD6, disorders, obsessive–compulsive disorders delays as well as cardiovascular-related disorders. 14 Medical Drive, #14-01, Singapore for individuals diagnosed with Prader–Willi It is hoped that this review article will provide 117599. Email: melvyn_wb_zhang@ imh.com.sg syndrome (PWS) (Dykens 1992), or the psychiatrist with an update about the clinical and schizoaffective disorders for individuals with features of each of the common microdeletion Copyright and usage 22q11.2 deletion syndrome (22q11DS) (Gothelf syndromes and their association with intellectual © The Royal College of Psychiatrists 2017. 2009). The prevalence of intellectual disabilities disabilities, and share recent insights and updates has been estimated to be approximately 1–3% regarding clinical management and genetic testing in high- and middle-income countries. This may for each of the individual syndromes. result in marked psychosocial impairments, particularly for those with moderate, severe and Chromosome 22q11.2 deletion syndrome profound intellectual disabilities. Microdeletion is considered to be one of the prenatal causes Background of . Other prenatal causes This syndrome (22q11DS) refers to patients with include central nervous system , a hemizygous deletion of chromosome 22q11.2. exposure to radiation, maternal use of various The syndrome is well recognised worldwide and substances and drugs, as well as malnutrition. commonly known as either DiGeorge syndrome

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cleft palates having 22q11DS (Shprintzen 1985). BOX 1 Microdeletion syndromes Despite the fact that immune disorders are also relatively common, few affected individuals have Most common microdeletion syndromes 8q24.11 deletion syndrome (Langer– severe (Shprintzen 2008). 15q11-13 maternal deletion syndrome Giedion syndrome or trichorhinophalangeal syndrome type II) (Angelman syndrome) Psychiatric comorbidity and intellectual 15q11-13 paternal deletion syndrome 9q22 deletion syndrome disabilities (Prader–Willi syndrome) 9q34.3 deletion syndrome Speech and language impairment is commonly 7q11.23 deletion syndrome (Williams DiGeorge syndrome/velocardiofacial seen, with approximately 75% of affected syndrome) syndrome complex 2 individuals having and a high 4p deletion syndrome (Wolf–Hirschhorn 11q13 deletion syndrome (WAGR syndrome) percentage having severe articulation impairment syndrome) 11q11.2 deletion syndrome (Potocki–Shaffer (Shprintzen 2008). Speech development is usually syndrome) mildly delayed and receptive language abilities DiGeorge syndrome 11q24.1 () exceed expressive abilities (Golding-Kushner Rubinstein–Taybi syndrome 13q14 deletion syndrome (retinoblastoma 1985). Psychiatric disorders seen in children and Other microdeletion syndromes syndrome) adolescents with 22q11DS include attention- 1q36 deletion syndrome 15q11.2 deletion syndrome (BP1-2) deficit hyperactivity disorder (ADHD; 35–46%) 15q13.3 deletion syndrome 1q21.1 deletion syndrome (Niarchou 2015), oppositional defiant disorder 15q15.3 deletion syndrome -absent radius syndrome (16–43%), specific and social phobias (23–61%), 2q15-16.1 deletion syndrome 15q24 deletion syndrome generalised anxiety disorder (GAD; 17–29%), 2q23.1 deletion syndrome 16p13.11 deletion syndrome separation anxiety disorder (16–21%), obsessive– 2q37 deletion syndrome 17p13.3 deletion syndrome compulsive disorder (OCD; 4–33%), major depressive disorder and dysthymia (10–20%) 3p deletion syndrome 17p1.2 deletion syndrome and autism spectrum disorders (14–45%) (Tang 17q12 deletion syndrome 3q29 deletion syndrome 2015). By late adolescence and adulthood, up 17q21.31 deletion syndrome 5q35 deletion syndrome (Sotos syndrome) to one-third of patients with 22q11DS develop 6p25 deletion syndrome 18p deletion syndrome psychotic disorders resembling schizophrenia 8p23.1 deletion syndrome 20p11 deletion syndrome and schizoaffective disorders (Gothelf 2009). 8q22.1 deletion syndrome (Nablus mask-like Individuals diagnosed with schizophrenia in facial syndrome) the general population tend to have a premorbid period in which they have gradual worsening of their social and academic functioning. Individuals with 22q11DS tend to have a more chronic and or velocardiofacial syndrome. The hemizygous prolonged duration of impaired functioning, from deletion is inherited in an autosomal dominant childhood to adolescence (Radoeva 2017). pattern. Hence, affected parents have a substantial The average full-scale IQ score in affected risk of passing on the deletion to their children; individuals is in the mid-70s, within the borderline 22q11DS is estimated to occur in nearly 1 in 3000 intelligence range (Swillen 1997); 25 to 40% score children. in the intellectual disability range. The cognitive profile of individuals with this condition is Clinical features characterised by relative strengths in the areas of The clinical features of 22q11DS are diverse, but reading, spelling, and rote memory, and relative common features include a conotruncal cardiac weaknesses in the areas of visuospatial memory anomaly, mild-to-moderate immune deficiency, and arithmetic (Simon 2005). developmental delays, palatal dysfunction, and feeding difficulties in infants (Shprintzen 2008). Of note, patients with 22q11DS do not tend to With improved palliative cardiac repair and have noticeable facial dysmorphisms (Shprintzen medical management of immunodeficiency, infant 2008). More importantly, 22q11DS is commonly mortality in 22q11DS is approximately 8% (Ryan associated with congenital heart ; the 1997). Individuals with 22q11DS can have normal deletion is found in a large percentage of children lifespans if they undergo corrective cardiac with conotruncal heart anomalies (Goldmuntz procedures. The immune problems for some of 1998). Palatal dysfunction is also relatively these individuals also tend to remit over time. The common, with 8% of children with cleft palates, associated endocrinology problems can be treated submucous cleft palate and occult submucous with appropriate medications (Shprintzen 2008).

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TABLE 1 Summary of the core features of each of the common microdeletion syndromes

Wolf– Rubinstein– Prader–Willi Angelman Williams Hirschhorn Cri du chat DiGeorge Taybi syndrome syndrome syndrome syndrome syndrome syndrome syndrome

Prevalence 1 in 50 000 1 in 10 000 to 1 in 7500 to 1 in 50 000 to 1 in 15 000 to 1 in 3000 1 in 100 000 to 1 in 20 000 1 in 20 000 1 in 20 000 1 in 50 000 1 in 125 000 Clinical Low birth Ataxic, Elfin-like facies, Characteristic Low birth Conotruncal Intellectual features weight, tremulous broad brow, flat facial features weight, cardiac anomaly, disability, hypotonia, movement of nasal bridge, such as prominent dysmorphic mild/moderate postnatal feeding limbs, frequently short upturned nose, prominence facies, immune growth difficulties, smiling with nose, irregular of glabella, prominent large deficiency, deficiency, hyperphagia, associated dentition, , nasal bridge, developmental , obesity developmental 'cocktail party’ epicanthal fold hypertelorism, delay, typical specific facial delays personality and distinct cat-like cry facies, palatal characteristics, downturned dysfunction, broad thumbs corners of the feeding and big toes mouth difficulties in infants IQ Mild disability Severe to Average IQ Mild intellectual Severe mental Average full- Global (mean IQ 60–70) profound 50–60, better disability in and development scale IQ in the intellectual intellectual verbal than 10% of cases, retardation, IQ mid-70s disability is disability motor abilities moderate in usually between characteristic, 25% and severe/ 20th and 50th with an average profound in 65% per centile IQ of 35–50 Comorbidities Sleep, Orthopaedic Growth-related, Musculoskeletal, Growth Heart Growth/weight behavioural, and movement cardiovascular, neurological and retardation, abnormalities, problems, psychiatric difficulties, endocrine, midline defects sensory issues palatal constipation, and endocrine behavioural and neurological and and cardiac dysfunction, hypotonia, abnormalities sleep problems, genitourinary deformities immune congenital heart epileptic problems disorders, defects, renal , comorbid anomalies, gastrointestinal psychiatric ophthalmologic problems disorders problems, orthopaedic problems Treatment Manage poor Evaluate Routine Largely symptom- No specific No specific No specific feeding, evaluate and treat for assessment targeted and management management management for endocrine neurological with accurate supportive at best approach approach approach abnormalities, complications; assessment has been has been has been manage obesity, evaluate of growth, recommended recommended recommended monitoring for for feeding blood pressure scoliosis and difficulties; monitoring, therapy for specialised developmental behavioural therapy for assessment, issues developmental routine vision/ delays hearing screening and cardiac evaluation Prognosis Able to reach No data on Generally low Favourable only Mortality is Low infant Normal life adulthood and estimated life educational and if the three major about 10%; 75% mortality; life expectancy function in group expectancy employment medical problems of deaths in the spans tend to home settings attainments are looked into first months of be normal if life, up to 90% in problems are the first year dealt with

Prader–Willi syndrome and processing in brain and muscle (Young 2005). Approximately 70% of cases result from 4-Mb Background microdeletions involving the paternally derived PWS is a complex multisystem genetic disorder . Approximately 25% of cases that is caused by the lack of expression of paternally result from maternal (UPD) for inherited imprinted genes on chromosome chromosome 15. The remaining cases are due to a 15q11-q13 (Jin 2011). The main gene implicated is or tiny deletion in the PWS imprinting SNRPN (small nuclear ribonucleoprotein N). This centre or SNRPN promotor. The prevalence of encodes a protein involved in pre-mRNA splicing PWS varies from 1 in 8000 to 1 in 20 000, with

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population prevalence at approximately 1 in anorectic agents have not shown any effectiveness 50 000 (Jin 2011). (Martin 1998). Psychiatric medications such as selective serotonin reuptake inhibitors might Clinical features regulate the behavioural symptoms commonly seen The common clinical features of PWS include in patients with PWS, but these do not mediate the low birth weight, severe hypotonia and binge eating and weight gain symptoms (Martin feeding difficulties in early infancy, followed 1998). Psychotropic drugs could be initiated to by hyperphagia and obesity starting in early help with behavioural management (Martin 1998). childhood (Buiting 2010). Common comorbidities include sleep abnormalities, behavioural and Prognosis psychiatric disturbances, and endocrinological Patients with PWS frequently reach adulthood abnormalities. Individuals with PWS are and are able to function in a group home predisposed to sleep-disordered breathing, setting, performing vocational work or attending including central and obstructive sleep apnoea, community college classes. Complications from abnormal arousal, abnormal circadian rhythms in hypogonadism (e.g. osteoporosis/pathological rapid eye movement (REM) sleep, reduced REM fracture), behavioural issues (e.g. temper tantrums latency, and abnormal response to hypercapnia, and stubbornness) and morbid obesity (e.g. type as well as excessive daytime sleepiness (Nixon 2 diabetes mellitus and cor pulmonale) may 2002). PWS has been found to be associated with shorten life expectancy and affect the quality of endocrinological abnormalities such as obesity, life (Jin 2011). deficiency and hypogonadism. Angelman syndrome Psychiatric comorbidity and intellectual disabilities Background Previous research has found that children with Angelman syndrome involves microdeletion PWS tend to have behavioural and psychiatric of the maternally derived chromosome 15 in disturbances, which usually include behavioural approximately 70% of cases, and paternal UPD for patterns such as temper tantrums, obsessive– chromosome 15 in 2–3% of cases. Most commonly, compulsive characteristics, autism spectrum the microdeletion involves the 15q12 site. Most of disorder, and attention-deficit hyperactivity the remainder of cases are caused by symptoms (Dykens 1992). Previous research in UBE3A (ubiquitin-protein ligase E3A) or has found a close association between this another gene involved in the imprinting process. microdeletion syndrome and bipolar disorder Severe psychomotor retardation is attributed to (Boer 2002; Verhoeven 2003). Based on a prior abnormal expression of UBE3A, which encodes a population-based study of 25 individuals aged protein ligase thought to play an important part 18 or more, it was ascertained that 28% have an in the localisation of proteins in the brain (Young underlying bipolar disorder and the medium age 2005). The incidence of Angelman syndrome of onset is approximately 26 years (Boer 2002). A is estimated to be between 1 in 10 000 and 1 in combination of medications such as 20 000 (Williams 2005). and mood stabilisers have been used in the treatment of those diagnosed with bipolar disorder Clinical features (Boer 2002). Patients with Angelman syndrome tend to have In addition, previous research has highlighted ataxia and tremulous limb movements. They that most individuals with PWS are diagnosed tend to have a happy demeanour with sudden with mild intellectual disability, with a mean IQ bursts of laughter. In addition, they often have of 60–70. However, 20% of individuals with PWS developmental delays (Williams 2006). Some of are diagnosed as having moderate intellectual the common physical features of the syndrome disability (Jin 2011). include hypotonia, microbrachycephaly, vertical inclination of skull base, occipital furrow, fair Clinical management hair, ocular abnormalities, midface hypoplasia, Care for patients with PWS includes management macrostomia and widely spaced teeth, tongue of hypotonia or poor feeding, evaluation for protrusion with drooling, and prognathism endocrine abnormalities, management of obesity, (Schinzel 1988). The most common comorbidities monitoring for scoliosis and therapy for behavioural include orthopaedic and movement difficulties, issues. With regards to the management of behavioural issues and sleep problems, the hyperphagia and binge eating behaviours, epileptic seizures and gastrointestinal problems pharmacological approaches such as use of (Larson 2015).

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Psychiatric comorbidity and intellectual at 7q11.23 (Morris 2000). The deletion results disabilities in the loss of approximately 28 genes, including Individuals with Angelman syndrome tend to ELN itself. The estimated prevalence of Williams have severe to profound intellectual disabilities, syndrome ranges from 1 in 7500 to 1 in 20 000 with developmental delays that are first noted at (Martens 2008). around 6 months of age. They tend to be able to sit unsupported at only 12 months of age, crawl Clinical features at the age of 18–24 months and walk at the age Individuals with have a of 4 years (Clayton-Smith 1993). They tend to characteristic elfin facies, with a broad brow, flat have limited vocabulary of only one or two words, nasal bridge, short upturned nose, wide mouth despite having reasonable comprehension of simple with full lips, and irregular dentition (Morris commands and sentences (Laan 1999). It should 1999). They often have an engaging ‘cocktail be noted that the results of any neuropsychological party’ personality which conceals mild intellectual tests might be confounded by the patient’s inability disability (Young 2005). The most common to focus, underlying hyperactivity and inability to comorbidities include growth-related problems, communicate (Williams 2010). and cardiovascular, endocrine, neurological and Prior research has highlighted that another genitourinary abnormalities. common comorbid condition in Angelman syndrome (in addition to intellectual disability) Psychiatric comorbidity and intellectual is autism spectrum disorder (Ornoy 2016). disabilities Individuals with class I deletions, which involve Individuals with Williams syndrome are noted multiple breakpoints in chromosome 15q11-13, to have mild-to-moderate developmental delay. were found to have a higher incidence of autism In neuropsychological testing, it is consistently spectrum disorder. noted that they tend to have higher verbal intel­ ligence scores compared with their performance Clinical management intelligence scores. The average IQ for patients Eighty per cent of patients with Angelman syndrome with Williams syndrome lies between 50 and 60 have neurological complications such as epilepsy. (Martens 2008). Hence, it is not uncommon to find Early screening is therefore essential, as are that these individuals have better verbal abilities further evaluations such as electroencephalogram as compared to motor abilities (Martens 2008). (EEG) to check for the presence of seizures. In Recent studies have found increased prevalence of addition, in view of the developmental delays as autism spectrum disorders among patients with well as the communication difficulties, patients Williams syndrome (Ornoy 2016). Clinicians need should be referred for speech therapy. For patients to be cognisant of the fact that the microdeletion with gait and movement problems, physical and in Williams syndrome could lead to a range of occupational therapy should be considered. With social communications deficits, ranging from lack regards to sleep disturbances, medications such as of verbal language to being excessively talkative melatonin could be considered. (Tordjman 2012).

Prognosis Clinical management There are no data on the life expectancy for patients It is recommended that a multidisciplinary team with Angelman syndrome. It is to be expected follows up the patient, owing to the numerous that patients with Angelman syndrome would complications associated with Williams syndrome. continue to have epileptic seizures throughout The American Academy of Pediatrics guidance adulthood, with atypical absence seizures and (Committee on 2001) previously myoclonic seizures being the most prominent. recommended evaluations based on the patient's With advancing age, adults tend to become less age. In general, the recommendations emphasise active, largely due to joint contractures, thus the importance of routine physical assessment with leading to significant difficulties with walking. accurate assessment of growth, as well as blood Some individuals eventually require a wheelchair pressure monitoring, developmental assessment, (Buggenhout 2009). routine vision and hearing screening, and – of paramount importance – routine cardiac evaluation. Williams syndrome Background Prognosis Williams syndrome is caused by a ~1.5-Mb Owing to the multitude of complications (both deletion encompassing the elastin gene (ELN) physical and psychiatric) associated with Williams

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syndrome, individuals with this condition have the presence of midline defects, routine thorough generally low educational and employment cardiovascular examination is required. In addition, attainments (Howlin 2006). in view of the presence of ptosis and hearing defects, it might also be wise to conduct audiological and Wolff–Hirschorn syndrome ophthalmological screening periodically.

Background Prognosis Patients with Wolff–Hirschorn syndrome (WHS) The prognosis of patients with WHS is have a deletion of variable size involving the considered to be favourable if the three major short arm of , always including medical problems (seizures, feeding difficulties the band 4p16. Eighty per cent of deletions arise and developmental disabilities) are carefully de novo, while 20% occur as a result of a parentally investigated and managed (Battaglia 2008). If transmitted unbalanced translocation (Young diagnosed early, cardiac, ophthalmological and 2005). The gene affected is the WHS candidate dental abnormalities can be treated with good 1 gene, which has a role in the transcription outcomes (Battaglia 2008). process (Baradaran-Heravi 2013). The incidence is estimated at 1 in 50 000 to 1 in 20 000 births, Cri du chat syndrome with a female predilection of 2:1 (Battaglia 2008). Background Clinical features Cri du chat syndrome (CdCS) is a genetic disorder Individuals with WHS can be easily identified, resulting from a deletion of variable size occurring as they tend to have a characteristic facial on the short arm of (5p–). This appearance, with a prominent nose due to a rare disease has an incidence ranging from 1 in high forehead, prominence of the glabella, 15 000 to 1 in 50 000 live-born infants (Mainardi hypertelorism, epicanthal fold, and a distinct 2006). CdCS affects less than 1% of the population mouth with downturned corners (Battaglia 2008). with mild intellectual disability; its prevalence This characteristic facial appearance is commonly has been previously reported as 1 in 350 among known as the ‘Greek warrior helmet’ appearance. 6000 individuals with intellectual disability Other common clinical features include (Niebuhr 1978). musculoskeletal and neurological abnormalities, as well as midline defects. The most commonly Clinical features associated medical problems are seizures, feeding Patients with CdCS are noted to have low difficulties, and cardiac, ophthalmological and weight at birth (mean 2614 g). In addition, they dental abnormalities (Battaglia 2008). may have dysmorphic facies, characterised by microcephaly, round face, prominent large nasal Psychiatric comorbidity and intellectual disabilities bridge, hypertelorism, epicanthal folds, downward Global developmental delay is often exhibited, slanting palpebral fissures, downturned corners of with mild intellectual disability in 10%, moderate the mouth, low-set ears, micrognathia, abnormal in 25% and severe/profound in 65% of cases. dermatoglyphics (transverse flexion creases) Expressive language, although limited to guttural and the typical cat-like cry (Jones 2006). The or disyllabic sounds in most individuals, was at phenotypic features of the cat-like cry have the level of simple sentences in 6%. Comprehension been localised to the region of 5p15.3 (Mainardi seems to be limited to a specific context. Indivi­ 2001). It is important for clinicians to note that duals’ abilities to communicate gradually improve these features might become less prominent with over time as they learn more gestures to facilitate advancing age, which could cloud the clinical communication (Battaglia 2008). diagnosis; in particular, it appears that the face tends to become longer and narrower (Mainardi Clinical management 2006). In addition, patients with CdCS may have Clinical management is largely symptom targeted growth retardation, sensory issues and cardiac and supportive at best. It is essential to note deformities. that patients diagnosed with WHS are prone to recurrent aspirations, and hence they are prone Psychiatric comorbidity and intellectual disabilities to recurrent episodes of respiratory infections. In Patients with this condition tend to have severe view of the expected difficulties with feeding, there mental and developmental retardation. The IQ have been recommendations for the consideration is usually below the 20th and 50th per centile, of placement of a gastrostomy tube. In view of respectively. In a study of 26 UK children with

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CdCS, full-scale IQ on the Wechsler Intelligence coordination, as well as sudden mood changes in Scale for Children (WISC-III) varied from below adulthood (Hennekam 2006). In addition, recent 40 (4 children) to between 40 and 57 (the studies have highlighted the association between remaining children), with a mean of 48 (Cornish this disorder and characteristic behaviours 1999). Neuropsychological testing has revealed such as motor stereotypies (Galera 2009). Other that patients tend to have better abilities in studies have demonstrated an age-related change comprehension of speech compared with their in symptoms, with anxiety, mood instability and ability to communicate (Mainardi 2006). aggression being more prominent as age advances (Yagihasi 2012). However, individuals are usually Prognosis described as loving, friendly and happy as children After the first year of life, survival rates are (Stevens 1990). Global intellectual disability is high and morbidity is low. It has been found that characteristic, with an average IQ between 35 and mortality is about 10%, with 75% of premature 50 (Hennekam 1992). deaths occurring in the first months of life, and up to 90% within the first year (Niehbur 1978). Prognosis Survival rates in general are good, with apparently Rubinstein–Taybi syndrome normal life expectancy and frequent reports of Background adults with RSTS (Hennekam 2006). Rubinstein–Taybi syndrome (RSTS) generally occurs sporadically, and 55% of affected Prevention of microdeletion syndromes and individuals show a microdeletion of chromosome associated disabilities 16p13.3, or a mutation in the gene encoding either Prevention of microdeletion syndromes can be done CREB-binding protein or EIA-binding protein. via DNA-based prenatal diagnosis. The purpose However, these mutations cannot be found in of DNA-based prenatal diagnosis is usually to 45% of individuals with the syndrome, leaving determine whether the fetus has inherited the the diagnosis to rest on clinical features alone disease-causing mutation(s) identified in one or (Hennekam 2006). The syndrome is rare, with the both parents. It is also led by ultrasound findings birth prevalence ranging from 1 in 100 000 to 1 in that may occasionally suggest a specific disorder, 125 000 (Hennekam 2006). such as investigations for decreased fetal motor activity in PWS (Schinzel 1986). Clinical features Karyotyping remains the gold standard of RSTS is well defined by several congenital chromosome analysis; however, this technique anomalies, including intellectual disability, has limited resolution and is therefore unable postnatal growth deficiency, microcephaly, specific to reliably detect small discrete chromosomal facial characteristics, broad thumbs and big toes abnormalities involving genomic regions of less (Rubinstein 1963). Patients with RSTS have a than 6–10 Mb, such as microdeletions. With the striking facial appearance, with highly arched advances in cytogenetics, the development of the eyebrows, long eyelashes, down-slanting palpebral FISH technique makes this possible. Fetal cells fissures, broad nasal bridge, beaked nose with can be extracted from amniotic fluid samples the nasal septum extending well below the alae, and analysed using FISH. However, the majority highly arched palate, and mild micrognathia. of FISH assays are highly targeted and will only Their facial expression tends to have a grimace uncover abnormalities for which specific probes or unusual smile with almost closing of the eyes. have been designed. They also often have talon cusps at the permanent As such, these DNA-based prenatal diagnosis incisors, and broad thumbs and broad big toes methods are mostly targeted towards families at (Hennekam 2006). Common comorbidities include risk of an inherited condition, and are not used as a growth/weight problems, constipation, hypotonia, screening test because of cost, technical complexity congenital heart defects, renal anomalies, and limited resources. The family should first problems with anaesthesia, ophthalmologic undergo molecular genetic testing and genetic problems, orthopaedic problems, increased risk counselling before embarking upon a DNA-based for tumours, seizures, behavioural issues and prenatal diagnosis (Bui 2002; Konialis 2011). intellectual disability (Hennekam 2006). With regards to the secondary disabilities that might arise as a of the underlying Psychiatric comorbidity and intellectual disabilities microdeletion syndrome, other rehabilitation Affected individuals have several behavioural options may be useful, such as physiotherapy and issues, including short attention span and poor speech and language therapies.

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Conclusions Jones KL (2006) Smith’s Recognizable Patterns of Human Malformation MCQ answers (6th edn). Elsevier Saunders, 2006. 1 a 2 e 3 c 4 e 5 c This article has highlighted the association Konialis C, Hagnefelt B, Sevastidou S, et al (2011) Uncovering recurrent between common microdeletion syndromes and microdeletion syndromes and subtelomeric deletions/duplications intellectual disabilities. Genetic testing would through non-selective application of a MLPA-based extended prenatal panel in routine prenatal diagnosis. Prenatal Diagnosis, 31: 571–7. help in early detection, so that appropriate clinical management plans could be formulated to help Laan LA, van Haeringen A, Brouwer OF (1999) Angelman syndrome: a review of clinical and genetic aspects. Clinical Neurology and individuals better manage the other complications Neurosurgery, 101: 161–70. arising from microdeletion syndromes. Larson AM, Shinnick JE, Shaaya EA, et al (2015) Angelman syndrome in adulthood. 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MCQs 3 IQ of 50–60, with higher verbal than 5 Common comorbidities for individuals with Select the single best option for each question stem performance intelligence score, is 22q11.2 deletion syndrome do not include: commonly found in: a hyperkinetic disorder 1 The estimated incidence of intellectual a Prader–Willi syndrome b oppositional defiant disorder disability owing to microdeletion syndromes b Angelman syndrome c enuresis in high- and middle-income countries is: c Williams syndrome d separation anxiety disorder a 1–3% d cri du chat syndrome e obsessive–compulsive disorder. b 4–5% e 22q11.2 deletion syndrome. c 5–7% d 7–10% 4 The second most common cause of e More than 10%. developmental delay and the major cause of congenital heart disease after Down 2 Schizophrenia occurs most frequently in: syndrome is: a Prader–Willi syndrome a Prader–Willi syndrome b Angelman syndrome b Angelman syndrome c Williams syndrome c Williams syndrome d cri du chat syndrome d cri du chat syndrome e 22q11.2 deletion syndrome. e 22q11.2 deletion syndrome.

BJPsych Advances (2017), vol. 23, 149–157 doi: 10.1192/apt.bp.114.012864 157 Downloaded from https://www.cambridge.org/core. 25 Sep 2021 at 01:46:41, subject to the Cambridge Core terms of use.