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Autism spectrum disorders in XYY syndrome: two new cases and systematic review of the literature Lucia Margari, Anna Linda Lamanna, Francesco Craig, Marta Simone & Mattia Gentile European Journal of Pediatrics ISSN 0340-6199 Eur J Pediatr DOI 10.1007/s00431-014-2267-9

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Author's personal copy Eur J Pediatr DOI 10.1007/s00431-014-2267-9

REVIEW

Autism spectrum disorders in XYY syndrome: two new cases and systematic review of the literature Lucia Margari & Anna Linda Lamanna & Francesco Craig & Marta Simone & Mattia Gentile

Received: 1 October 2013 / Revised: 8 January 2014 / Accepted: 16 January 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Abnormalities of the sex chromosomes (47, XXY, 47 XYY, 45,X/46,XY mosaicism) are frequently associated with Autism Spectrum Disorders (ASD), but the male predisposition to these disorders has not been clearly explained. Previously, the role of the X chromosome was considered important in the ASD mainly because autistic symptoms were detected in genetic syndromes involving X chromosome (fragile X syndrome, Rett syndrome, Klinefelter syndrome). Instead, few studies have analyzed the possible role of the Y chromosome in the ASD. This study explores the role of the Y chromosome in ASD through a systematic literature review about the association between ASD and XYY syndrome and a description of two new cases with this association. The literature review considered studies published in peer-reviewed journals, included in the MEDLINE and PubMed databases, that examined the association between ASD and XYY syndrome. Few studies reported the occurrence of ASD in children with XYY karyotype and the majority of them did not reported a well-defined autism diagnostic category associated with an extra Y chromosome, but several clinical conditions that are

generically described as language and social impairment. Conclusion: This study underlines the underestimated role of the Y chromosome in ASD, and we postulate that all the ASD associated with the XYY karyotype may presumably fall within mild degree of ASD as in our cases.

Communicated by Peter de Winter

A series of genetic studies have provided clear evidence that genetic factors play a major role in the etiology of autism; however, the genetics of the disorder appear to be complex, involving multiple loci and interaction of multiple genes [16]. Moreover, there are many genetic syndromes in which autistic manifestations are described, and this further shows the role played by genetics in autism [1, 29]. Abnormalities of the sex chromosomes (47, XXY, 47 XYY, 45,X/46,XY mosaicism) are frequently associated with Autism Spectrum Disorders (ASD), but the male predisposition to these disorders has not been clearly explained. In recent years, there has been an increasing interest in the role of the X chromosome in ASD because autistic symptoms were detected in genetic syndromes involving X chromosome (fragile X syndrome, Rett syndrome, Klinefelter syndrome,

L. Margari : A. L. Lamanna : F. Craig : M. Simone Unit of Child Neuropsychiatry, Department of Basic Medical Sciences, Neuroscience and Sense Organs, “Aldo Moro” University of Bari, Bari, Italy M. Gentile Department of Research, Medical Genetic Unit, IRRCS Saverio de Bellis, Castellana Grotte, Bari, Italy M. Gentile Department of Medical Genetics, Hospital Di Venere, Bari, Italy L. Margari (*) Child Neuropsychiatry Unit, Department of Basic Medical Sciences, Neuroscience and Sense Organs, “Aldo Moro” University of Bari, Piazza Giulio Cesare 11, Bari, Italy e-mail: [email protected]

Keywords XYY syndrome . Autism Spectrum Disorders . ASD . Y chromosome Abbreviations ADI-R Autism Diagnostic Interview—Revised ASD Autism Spectrum Disorders CC Cranial Circumference KS Klinefelter syndrome PDD Pervasive Developmental Disorders SCTs sex chromosome trisomies

Introduction

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KS), while few studies have focused on the role of the Y chromosome in ASD. In this study, we performed a literature review and described two new cases about the association between XYY syndrome and ASD, to understand the possible role of the Y chromosome in ASD.

Method The literature search considered studies written in English that were published in peer-reviewed journals, in the period from 1983 to May 2013, and included in the MEDLINE and PubMed databases. The search was conducted using single and in combinations of the search terms such as XYY syndrome, Autism, Autism Spectrum Disorders, ASD, Pervasive Developmental Disorders, and PDD. Further literature data were obtained by exploring the reference lists of studies and by reviewing articles related to included papers. The inclusion criteria for literature review were that the title and abstract of the study indicated the search terms, with child limits set for all searches. Moreover, we described two new cases where the informed written consent was obtained from parents.

Result After screening by title and abstract, a total of 15 studies were analyzed in this paper. The considered studies included three reviews, five case–control studies, three cross-sectional studies, one longitudinal study, and three case reports. In Table 1, we exclusively report the results of the studies that analyzed the frequency of the association between ASD and XYY

syndrome as well as the characteristics of our cases described below. However, all of the studies that were taken in consideration were extensively argued in the “Discussion” section. Case 1 The patient is a three-and-a-half-year-old child. His medical history reports a family history of Duchenne's disease, Down syndrome, and mood disorders. There is no consanguinity between his parents. The pregnancy had a normal course. Amniocentesis, performed at the fourth month of pregnancy, showed supernumerary Y chromosome. He was born at term by planned caesarean section because of intrauterine growth arrest. Birth weight was 2,700 g. No perinatal complications were reported. Motor development was normal. The language development occurred late. We firstly observed the patient when he was two-and-a-half years old. At this time, he attended nursery school with relationship difficulties in his peer group (a tendency to isolation, poor social initiative). He had not yet acquired sphincter control. The feeding and sleep patterns were normal. Physical, neurological, cardiac, and otorinolaringoiatric examinations were normal. Height was 90 cm (50th centile), weight was 13 kg (50th centile), and the CC was 51.5 cm (90th centile). Large laboratory studies including blood count, liver and renal functions and urine test were normal. Acoustic brain-stem response was normal. Sleep electroencephalogram showed excess of polymorphic delta slow wave on the right temporal regions. Brain magnetic resonance imaging showed slight hyperintensity in T2weighted sequences in the posterior periventricular white matter. The examination of brain spectroscopy, performed on the frontal white matter, revealed no significant alterations

Table 1 Literature analysis of the association between Autistic Spectrum Disorder and XYY syndrome Author

Year

XYY syndrome Cases Number

Autistic disorder Number

PDD/PDD-NOS Asperger disorder Number Number

ASD Number

Autistic behaviors Number

Gillberg et al. Nicolson et al. Weidmer-Mikhail Kuczynski et al. Cashion and Van Roden Bishop et al. Ross et al. Cordeiro et al. Lalatta et al. Bryant et al. Present Cases N total cases

1984 1998 1998 2009 2011 2011 2012 2012 2012 2012 2013

1 2 3 1 1 58 26 40 11 8 2 Number 253

1 1 1 1 – – – – – – – N (%) 4 (1.5 %)

– 1 2 – – – – – 1 – – N (%) 4 (1.5 %)

– – – – – 11 – 20 – 5 2 N (%) 38 (15 %)

– – – – – – 13 – – – – N (%) 13 (5.1 %)

– – – – 1 – – – – – – N (%) 1 (0.3 %)

ASD Autistic Spectrum disorder, PDD NOS Pervasive Developmental Disorder Not Otherwise Specified

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in brain metabolites. The behavioral profile was characterized by a prevalent impairment in social interaction and communication. In particular, the boy showed poor social initiative in interacting with peers and examiners, lack of response to the smile, lack of response to his name, inconstant visual coupling, and mostly finalized to an instrumental use. The play was characterized by the use of simple, repetitive patterns of action and was basically solitary. He had acquired simple constructive play. He hinted just few imitative sequences with everyday objects. The child performed only simple and contextual commands, concerning everyday life. The expressive verbal language was limited to the use of mono- or bisyllabic sounds and vocalizations, rarely used for a communicative purpose. He inconstantly used to request by pointing. He showed occasional stereotyped repetitive movements (flapping hands in emotionally charged moments). The intelligence level scale Leiter-R certified a nonverbal brief intelligence quotient (I.Q.) of 82, attesting low average intellective functioning. At Autism Diagnostic Observation Schedule (ADOS), he exceeded the cut-off for autism in language and communication and social reciprocal interaction. The score totaled at Autism Diagnostic Interview—Revised (ADI-R) exceeded the cut-off with regard to qualitative abnormalities in social reciprocal interaction and communication. At Childhood Autism Rating Scale (CARS), he exceeded the cut-off for autism mild degree. At 1 year follow-up, height was 98 cm (50th centile), weight was 15.6 kg (50th centile), and the CC was 52 cm (>75th centile97th centile). Large laboratory studies including blood count, liver and renal functions and urine test were normal. Acoustic brain-stem response and awake and sleep tests were normal. Sleep electroencephalogram showed in all phases of sleep, paroxysmal abnormalities like spikes and spike and wave complexes on the central regions of the right hemisphere without clinical manifestation. Brain magnetic resonance imaging (MRI) showed moderate asymmetric dilatation of left lateral ventricle and slight hyperintensity in T2-weighted sequences in the posterior periventricular white matter and in posterior semi-oval centers. Karyotype analysis showed supernumerary Y chromosome. The behavioral profile was characterized by a prevalent impairment in social interaction and communication. In particular, the environmental exploration appeared deficient: he showed globally little interest in people and in ludic material proposed. Visual coupling tended to be elusive. In play, spontaneously, he used simple patterns of action. In some occasions, he clearly showed interest in some objects proposed (e.g., puppets): he smiled, looking alternately at the object and the examiner; however, he lost interest easily. The relationship was globally discontinuous and characterized by inadequate reciprocity and emotional sharing. With parent, a relational exchange primarily targeted to the satisfaction of basic needs was detected. He did not react to the removal of the parental figures. He responded inconsistently to the verbal warning. The child did not perform simple and contextual commands. The mimicry was poorly modulated. Verbal language was limited to few words little used for communication purposes. Stereotyped behaviors (turn on and off the lights) and peculiar and stereotyped perceptive interests (observe the lights) were detected. He showed cognitive delay on most of the scales of Uzgiris Hunt. In particular, a greater impairment in the scale of causality emerged: he reached the third stage of Piaget or stage of secondary circular reactions (4–8 months). In the scale of the development of object permanence and in the scale of relationship patterns with objects, he reached the fourth stage of Piaget or stage of coordination of patterns (8–12 months). The scale of the development of means–purposes and the scale of spatial relationships between objects were relatively preserved: he reached the fifth stage of Piaget or stage of tertiaries circular reactions (12–18 months). The score totaled at ADI-R exceeded the cut-off with regard to the anomalies of reciprocal social interaction, verbal-nonverbal communication, and developmental abnormalities evidenced before 36 months. According to the Zero to Three criteria, a diagnosis of Multisystemic Developmental Disorder in a subject with XYY karyotype was made. At 1 year follow-up, the height was 90 cm (>50th centile50th centile97th

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centile). He showed few improvements: the frequency of stereotyped behaviors and peculiar and stereotyped perceptive interests was reduced. Little interest in people and in ludic material proposed, elusive visual coupling, inadequate reciprocity and emotional sharing in the relationship, simple patterns of action in spontaneous play, and poor environmental exploration persisted. Although showed enrichment of the vocabulary, language was still severely compromised. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria, a diagnosis of Autism Spectrum Disorder mild degree in a subject with XYY karyotype was made.

Discussion The role of chromosome X in ASD has been studied for a long time for the following reasons: (1) the high incidence of ASD in males; (2) the high presence of autistic symptoms in genetic syndromes involving X chromosome (fragile X syndrome, Rett syndrome, Klinefelter syndrome); (3) the detection of association between mutations in X-linked genes as neuroligin NLGN3 on Xq13, NLGN4 on Xq22.39 [24] and Aristalessrelated homeobox gene and autism spectrum disorders [25]. The high incidence of ASD in males is also a reason why the Y chromosome is of interest in ASD; nevertheless, few authors have suggested an involvement of the Y chromosome in ASD. In order to clarify the possible role of Y chromosome in ASD, we performed a literature review, about the association between XYY syndrome and ASD. Gillberg et al. (1984) reported an XYY case of infantile autism, suggesting that the sex chromosomes may be of major importance in the genesis of some cases of autism [10]. Nicolson et al. (1998) showed that, in a clinic for children with developmental disorders, 2 out of 40 male referrals had 47, XYY karyotypes and suggested that an extra Y chromosome may be related to abnormal brain development, which in turn may predispose vulnerable males to PDD [17]. In a sample of 92 children with PDD, Weidmer-Mikhail et al. (1998) found that a PDD Not Otherwise Specified patient had the XYY syndrome and proposed that chromosomal abnormalities are uncommon in traditional autism and may be relatively more frequent in people with PDD Not Otherwise Specified [27]. Jamain et al. (2002) found no significant differences in Y-haplotype distribution between a group of 111 autistic subjects (from France, Sweden, and Norway) and a control group [11]. Geerts et al. (2003) detected that the XYY patients are at considerably increased risk for delayed language and/or motor development and from primary school age on, for child psychiatric disorders such as autism [9]. A small candidate gene study failed to find associations between variants in PCDH11Y and autism [8], while ZFY has not been specifically investigated. One study has reported a missed variant in

NLGN4Y in a single patient with autism and his father with learning difficulties [28]. Kuczynski et al. (2009) reported an adolescent with a diagnosis of infantile autism and 47,XYY karyotype [12]. Visootsak (2009) found that males with sex chromosomal aneuploidy (e.g., 47, XXY, 48, XXYY; 48, XXXY; 47, XYY) may have increased vulnerability for autistic features as evidenced in their social behavior and communication impairment [26]. The authors emphasized the potential influence of an extra X and/or Y chromosome for development of autism-like features. Ross et al. (2009) contrasting the cognitive phenotypes in 21 boys with 47,XYY karyotype and 93 boys with 47,XXY karyotype (KS) found more severe and pervasive language impairment in boys with XYY and greater motor impairment in gross motor function and coordination in boys with KS [19]. In contrast with the study of Jamain et al., Serajee et al. (2009) found significant differences in Yhaplotype analysis between 146 autistic participants and 102 control participants, suggesting a Y chromosome effect in autism [20]. Leggett (2010) has reviewed the neurodevelopmental characteristics of individuals with sex chromosome trisomies (SCTs), XXX, XXY, and XYY, and concluded that individuals with SCTs are at risk of cognitive and behavioral difficulties [15]. In particular, males with XYY had normal-range IQs but had marked difficulties in speech and language, motor skills, and educational achievement. Cashion and Van Roden (2011) reported a case of Asperger's disorder in an adolescent with 47,XYY chromosomal syndrome [6]. Bishop et al. (2011) made diagnosis of ASD in 11 out of 58 patients with XYY (19 %) and 2 out of 19 cases of XXY (11 %) [3]. The authors hypothesized that not only the X-linked neuroligin but also the Y-linked neuroligin may play a significant role in the etiology of communication impairments and ASD. Bishop and Scerif (2011) remarked this hypothesis noting that different SCTs, XXX and XYY share with XXY (KS) a tendency to have problems with language and communication [2]. This tendency could imply that the phenotype is affected by genes on the X chromosome which escape inactivation and have a homologue on the Y chromosome. Ross et al. (2012) investigated the behavioral and social phenotypes including a screen for autistic behaviors in 26 boys with 47, XYY syndrome and 82 boys with KS, showing that 50 and 12 % of the XYYand KS groups, respectively, had scores >15 for autism screening from the Social Communication Questionnaire [18]. Cordeiro et al. (2012) compared social skills in three groups of males with sex chromosomal aneuploidy using the Social Responsiveness Scale (SRS) [7]. XXY patients had lower (better) SRS scores compared to XYY and XXYY patients. Scores were not significantly different between XYY and XXYY. The authors suggest that an additional Y chromosome may contribute to increased risk of autistic behaviors. In a cohort of 13 children prenatally diagnosed with 47, XYY, language delay was detected in 8 out of

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11 children older than 20 months of age. In one of these patients, the particular relationship difficulties might suggest a pervasive developmental disorder [13]. Bryant et al. (2012) measured autism diagnostic criteria in eight males with XYY syndrome and in 31 males with KS using the SRS and the ADI-R [5]. In five out of eight males with XYY syndrome, the SRS score exceeded the cut-off for a likely diagnosis of ASD. In three out of eight males with XYY syndrome, the ADI-R score met the cut-off for ASD diagnosis; in another two, ADIR scores within the social and communication domains met the cut-off values for a diagnosis of ASD. The authors also examined the brain structure of these patients, showing that total white and gray matter volumes were significantly, or nearly significantly, higher in males with XYY syndrome than in males belonging to the KS group. The authors suggest that there is a relationship between Y chromosome gene dosage and the increased brain matter volumes, a finding putatively related to the increased frequency of ASDs in individuals with this condition. Lee et al. (2012) showed that both supernumerary X and Y chromosomes were related to depressed structural and pragmatic language skills and increased autistic traits. In particular, the addition of a Y chromosome had a disproportionately greater impact on pragmatic language; so

they suggested that X/Y aneuploidies may provide clues to genetic mechanisms contributing to idiopathic language impairment and autism spectrum disorders [14]. Based on the study of Lee, Bishop (2012) suggested that the higher rate of criminality among XYY males found in old studies [4] may be related to deficits in social communication and interpersonal skills, rather than unnatural levels of aggression. Instead, Stochholm et al. suggest that the overall risk of conviction was moderately increased in men with 47,XYY or KS; however, it was similar to controls when adjusting for socioeconomic parameters. The authors concluded that the increased risk of convictions may be partly or fully explained by the poor socioeconomic conditions related to the chromosome aberrations [23]. Furthermore, Bishop suggested that we must be cautious in interpreting findings based on cases where an unusual karyotype only comes to light when a child is investigated for behavior problems, although all recent studies have found evidence of an increase in autistic features in boys with XYY identified prenatally, where ascertainment bias is unlikely to account for associations with developmental difficulties [4]. However, all these studies are hampered also by severe ascertainment bias because 47,XYY syndrome is quite rare

Fig. 1 Possible effect of an extra Y chromosome on brain and neurocognitive development

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(about 1 in 1,000 live male births), no discernible clinical phenotype is present [21] and is rarely diagnosed. In fact, Stochholm et al. [22] documented that only 14 per 100,000 males were diagnosed in Denmark, emphasizing that significant under-diagnosis is present for all sex chromosome aberrations and despite conventional thinking that 47,XYY is a diagnosis made by pediatricians, the average age at diagnosis was 17 years with a wide age range [21]. In agreement with these authors, we suggest that similar patterns of diagnosis may be present in other countries. In conclusion, the association between ASD and XYY karyotype should prompt to look on the effects of an extra Y chromosome on brain and neurocognitive development. It is hypothesized that the Y chromosome susceptibility genes, probably the neuroligin as suggested by Bishop et al. [3], could lead to communication impairments and ASD (Fig. 1) and could explain the predisposition of males to these disorders. Few studies reported a well-defined autism diagnostic category associated with an extra Y chromosome. The majority of the literature studies detected an association between numerical sex chromosome abnormalities and several clinical conditions that are generically described as language and social impairment but that may presumably fall within milddegree ASD. The behavioral phenotypes of our case reports (with prevalent impairment in social interaction and communication) are in agreement with this hypothesis suggesting that mild degree ASD may be typical form of autism associated with XYY syndrome. For this reason, we suggest to screen all with autistic features for 47, XYY. However, more detailed clinical studies are necessary to confirm this hypothesis.

Conflict of interest None of the authors have a conflict of interest, financial or otherwise, directly or indirectly related to this work

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