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Autism in two females with duplications involving Xp11.22-p11.23

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We present two phenotypically similar females with Xp duplication who have autism and epilepsy. Case 1 is a 14-year-old Honduran female with autism and medically refractory complex partial, secondarily generalized epilepsy. Case 2 is a 3-year-old
  Autism in two females with duplications involving Xp11.22–p11.23 ANNA C EDENS 1   MICHAEL J LYONS 2   REYNA M DURON 3   BARBARA R DUPONT 2   KENTON R HOLDEN 2,4 1  College of Medicine, Medical University of South Carolina, Charleston, SC, USA.  2  Greenwood Genetic Center, Greenwood, SC, USA.  3  Neurosurgery Training Program,National Autonomous University of Honduras, Tegucigalpa, Honduras.  4  Departments of Neurosciences (Neurology) and Pediatrics, Medical University of South Carolina,Charleston, SC, USA. Correspondence to Anna C Edens at the Greenwood Genetic Center – Charleston Office, c  ⁄    o Michael J Lyons, 3520 West Montague Avenue, Suite 104, North Charleston, SC 29418, USA. PUBLICATION DATA Accepted for publication 26th November 2010.Published online. We present two phenotypically similar femaleswithXpduplication who have autismandepilepsy.Case 1 is a 14-year-old Honduran female with autism and medicallyrefractory complexpartial,secondarilygeneralized epilepsy. Case 2 is a 3-year-old Austrian female with autism and medicallyrefractory complex partialepilepsy. Both patientsalso share features ofsevere intellectualdisabil-ity (case 1 has a developmentalquotient of 23,case 2 has a developmental quotient of 42)anddysmorphic facial features. Autism was confirmed by thorough clinical evaluations and testing.Case 1 has a karyotype of 46,X,dup(X)(p11.2–p22.33)and a highly skewed X-inactivation pattern(94:6).Brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were abnormal.Case 2 has a 5-megabase duplication of Xp11.22–p11.23 on chromosome microarray analysis. Thepatient has a random X-inactivation pattern (77:23). Brain MRIwas normal,but EEG wasabnormal. Bothpatientshaveduplications involving the Xp11.22–p11.23region, indicating thatthis is an area of interest for future translationalautism research. Duplications of Xp without translocations or other largerearrangements are rare. There have been 23 previously reported females with duplications of part of the p arm of the X chromosome. 1–12 Prominent phenotypic findings in affectedfemales with Xp duplications are short stature, facial anoma-lies, and generalized muscular hypotonia. 2 Females withpartial Xp duplications have been reported with moderate tosevere intellectual disability and seizures, but the extent of neurological presentations has not always been fully described. 5–8  A recent report described a recurrent duplicationof Xp11.22–p11.23 associated with intellectual disability,electroencephalogram (EEG) abnormalities, and epilepsy. 12  There has only been one previous description of an autismspectrum disorder (ASD) in a female with a duplication of Xp. This was a brief report of a female with a duplication of  Xp11.22–p11.23 from a study of individuals with ASDs. 10  We describe two females with duplications of Xp that involve Xp11.22–p11.23. These cases confirm the associationof abnormal EEGs and epilepsy with duplications involving Xp11.22–p11.23. In addition, both patients have autismconfirmed by clinical evaluation and testing, indicating that individuals with duplications involving Xp11.22–p11.23appear to be at an increased risk for ASDs and that this is anarea of interest for translational autism research. Consent forthe publication of these reports was obtained from thepatients’ parents   ⁄   caregivers. CASE REPORTSCase 1  A 14-year-old Hispanic female was evaluated in Honduras,Central America, for autism with severe intellectual disability and medically refractory complex partial, secondarily general-ized epilepsy by one of the authors (KRH; Fig. 1). She was thesecond of three siblings born to healthy, non-consanguineousparents following a normal 40-week pregnancy, home labour,and vaginal delivery. Her birthweight was 3.6kg. The patient has an unaffected older sister and younger brother.She clinically demonstrated abnormalities in social interac-tion, communication, and behavior patterns; therefore weassessed her for autism. The patient displayed abnormal scoreson the Modified Checklist for Autism in Toddlers in Spanish,and the Autism Diagnostic Interview–Revised. She had a nor-mal score on the Pediatric Symptom Checklist in Spanish, which indicated her behaviors were unlikely to be related to anadditional underlying psychiatric disorder. She walked at 3 years. At age 14 years she used 10 to 20 single words orrarely, two-word phrases. She had no formal schooling or his-tory of special education services. She scribbles but is unableto write words. Her Social Communication Questionnaire –Spanish and Developmental Assessment of Young Childrenevaluations were at or below a developmental quotient of 23(range 10–23) with age equivalents at or below 43 months(range 18–43mo). ª  The Authors. Developmental Medicine & Child Neurology  ª  2011 Mac Keith Press DOI: 10.1111/j.1469-8749.2010.03909.x  1 DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY CASE REPORT  Seizures started at 7 months of age. They were tonic–clonic, had focal and generalized onset, often involving one orboth arms, with or without walking motions, lip smacking, orabsence. Typically, she screamed, her right arm and left leg were extended, her left arm and right leg were not involved, while her head and eyes deviated to the left. Seizures couldoccurdaily,weekly,orremitforaslongas1 monthonantiepi-lepticdrugs.Treatedforyearswithmultipleantiepilepticmed-ications,her seizuresarecurrentlywellcontrolledonvalproateandtopiramate,andherEEGhasrecentlynormalized.Her previously abnormal EEGs have displayed two distinct  wave patterns of isolated or 2–3Hz bursts of irregular spike- wave complexes with moderate disorganization of backgroundactivity (Fig. S1a,b, published online only). Brain magneticresonance imaging (MRI) performed in Honduras revealedabnormal signal and thickening of the cerebral cortex of theright greater than the left mesiotemporal lobes, suggestingcortical dysplasia and correlating with the abnormal EEG.On examination, head circumference was 55.5cm (75th cen-tile), weight was 66kg (90th centile), and height was 139.5cm(<3rd centile, 50th centile for a 10-year-old). She has distinct facial dysmorphism with a broad face, midface hypoplasia,prominent forehead, widely spaced eyes, coarse facial features,and eczema. Neurological examination revealed severe intel-lectual disability, aloofness, repetitive page-flipping, but nocranialnerve, cerebellar, motor, or sensory deficits.Initial high-resolution karyotype studies of peripheral bloodlymphocytes revealed an inverted duplication involving theshort arm of the X chromosome between bands Xp11.2 and Xp22.3. A copy gain of Xp11.2–p22.33 (55 megabase [Mb])and loss of Xp22.33 (0.45Mb, including the  SHOX   gene) were detected by targeted chromosome microarray analysis(Fig. S2). Raised by her paternal grandmother, the parents were unavailable for study. X-inactivation studies revealed ahighly skewed pattern (94:6). Plasma amino acids werenormal. Fluorescence in situ hybridization for chromosome15 microdeletion (Angelman syndrome) was negative. Case 2  A 3-year-old Austrian female was evaluated for neurodevelop-mental delay, epilepsy, and hypotonia by one of the authors(MJL; Fig. 2). She is the second child born to a 36-year-oldmother at 39 weeks’ gestation. She was delivered at home by spontaneous vaginal delivery without complications. Birth- weight was 3.7kg. There is no consanguinity, and the patient has a healthy older brother. The patient sat at 11 months of age, crawled at 15 months,and walked at 34 months. She is non-verbal but can sign‘more’ and follow some two-step directions. Autism was diag-nosed at 3 years of age. Clinical evaluation and testing con-firmed criteria for autism including abnormal SocialCommunication Questionnaire and Autism Diagnostic Obser- vation Schedule scores. She displayed constant abnormalitiesin sensory integration, social interactions, communication,and behavior. The Developmental Profile II, Cognitive Apti-tude Test, and Clinical Linguistic and Auditory MilestoneScale were at or below a developmental quotient of 42 (range29–42). She would not be cuddled, and her parents describedher as a ‘loner’.Seizures started at 6 months of age with a 7- to 10-minutegeneralized tonic–clonic seizures that self-resolved. Pheno-barbital initially improved her seizure control, but relapsescaused the medication to be changed to levetiracetam andlamotrigine. Currently, her medically refractory complexpartial seizures with and without secondary generalization,occur two times per month, typically in the morning and last less than 5 minutes. A gluten-free diet trial and a ketogenic,diet trial were not beneficial. Head computed tomography,brain MRI, and EEG performed at 6 months of age were nor-mal. At 2 years of age, EEG indicated right temporal–occipitalslowing with sharp and spike-wave discharges (Fig. S3). At 3 years, her head circumference was 46.2cm (<3rd cen-tile, 50th centile for an 18-month-old), weight was 15.2kg(50th centile), and height was 90.1cm (third centile). Distinct facial features included cupped ears with normal position,hooded appearance to the eyes, thick eyebrows, synophrys,long eyelashes, tubular nose, widely spaced teeth, prominent maxilla, and thin upper lip. Neurological examination revealed Figure 1:  Case 1, demonstrating the described dysmorphic facial features. Figure 2:  Case 2, demonstrating the described dysmorphic facialfeatures. What this paper adds •  Duplications of Xp are associated with autism as well as dysmorphic features,intellectual disability, and epilepsy. •  The Xp11.22–p11.23 region is an area of interest for translational autismresearch. 2  Developmental Medicine & Child Neurology   2011  severe intellectual disability, mild generalized hypotonia, but no cranial nerve, cerebellar, motor, or sensory deficits.She had normal high-resolution chromosome analysis, test-ing for Angelman and Rett syndrome, and metabolic studies.Chromosome microarray analysis revealed a duplication of  Xp11.22–p11.23 (5Mb), which was confirmed by fluorescencein situ hybridization (Fig. S4). Parental studies were normal. X-inactivation studies revealed a random pattern (77:23). DISCUSSION  We present two cases of Xp duplication, one involving most of the short arm (case 1), and one involving a narrower region Table I:  Comparison of 23 reported cases of females with Xp duplications with the two new cases ReportChromosomeabnormality ID   ⁄   NDD Autism Epilepsy EEG Cranial CT, MRI X-inactivationDeng et al. 1 dupXp(p11.4–p22.1)+ NR NR NR NR NRWyandt et al. 7 dupXp21–22.1 Normal NR + GeneralizedsharpparoxysmaldischargesCT: normal Late-replicatingTuck-Mulleret al.; 6 case 1dic inv dup (X)(qter fi p22.3::p22.3 fi cen:)+ NR + NR NR (89:11)Tuck-Mulleret al.; 6 case 2dic inv dup (X)(qter fi p22.3::p22.3 fi cen:)+ NR + NR NR (100:0)Zhang et al. 9 dup(X)(qter fi q21.3::p22.33 fi p22.32::p22.32 fi qter)+ NR NR NR NR Late-replicatingMatsuo et al. 3 dupXp11.21–p21.3+ NR NR Normal CT: normal (71:29)Portnoi et al. 5 dupXp11–21.2 Death at2 monthsNA + R parietalepilepticfocusMRI: Diffuse hypo-myelination, R>L perisylvianand opercular polymicrogyri(53:47)Kokalj-Vokac et al. 2 dupXp11.23–22.33+ NR NR NR NR Late-replicatingFroyen et al. 11 dupXp11.23 + ‘Autisticfeatures’NR NR NR (71:29)Monnot et al. 4 dupXp11.23–p11.4+ NR NR NR MRI: thin central corpuscallosum(68:32)Marshall et al. 10 dupXp11.22–p11.23+ + NR NR NR NRGiorda et al. 12 (11 females)dupXp11.22–p11.23+ (9),NR (2)NR (11) + (4); ) (1);NR (6)+ (6) Diffuseand focalRolandicparoxysmaldischargesawake   ⁄   typicalCSWS sleep; ) (3) NR (2)MRI: subarachnoid spacedilation (1),peritrigonalhyperintensity (1),normal (2),NR (7)Skewed (7),random (3),inconclusive (1)Zou and Milunsky 8 dupXp11.3–p11.4+ NR Two tonic–clonicseizures atage 6 and7 yearAbnormal slowbackgroundwith a diffuseirregularpattern; nospike   ⁄   waveactivityMRI: normal with prominentVirchow–Robin spacesRandom (58:42)Present Case1 dupXp22.3p11.2 + + + L frontaltypical   ⁄   atypicalspike-wavedischargesMRI: R mesio-temporalsclerosis(94:6)Present Case2 dupXp11.22-p11.23+ + + R temporal-occipitalslowingwith sharpandspike-wavedischargesMRI: normal (77:26)ID   ⁄   NDD, intellectual disability   ⁄   neurodevelopmental disabilities; EEG, electroencephalography; CT, computed tomography; MRI, magneticresonance imaging; NR, not recorded in previous publication; NA, not applicable; R, right; L, left; CSWS, continuous spike waves during slow-wavesleep. Case Report  3  (case 2). Both patients presented with autism, epilepsy, dys-morphic facial features, and intellectual disability. Case 1 alsohas a deletion of Xp22.33 involving the  SHOX   gene, whichprobably contributes to her short stature. The non-autisticclinical features in our cases overlap with the 12 previously reported affected females with Xp duplications and the 11females with a recurrent duplication of Xp11.22–p11.23 (see Table I). There is some overlap between the EEG findings inour patients and those previously described, but our patientsdid not demonstrate continuous spike-waves during slow-wavesleep pattern 12 (Table I). The identification of two females with autism from different ethnic backgrounds with duplications involving Xp11.22–p11.23 indicates that this chromosomal location may harbor agene or genes predisposing to ASDs. For example,  GRIPAP1 is a gene located at Xp11.23 that encodes the GRASP1protein. Overexpression of GRASP1 decreases targeting of  a -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA) receptors to the synapse. 13  The density of AMPA-type receptors is decreased in individuals with autism. 14  As aresult, autism in females with duplications involving Xp11.22–p11.23 may be related to overexpression of GRASP1 if   GRI-PAP1  is duplicated, as in both of our cases.In addition, the more centromeric Xp11.2 region is rich with critical genes for neurodevelopmental disorders and hasbeen proposed to harbour genetic candidates for autism sus-ceptibility, as males with autism have been reported to havemicrodeletions of the  FAM120C   and  WNK3  genes in a regionoverlapping with our duplication in case 1. 15 Females with duplications of the X chromosome are oftenclinically unaffected because the abnormal X is preferentially inactivated. 3,5,7,12 However, six of nine females with a recur-rent duplication of Xp11.22–p11.23 had preferential inactiva-tion of the normal X chromosome. 12 In females, functionaldisomy of one or more genes in the Xp11.22–p11.23 regionmay provide a selective advantage to those cells with an activeabnormal X chromosome. 12  Although testing to determine which X chromosome is inactivated was not done for either of our cases, preferential activation of the abnormal X chromo-some owing to involvement of the Xp11.22–p11.23 region would be expected to result in the clinical features seen in ourpatients. We describe two females with duplications of Xp who haveautism. The large duplicated area of Xp involved in case 1could explain her severe phenotype. The smaller Xp11.22–p11.23 duplication in case 2 overlaps with the Xp duplicationin case 1 and may help to narrow the area of interest forautism and epilepsy susceptibility to genes in this region. Asresearch on the genetic contributions to autism grows, thisinformation can provide additional candidate genes for ASDs. ACKNOWLEDGEMENTS  We acknowledge the assistance of Cindy Skinner (samples coordi-nator, Greenwood Genetic Center, Greenwood, SC, USA), JeanethBu (neuroradiologist, Tegucigalpa, Honduras), Maria G Matheus(neuroradiologist, Medical University of South Carolina, Charleston,SC, USA), and Lucia T Horowitz (clinical psychologist, GreenwoodGenetic Center, Greenwood, SC, USA). ONLINE MATERIAL  ⁄    SUPPORTING INFORMATION  Additional material and supporting information may be found in theonline version of this article. REFERENCES 1.  Deng HX, Xia JH, Ishikawa M, Niikawa N. Parental srcinand mechanism of formation of X chromosome structuralabnormalities: four cases determined with RFLPs.  Jinrui  Idengaku Zasshi   1990;  35:  245–51. 2.  Kokalj Vokac N, Seme Ciglenecki P, Erjavec A, Zagradis-nik B, Zagorac A. Partial Xp duplication in a girl withdysmorphic features: the change in replication pattern of late-replicating dupX chromosome.  Clin Genet   2002;  61: 54–61. 3.  Matsuo M, Muroya K, Kosaki K, et al. Random X-inactiva-tion in a girl with duplication Xp11.21–p21.3: report of apatient and review of the literature.  Am J Med Genet   1999; 86:  44–50. 4.  Monnot S, Giuliano F, Massol C, et al. Partial Xp11.23–p11.4 duplication with random X inactivation: clinical report and molecular cytogenetic characterization.  Am J Med Genet  A  2008;  146:  1325–9. 5.  Portnoi MF, Bouayed-Abdelmoula N, Mirc M, et al. 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