- Email: [email protected]
A de novo 3.57 Mb microdeletion in 8q12.3q13.2 in a patient with mild intellectual disability and epilepsy
European Journal of Medical Genetics 55 (2012) 358e361
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Original article
A de novo 3.57 Mb microdeletion in 8q12.3q13.2 in a patient with mild intellectual disability and epilepsy Willem M.A. Verhoeven a, b, *, Jos I.M. Egger a, c, d, Ilse Feenstra e, Nicole de Leeuw e a
Centre of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, The Netherlands Department of Psychiatry, Erasmus University Medical Centre, Rotterdam, The Netherlands c Donders Institute for Brain, Cognition and Behaviour, Centre for Cognition, Radboud University Nijmegen, Nijmegen, The Netherlands d Behavioural Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands e Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 September 2011 Accepted 22 October 2011 Available online 27 November 2011
A female patient, nine years of age, is reported with a history characterized by delay of psychomotor and speech development, mild to moderate intellectual disability and persistent sleep disturbances since the age of two. The patient showed facial dysmorphisms, a pectus excavatum and a sandal gap. Apart from lowered intelligence, neuropsychological functioning disclosed impaired attentional capacities and executive control as well as weak motor skills. Genome wide SNP array analysis revealed a 3.57 Mb de novo microdeletion in band q12.3 of chromosome 8. The long lasting sleep disorders turned out to originate from a rare juvenile epilepsy, continuous spike-waves during slow sleep (CSWS) syndrome, that includes the electrical status epilepticus in sleep (ESES) phenomenon. MRI-scanning of the brain showed no abnormalities. To the authors knowledge, this is the first report of a de novo 8q12.3q13.2 microdeletion syndrome that presents with ESES/CSWS. Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords: SNP array De novo microdeletion 8q12.3q13.2 Intellectual disability Dysmorphic features Neuropsychological dysfunction Epilepsy ESES CSWS
1. Methods of detection 1.1. Cytogenetics Chromosome analysis was performed on GTG-banded chromosomes (550 band-level) from cultured peripheral blood lymphocytes according to standard methods. 1.2. Genome wide SNP array analysis Array analysis with an average genome wide resolution of w200 kb was performed using the Affymetrix 250k SNP array platform, following the protocols provided by the manufacturers (Affymetrix Inc., Santa Clara, CA, USA). Copy number estimates
* Corresponding author. Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Stationsweg 46, 5803AC Venray, The Netherlands. Tel.: þ31 478527339; fax: þ31 478527110. E-mail addresses: [email protected], [email protected] (W.M.A. Verhoeven). 1769-7212/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2011.10.005
were determined using the updated version 2.0 of the CNAG (Copy Number Analyzer for Affymetrix GeneChip mapping) software package [1] and data analysis and interpretation were performed as previously described [2]. 1.3. Chromosomal anomaly Conventional cytogenetic analyses revealed a normal female karyotype. Subsequent SNP array analysis revealed a 3.57 Mb interstitial deletion: arr 8q12.3q13.2 (65,236,018e68,801,113) 1 (Human (GRCh37/hg19) Assembly). This region encompasses 27 known coding genes (Fig. 1). 1.4. Causative of the phenotype Carrier testing in the parents with 250k SNP array analysis resulted in normal outcomes and showed that the 8q12.3q13.2 microdeletion had occurred de novo in their child. At this moment, no similar losses (or gains) have been reported in control individuals (Database of Genomic Variants; http://projects.tcag.ca/variation).
W.M.A. Verhoeven et al. / European Journal of Medical Genetics 55 (2012) 358e361
359
Fig. 1. A. log2 intensity ratios of the SNP probes on chromosome 8 obtained with 250k SNP array analysis, showing the interstitial microdeletion in 8q12.3q13.2 (arr 8q12.3q13.2(65,236,018e68,801,113) 1 dn) detected by significantly lowered values of 221 consecutive probes. B. Screen shot of the UCSC Genome Browser (http://genome. ucsc.edu/; Human Genome, February 2009 (GRCh37/hg19) assembly) showing the deleted region 8q12.3q13.2 encompassing a total of 27 coding genes, including one known recessive disease gene CYP7B1 in 8q12.3.
2. Clinical description The patient, a 9-year-old female, was the second child of healthy, non-consanguineous parents of Caucasian origin. At birth, the mother was 32 years old and the father was aged 46. She had a younger brother and two older half sisters, who were all healthy and had a normal development. There was no family history of developmental delay, congenital anomalies or psychiatric disorders. A female second cousin from father had probably suffered from epilepsy during early childhood. She was born at 39 weeks of gestation after an uncomplicated pregnancy and had a birth weight of 3,980 g (>þ2 SD). No congenital anomalies were detected. During the first year, she had hypotonia and recurrent upper airway infections. There were no feeding problems or sleep disturbances. Since the patient could not walk independently until the age of 24 months and development of speech was also delayed, her parents expressed their doubts about her psychomotor development. Consequently, she was referred to a child neurologist who found slight hypotonia and clumsy motor functioning. Etiologic investigation including karyotyping, laboratory analyses for metabolic disorders, and MRI-scanning of the brain, did not show any abnormalities. Aged three years, sleep
disturbances became prominent. In addition, visual impairment was suspected and hypermetropia was diagnosed with a vision of þ8 dioptres bilaterally. From the age of four until six, the patient stayed in a medical day-care facility. In the beginning of this period, a developmental age of 2; 2 years (calendar age: 4; 3 years) was established by means of the Bayley scales [3]. In addition, problematic social and communicative skills with inadequate emotional reactivity and lack of peer interaction, impaired receptive language capacities as well as disinhibited and mild ritualistic behaviours (e.g., opening/closing doors and locks) were present. For all these reasons, she was referred to a specialized outpatient facility for child psychiatry at the age of six years. A mild intellectual disability (SON-R [4]: total IQ: 52, verbal and performal IQ: 57) was established as well as diminished eye contact, reduced attention span, and a restricted social repertoire with frequent misinterpretations. A preliminary diagnosis of atypical pervasive developmental disorder was made. Subsequently, treatment with methylphenidate was started. One year later, the patient was examined in a sleep clinic because of persistent and family unsettling sleep disorders. No formal sleep disorder could be diagnosed and treatment with melatonin was
360
W.M.A. Verhoeven et al. / European Journal of Medical Genetics 55 (2012) 358e361
started. In the following two years, challenging behaviours and sleep disturbances intensified with consequently more need for additional specialized support. At the age of nine, the patient was still treated with 18 mg longacting methylphenidate, 5 mg methylphenidate twice daily, and 3 mg melatonin. Physical examination disclosed a normal height and weight of 134 cm and 32.4 kg respectively (both <1 SD) and a head circumference of 55.5 cm (>þ2 SD). Speech was slightly nasal. The patient showed several dysmorphic features including hypertelorism, downslanting palpebral fissures, a long, pear shaped nose, and low-set, posteriorly rotated ears. Furthermore, bilateral flat feet and a sandal gap were present (Fig. 2). Apart from mild right convex thoracic scoliosis and pectus excavatum, no somatic or neurological abnormalities could be found. Extensive neuropsychological assessment using among others the Snijders-Oomen Nonverbal intelligence test (SON-R [4]), the Revised Amsterdam Children Intelligence Test (RAKIT [5]), and the Beery-Buktenica Developmental Test of Visual-Motor Integration [6], disclosed a mild to moderate intellectual disability (total IQ: 51; similar to the findings at the age of six) and a language development equivalent to the age of 4; 2 years. In addition, impaired inhibitory control and executive functioning were found. Relative to her intellectual capacities, memory performance was strong whereas attention and motor skills were weak. As to social cognition, emotion recognition was undisturbed. Mild anxieties and avoidance behaviours were noticed that, however, appeared to be secondary to her lowered intelligence and to overestimation of social skills by others. Six months later, unexpectedly, a nocturnal tonic-clonic seizure occurred with complete loss of consciousness for 10e15 min, tongue bruising due to jaw contractions, and postictal vomiting. Subsequent MRI-scanning of the brain disclosed no abnormalities. EEG-recording, however, demonstrated frequent epileptiform activity centroparietal bilaterally with marked increase during sleep. In fact, in about 60e70 percent of the sleep, spike-wave discharges were observed without clinical manifestations of epilepsy. A provisional diagnosis of electrical status epilepticus in
sleep (ESES) was made. Treatment with 5 mg clobazam ante noctem was started. Until now, at the age of almost ten years, severe sleep disturbances and behavioural problems persist. 3. Discussion Here, a 9-year-old female is described with a de novo microdeletion of 3.57 Mb in 8q12.3q13.2. She presented with a clinical phenotype comprising several dysmorphisms, psychomotor developmental delay, mild to moderate intellectual disability and marked sleep disturbances. In addition, this microdeletion syndrome might include a rare childhood epileptic encephalopathy (ESES), because it became apparent, retrospectively, that there had been signs of nocturnal seizures since the age of two years. More specifically, her disrupted sleep pattern was re-interpreted as short episodes with reduced awareness and muscle twitches of the arms and legs. Review of the current literature and available online databases like DECIPHER (http://decipher.sanger.ac.uk/ [7];) and ECARUCA (http://www.ecaruca.net [8];) does not provide any reports about a comparable microdeletion syndrome. Only three other patients with an (partially) overlapping and cytogenetically visible deletion have been reported [9e11]. These patients presented with neonatal hypotonia, developmental delay and some of them had minor somatic dysmorphisms and/or congenital anomalies. The clinical features of these three patients that are in common with those observed in our patient, include intellectual disability (2/3), short neck (1/3), and recurrent infections (1/3). Epilepsy was not reported as a clinical feature in any of these patients. As to the ESES-electroencephalographic (EEG) pattern, it should be noticed that this can be observed in continuous spike-waves during slow sleep (CSWS) syndrome, benign childhood epilepsy with centrotemporal spikes (BCECTS) and Landau-Kleffner syndrome (LKS) [12-14]. LKS is a rare disorder with acquired aphasia [15,16]. Some evidence is available on susceptibility genes for these epilepsy syndromes, i.e., SRPX2 (Xq22) and ELP4
Fig. 2. Female patient at the age of 9 1/6 years, presenting several characteristic facial features including hypertelorism, downslanting palpebral fissures, a long, pear shaped nose, low-set, posteriorly rotated ears, and a full lower lip. The extremities show a bilateral sandal gap and flat feet.
W.M.A. Verhoeven et al. / European Journal of Medical Genetics 55 (2012) 358e361
(16p11p12) [13] and GRIN2A (16p13) [17]. In about half of the patients with ESES, MRI-scanning of the brain does not display any structural abnormalities [18]. In general, conventional antiepileptics seem to play only a minimal role in the treatment of ESES/CSWS [12,14], while nowadays sulthiame seems to be the most appropriate agent [19,20]. Amongst the 27 genes in the deleted region, only one recessive disease gene, CYP7B1, is known which encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum membrane protein catalyzes the first reaction in the cholesterol catabolic pathway of extrahepatic tissues and converts cholesterol to bile acids. It likely plays a minor role in total bile acid synthesis, but may, however, be involved in the development of atherosclerosis, neurosteroid metabolism and sex hormone synthesis. Although a possible mutated recessive disease gene on the other allele could not be excluded, gene mutation analysis was not performed since the clinical phenotype of the present patient did not match with either two disease phenotypes that are associated with CYP7B1, i.e., Congenital bile acid synthesis defect 3 (phenotype 613812 (3)) and Spastic paraplegia-5A (phenotype 270800 (3)), respectively. Based on the genotype information obtained from the SNP arrays from the patient and her parents, the paternal allele of 8q12.3q13.2 turned out to be deleted. At present, however, this region does not seem to contain any imprinted genes. Given the patient’s profile of neuropsychological dysfunction, it was advised to avoid overestimation of cognitive and language capacities, and to use educational and learning strategies based on modelling rather than on verbal instruction. Pharmacological treatment was kept unchanged and regular follow-up to monitor developmental processes by means of repeated neuropsychological assessments was planned. In conclusion, the combination of the specific EEG pattern, neuropsychological dysfunction, impaired language and motor skills, suggests ESES/CSWS to be the most appropriate epilepsy diagnosis in the here reported patient. Consequently, this de novo 8q12.3q13.2 microdeletion syndrome may be associated with ESES/ CSWS. 4. Note Because of non-responsiveness to clobazam, this compound was discontinued and replaced for the anti-epileptic sulthiame (150 mg daily) upon which the patient’s sleep pattern markedly improved. 5. Dissemination of information The case has been submitted to the ECARUCA database (http:// www.ecaruca.net) with identification number 4790. Acknowledgements This study is part of a collaborative project of the research group ‘Psychopathology and Genetics’ of the Radboud University Nijmegen and the Vincent van Gogh Institute for Psychiatry, Venray, the Netherlands. The authors are indebted to the patients and her parents for their cooperation. Written informed consent was obtained from the parents for printing the pictures of the patient. Epilepsy diagnosis and treatment was performed
361
by Mrs. E.A.J Peeters and Mrs. I.N. Snoeck, child neurologists at the Haga Hospital in The Hague, the Netherlands. References [1] Y. Nannya, M. Sanada, K. Nakazaki, N. Hosoya, L. Wang, A. Hangaishi, M. Kurokawa, S. Chiba, D.K. Bailey, G.C. Kennedy, S. Ogawa, A robust algorithm for copy number detection using high-density oligonucleotide singlenucleotide polymorphism genotyping arrays, Cancer Res. 65 (2005) 6071e6079. [2] N. de Leeuw, J.Y. Hehir-Kwa, A. Simons, A.H.M. Geurts van Kessel, D.F.C.M. Smeets, B.H.W. Faas, and R. Pfundt, SNP array analysis in constitutional and cancer genome diagnostics e copy number variants, Genotyping Qual. Control. Cytogen Gen. Res. (2011) [Epub ahead of print]. [3] M.M. Black, K. Matula, Essentials of Bayley Scales of Infant Development II Assessment, John Wiley, New York, 1999. [4] P.J. Tellegen, M. Winkel, B.J. Wijnberg-Williams, J.A. Laros, Snijders-Oomen nonverbal intelligence test manual, Swets and Zeitlinger (1998) (Lisse). [5] N. Bleichrodt, P.J.D. Drenth, J.N. Zaal, W.C.M. Resing, RAKIT (Revised Amsterdam Children Intelligence Test), Pearson, Amsterdam, 1987. [6] K.E. Beery, N.A. Buktenica, N.A. Beery, The Beery-Buktenica Developmental Test of Visual-Motor Integration Beery VMI, fifth ed. Pearson, Sant Antonio, Texas, 2004. [7] H.V. Firth, S.M. Richards, A.P. Bevan, S. Clayton, M. Corpas, D. Rajan, S. Van Vooren, Y. Moreau, R.M. Pettett, N.P. Carter, DECIPHER: database of chromosomal imbalance and phenotype in humans using ensembl resources, Am. J. Hum. Genet. 4 (2009) 524e533. [8] I. Feenstra, J. Fang, D.A. Koolen, A. Siezen, C. Evans, R.M. Winter, M.M. Lees, M. Riegel, B.B.A. de Vries, C.M.A. van Ravenswaay, A. Schinzel, European cytogenetics association register of unbalanced chromosome aberrations (ECARUCA); an online database for rare chromosomal abnormalities, Eur. J. Med. Genet. 49 (2006) 279e291. [9] A.A. Schinzel, W.P. Robinson, F. Binkert, A. Fanconi, An interstitial deletion of proximal 8q (q11-q13) in a girl with Silver-Russell syndrome-like features, Clin. Dysmorphol. 3 (1994) 63e69. [10] C. Vincent, V. Kalatzis, S. Compain, J. Levilliers, R. Slim, F. Graia, M. de LurdesPereira, A. Nivelon, M.F. Croquette, D. Lacombe, J. Vigneron, J. Helias, M. Broyer, D.F. Callen, E.A. Haan, J. Weissenbach, B. Lacroix, C. BellanéChantelot, D. Le Paslier, D. Cohen, C. Petit, A proposed new contiguous gene syndrome on 8q consists of Branchio-Oto-Renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications for the mapping of the BOR gene, Hum. Mol. Genet. 3 (1994) 1859e1866. [11] G. Calabrese, L. Stuppia, E. Morizio, P. Guanciali Franchi, F. Pompetti, R. Mingarelli, T. Marsilio, M. Rocchi, P.E. Gallenga, G. Palka, B. Dallapiccola, Detection of an insertion deletion of region 8q13-q21.2 in a patient with Duane syndrome: implications for mapping and cloning a Duane gene, Eur. J. Hum. Genet. 6 (1998) 187e193. [12] K. Nickels, E. Wirrell, Electrical status epilepticus in sleep, Semin. Pediatr. Neurol. 15 (2008) 59e60. [13] G. Rudolf, M.P. Valeti, E. Hirsch, P. Szepetowski, From rolandic epilepsy to continuous spike-and-waves during sleep and Landau-Kleffner syndromes: insights into possible genetic factors, Epilepsia 50 (Suppl. 7) (2009) 25e28. [14] J.R. Hughes, A review of the relationship between Landau-Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep, Epilepsy Behav. 20 (2011) 247e253. [15] A.S. Galanopoulou, A. Bojko, F. Lado, S.L. Moshé, The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in sleep, Brain Dev. 22 (2000) 279e295. [16] K. McVicar, S. Shinnar, Landau-Kleffner syndrome, electrical status epilepticus in slow wave sleep, and language regression in children, Ment. Retard. Dev. Disabil. Res. Rev. 10 (2004) 144e149. [17] R. Reutlinger, I. Helbig, B. Gawelczyk, J.I.M. Subero, H. Tönnies, H. Muhle, K. Finsterwalder, S. Vermeer, R. Pfundt, J. Sperner, I. Stefanova, G. GillessenKaesbach, S. von Spiczak, A. van Baalen, R. Boor, R. Siebert, U. Stephani, A. Caliebe, Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region, Epilepsia 51 (2010) 1870e1873. [18] M. Van Hirtum-Das, E.A. Licht, S. Koh, J.Y. Wu, W.D. Shields, R. Sankar, Children with ESES: variability in the syndrome, Epilepsy Res. 70S (2006) 248e258. [19] F. Engler, M. Maeder-Ingvar, E. Roulet, T. Deonna, Treatment with sulthiamine (Ospolot) in benign partial epilepsy of childhood and related syndromes: an open clinical and EEG study, Neuropediatrics 34 (2003) 105e109. [20] E. Wirrell, A. Wen-Chi Ho, L. Hamiwka, Sulthiame therapy for continuous spike and wave in slow-wave sleep, Pediatr. Neurol. 35 (2006) 204e208.
Contents lists available at SciVerse ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Original article
A de novo 3.57 Mb microdeletion in 8q12.3q13.2 in a patient with mild intellectual disability and epilepsy Willem M.A. Verhoeven a, b, *, Jos I.M. Egger a, c, d, Ilse Feenstra e, Nicole de Leeuw e a
Centre of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, The Netherlands Department of Psychiatry, Erasmus University Medical Centre, Rotterdam, The Netherlands c Donders Institute for Brain, Cognition and Behaviour, Centre for Cognition, Radboud University Nijmegen, Nijmegen, The Netherlands d Behavioural Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands e Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 September 2011 Accepted 22 October 2011 Available online 27 November 2011
A female patient, nine years of age, is reported with a history characterized by delay of psychomotor and speech development, mild to moderate intellectual disability and persistent sleep disturbances since the age of two. The patient showed facial dysmorphisms, a pectus excavatum and a sandal gap. Apart from lowered intelligence, neuropsychological functioning disclosed impaired attentional capacities and executive control as well as weak motor skills. Genome wide SNP array analysis revealed a 3.57 Mb de novo microdeletion in band q12.3 of chromosome 8. The long lasting sleep disorders turned out to originate from a rare juvenile epilepsy, continuous spike-waves during slow sleep (CSWS) syndrome, that includes the electrical status epilepticus in sleep (ESES) phenomenon. MRI-scanning of the brain showed no abnormalities. To the authors knowledge, this is the first report of a de novo 8q12.3q13.2 microdeletion syndrome that presents with ESES/CSWS. Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords: SNP array De novo microdeletion 8q12.3q13.2 Intellectual disability Dysmorphic features Neuropsychological dysfunction Epilepsy ESES CSWS
1. Methods of detection 1.1. Cytogenetics Chromosome analysis was performed on GTG-banded chromosomes (550 band-level) from cultured peripheral blood lymphocytes according to standard methods. 1.2. Genome wide SNP array analysis Array analysis with an average genome wide resolution of w200 kb was performed using the Affymetrix 250k SNP array platform, following the protocols provided by the manufacturers (Affymetrix Inc., Santa Clara, CA, USA). Copy number estimates
* Corresponding author. Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Stationsweg 46, 5803AC Venray, The Netherlands. Tel.: þ31 478527339; fax: þ31 478527110. E-mail addresses: [email protected], [email protected] (W.M.A. Verhoeven). 1769-7212/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2011.10.005
were determined using the updated version 2.0 of the CNAG (Copy Number Analyzer for Affymetrix GeneChip mapping) software package [1] and data analysis and interpretation were performed as previously described [2]. 1.3. Chromosomal anomaly Conventional cytogenetic analyses revealed a normal female karyotype. Subsequent SNP array analysis revealed a 3.57 Mb interstitial deletion: arr 8q12.3q13.2 (65,236,018e68,801,113) 1 (Human (GRCh37/hg19) Assembly). This region encompasses 27 known coding genes (Fig. 1). 1.4. Causative of the phenotype Carrier testing in the parents with 250k SNP array analysis resulted in normal outcomes and showed that the 8q12.3q13.2 microdeletion had occurred de novo in their child. At this moment, no similar losses (or gains) have been reported in control individuals (Database of Genomic Variants; http://projects.tcag.ca/variation).
W.M.A. Verhoeven et al. / European Journal of Medical Genetics 55 (2012) 358e361
359
Fig. 1. A. log2 intensity ratios of the SNP probes on chromosome 8 obtained with 250k SNP array analysis, showing the interstitial microdeletion in 8q12.3q13.2 (arr 8q12.3q13.2(65,236,018e68,801,113) 1 dn) detected by significantly lowered values of 221 consecutive probes. B. Screen shot of the UCSC Genome Browser (http://genome. ucsc.edu/; Human Genome, February 2009 (GRCh37/hg19) assembly) showing the deleted region 8q12.3q13.2 encompassing a total of 27 coding genes, including one known recessive disease gene CYP7B1 in 8q12.3.
2. Clinical description The patient, a 9-year-old female, was the second child of healthy, non-consanguineous parents of Caucasian origin. At birth, the mother was 32 years old and the father was aged 46. She had a younger brother and two older half sisters, who were all healthy and had a normal development. There was no family history of developmental delay, congenital anomalies or psychiatric disorders. A female second cousin from father had probably suffered from epilepsy during early childhood. She was born at 39 weeks of gestation after an uncomplicated pregnancy and had a birth weight of 3,980 g (>þ2 SD). No congenital anomalies were detected. During the first year, she had hypotonia and recurrent upper airway infections. There were no feeding problems or sleep disturbances. Since the patient could not walk independently until the age of 24 months and development of speech was also delayed, her parents expressed their doubts about her psychomotor development. Consequently, she was referred to a child neurologist who found slight hypotonia and clumsy motor functioning. Etiologic investigation including karyotyping, laboratory analyses for metabolic disorders, and MRI-scanning of the brain, did not show any abnormalities. Aged three years, sleep
disturbances became prominent. In addition, visual impairment was suspected and hypermetropia was diagnosed with a vision of þ8 dioptres bilaterally. From the age of four until six, the patient stayed in a medical day-care facility. In the beginning of this period, a developmental age of 2; 2 years (calendar age: 4; 3 years) was established by means of the Bayley scales [3]. In addition, problematic social and communicative skills with inadequate emotional reactivity and lack of peer interaction, impaired receptive language capacities as well as disinhibited and mild ritualistic behaviours (e.g., opening/closing doors and locks) were present. For all these reasons, she was referred to a specialized outpatient facility for child psychiatry at the age of six years. A mild intellectual disability (SON-R [4]: total IQ: 52, verbal and performal IQ: 57) was established as well as diminished eye contact, reduced attention span, and a restricted social repertoire with frequent misinterpretations. A preliminary diagnosis of atypical pervasive developmental disorder was made. Subsequently, treatment with methylphenidate was started. One year later, the patient was examined in a sleep clinic because of persistent and family unsettling sleep disorders. No formal sleep disorder could be diagnosed and treatment with melatonin was
360
W.M.A. Verhoeven et al. / European Journal of Medical Genetics 55 (2012) 358e361
started. In the following two years, challenging behaviours and sleep disturbances intensified with consequently more need for additional specialized support. At the age of nine, the patient was still treated with 18 mg longacting methylphenidate, 5 mg methylphenidate twice daily, and 3 mg melatonin. Physical examination disclosed a normal height and weight of 134 cm and 32.4 kg respectively (both <1 SD) and a head circumference of 55.5 cm (>þ2 SD). Speech was slightly nasal. The patient showed several dysmorphic features including hypertelorism, downslanting palpebral fissures, a long, pear shaped nose, and low-set, posteriorly rotated ears. Furthermore, bilateral flat feet and a sandal gap were present (Fig. 2). Apart from mild right convex thoracic scoliosis and pectus excavatum, no somatic or neurological abnormalities could be found. Extensive neuropsychological assessment using among others the Snijders-Oomen Nonverbal intelligence test (SON-R [4]), the Revised Amsterdam Children Intelligence Test (RAKIT [5]), and the Beery-Buktenica Developmental Test of Visual-Motor Integration [6], disclosed a mild to moderate intellectual disability (total IQ: 51; similar to the findings at the age of six) and a language development equivalent to the age of 4; 2 years. In addition, impaired inhibitory control and executive functioning were found. Relative to her intellectual capacities, memory performance was strong whereas attention and motor skills were weak. As to social cognition, emotion recognition was undisturbed. Mild anxieties and avoidance behaviours were noticed that, however, appeared to be secondary to her lowered intelligence and to overestimation of social skills by others. Six months later, unexpectedly, a nocturnal tonic-clonic seizure occurred with complete loss of consciousness for 10e15 min, tongue bruising due to jaw contractions, and postictal vomiting. Subsequent MRI-scanning of the brain disclosed no abnormalities. EEG-recording, however, demonstrated frequent epileptiform activity centroparietal bilaterally with marked increase during sleep. In fact, in about 60e70 percent of the sleep, spike-wave discharges were observed without clinical manifestations of epilepsy. A provisional diagnosis of electrical status epilepticus in
sleep (ESES) was made. Treatment with 5 mg clobazam ante noctem was started. Until now, at the age of almost ten years, severe sleep disturbances and behavioural problems persist. 3. Discussion Here, a 9-year-old female is described with a de novo microdeletion of 3.57 Mb in 8q12.3q13.2. She presented with a clinical phenotype comprising several dysmorphisms, psychomotor developmental delay, mild to moderate intellectual disability and marked sleep disturbances. In addition, this microdeletion syndrome might include a rare childhood epileptic encephalopathy (ESES), because it became apparent, retrospectively, that there had been signs of nocturnal seizures since the age of two years. More specifically, her disrupted sleep pattern was re-interpreted as short episodes with reduced awareness and muscle twitches of the arms and legs. Review of the current literature and available online databases like DECIPHER (http://decipher.sanger.ac.uk/ [7];) and ECARUCA (http://www.ecaruca.net [8];) does not provide any reports about a comparable microdeletion syndrome. Only three other patients with an (partially) overlapping and cytogenetically visible deletion have been reported [9e11]. These patients presented with neonatal hypotonia, developmental delay and some of them had minor somatic dysmorphisms and/or congenital anomalies. The clinical features of these three patients that are in common with those observed in our patient, include intellectual disability (2/3), short neck (1/3), and recurrent infections (1/3). Epilepsy was not reported as a clinical feature in any of these patients. As to the ESES-electroencephalographic (EEG) pattern, it should be noticed that this can be observed in continuous spike-waves during slow sleep (CSWS) syndrome, benign childhood epilepsy with centrotemporal spikes (BCECTS) and Landau-Kleffner syndrome (LKS) [12-14]. LKS is a rare disorder with acquired aphasia [15,16]. Some evidence is available on susceptibility genes for these epilepsy syndromes, i.e., SRPX2 (Xq22) and ELP4
Fig. 2. Female patient at the age of 9 1/6 years, presenting several characteristic facial features including hypertelorism, downslanting palpebral fissures, a long, pear shaped nose, low-set, posteriorly rotated ears, and a full lower lip. The extremities show a bilateral sandal gap and flat feet.
W.M.A. Verhoeven et al. / European Journal of Medical Genetics 55 (2012) 358e361
(16p11p12) [13] and GRIN2A (16p13) [17]. In about half of the patients with ESES, MRI-scanning of the brain does not display any structural abnormalities [18]. In general, conventional antiepileptics seem to play only a minimal role in the treatment of ESES/CSWS [12,14], while nowadays sulthiame seems to be the most appropriate agent [19,20]. Amongst the 27 genes in the deleted region, only one recessive disease gene, CYP7B1, is known which encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum membrane protein catalyzes the first reaction in the cholesterol catabolic pathway of extrahepatic tissues and converts cholesterol to bile acids. It likely plays a minor role in total bile acid synthesis, but may, however, be involved in the development of atherosclerosis, neurosteroid metabolism and sex hormone synthesis. Although a possible mutated recessive disease gene on the other allele could not be excluded, gene mutation analysis was not performed since the clinical phenotype of the present patient did not match with either two disease phenotypes that are associated with CYP7B1, i.e., Congenital bile acid synthesis defect 3 (phenotype 613812 (3)) and Spastic paraplegia-5A (phenotype 270800 (3)), respectively. Based on the genotype information obtained from the SNP arrays from the patient and her parents, the paternal allele of 8q12.3q13.2 turned out to be deleted. At present, however, this region does not seem to contain any imprinted genes. Given the patient’s profile of neuropsychological dysfunction, it was advised to avoid overestimation of cognitive and language capacities, and to use educational and learning strategies based on modelling rather than on verbal instruction. Pharmacological treatment was kept unchanged and regular follow-up to monitor developmental processes by means of repeated neuropsychological assessments was planned. In conclusion, the combination of the specific EEG pattern, neuropsychological dysfunction, impaired language and motor skills, suggests ESES/CSWS to be the most appropriate epilepsy diagnosis in the here reported patient. Consequently, this de novo 8q12.3q13.2 microdeletion syndrome may be associated with ESES/ CSWS. 4. Note Because of non-responsiveness to clobazam, this compound was discontinued and replaced for the anti-epileptic sulthiame (150 mg daily) upon which the patient’s sleep pattern markedly improved. 5. Dissemination of information The case has been submitted to the ECARUCA database (http:// www.ecaruca.net) with identification number 4790. Acknowledgements This study is part of a collaborative project of the research group ‘Psychopathology and Genetics’ of the Radboud University Nijmegen and the Vincent van Gogh Institute for Psychiatry, Venray, the Netherlands. The authors are indebted to the patients and her parents for their cooperation. Written informed consent was obtained from the parents for printing the pictures of the patient. Epilepsy diagnosis and treatment was performed
361
by Mrs. E.A.J Peeters and Mrs. I.N. Snoeck, child neurologists at the Haga Hospital in The Hague, the Netherlands. References [1] Y. Nannya, M. Sanada, K. Nakazaki, N. Hosoya, L. Wang, A. Hangaishi, M. Kurokawa, S. Chiba, D.K. Bailey, G.C. Kennedy, S. Ogawa, A robust algorithm for copy number detection using high-density oligonucleotide singlenucleotide polymorphism genotyping arrays, Cancer Res. 65 (2005) 6071e6079. [2] N. de Leeuw, J.Y. Hehir-Kwa, A. Simons, A.H.M. Geurts van Kessel, D.F.C.M. Smeets, B.H.W. Faas, and R. Pfundt, SNP array analysis in constitutional and cancer genome diagnostics e copy number variants, Genotyping Qual. Control. Cytogen Gen. Res. (2011) [Epub ahead of print]. [3] M.M. Black, K. Matula, Essentials of Bayley Scales of Infant Development II Assessment, John Wiley, New York, 1999. [4] P.J. Tellegen, M. Winkel, B.J. Wijnberg-Williams, J.A. Laros, Snijders-Oomen nonverbal intelligence test manual, Swets and Zeitlinger (1998) (Lisse). [5] N. Bleichrodt, P.J.D. Drenth, J.N. Zaal, W.C.M. Resing, RAKIT (Revised Amsterdam Children Intelligence Test), Pearson, Amsterdam, 1987. [6] K.E. Beery, N.A. Buktenica, N.A. Beery, The Beery-Buktenica Developmental Test of Visual-Motor Integration Beery VMI, fifth ed. Pearson, Sant Antonio, Texas, 2004. [7] H.V. Firth, S.M. Richards, A.P. Bevan, S. Clayton, M. Corpas, D. Rajan, S. Van Vooren, Y. Moreau, R.M. Pettett, N.P. Carter, DECIPHER: database of chromosomal imbalance and phenotype in humans using ensembl resources, Am. J. Hum. Genet. 4 (2009) 524e533. [8] I. Feenstra, J. Fang, D.A. Koolen, A. Siezen, C. Evans, R.M. Winter, M.M. Lees, M. Riegel, B.B.A. de Vries, C.M.A. van Ravenswaay, A. Schinzel, European cytogenetics association register of unbalanced chromosome aberrations (ECARUCA); an online database for rare chromosomal abnormalities, Eur. J. Med. Genet. 49 (2006) 279e291. [9] A.A. Schinzel, W.P. Robinson, F. Binkert, A. Fanconi, An interstitial deletion of proximal 8q (q11-q13) in a girl with Silver-Russell syndrome-like features, Clin. Dysmorphol. 3 (1994) 63e69. [10] C. Vincent, V. Kalatzis, S. Compain, J. Levilliers, R. Slim, F. Graia, M. de LurdesPereira, A. Nivelon, M.F. Croquette, D. Lacombe, J. Vigneron, J. Helias, M. Broyer, D.F. Callen, E.A. Haan, J. Weissenbach, B. Lacroix, C. BellanéChantelot, D. Le Paslier, D. Cohen, C. Petit, A proposed new contiguous gene syndrome on 8q consists of Branchio-Oto-Renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications for the mapping of the BOR gene, Hum. Mol. Genet. 3 (1994) 1859e1866. [11] G. Calabrese, L. Stuppia, E. Morizio, P. Guanciali Franchi, F. Pompetti, R. Mingarelli, T. Marsilio, M. Rocchi, P.E. Gallenga, G. Palka, B. Dallapiccola, Detection of an insertion deletion of region 8q13-q21.2 in a patient with Duane syndrome: implications for mapping and cloning a Duane gene, Eur. J. Hum. Genet. 6 (1998) 187e193. [12] K. Nickels, E. Wirrell, Electrical status epilepticus in sleep, Semin. Pediatr. Neurol. 15 (2008) 59e60. [13] G. Rudolf, M.P. Valeti, E. Hirsch, P. Szepetowski, From rolandic epilepsy to continuous spike-and-waves during sleep and Landau-Kleffner syndromes: insights into possible genetic factors, Epilepsia 50 (Suppl. 7) (2009) 25e28. [14] J.R. Hughes, A review of the relationship between Landau-Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep, Epilepsy Behav. 20 (2011) 247e253. [15] A.S. Galanopoulou, A. Bojko, F. Lado, S.L. Moshé, The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in sleep, Brain Dev. 22 (2000) 279e295. [16] K. McVicar, S. Shinnar, Landau-Kleffner syndrome, electrical status epilepticus in slow wave sleep, and language regression in children, Ment. Retard. Dev. Disabil. Res. Rev. 10 (2004) 144e149. [17] R. Reutlinger, I. Helbig, B. Gawelczyk, J.I.M. Subero, H. Tönnies, H. Muhle, K. Finsterwalder, S. Vermeer, R. Pfundt, J. Sperner, I. Stefanova, G. GillessenKaesbach, S. von Spiczak, A. van Baalen, R. Boor, R. Siebert, U. Stephani, A. Caliebe, Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region, Epilepsia 51 (2010) 1870e1873. [18] M. Van Hirtum-Das, E.A. Licht, S. Koh, J.Y. Wu, W.D. Shields, R. Sankar, Children with ESES: variability in the syndrome, Epilepsy Res. 70S (2006) 248e258. [19] F. Engler, M. Maeder-Ingvar, E. Roulet, T. Deonna, Treatment with sulthiamine (Ospolot) in benign partial epilepsy of childhood and related syndromes: an open clinical and EEG study, Neuropediatrics 34 (2003) 105e109. [20] E. Wirrell, A. Wen-Chi Ho, L. Hamiwka, Sulthiame therapy for continuous spike and wave in slow-wave sleep, Pediatr. Neurol. 35 (2006) 204e208.