Orphanet Journal of Rare Diseases


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The inv dup (15) or idic (15) syndrome (Tetrasomy 15q)
Agatino Battaglia
Address: Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Calambrone, Pisa, Italy Email: Agatino Battaglia - abattaglia@inpe.unipi.it

Published: 19 November 2008 Orphanet Journal of Rare Diseases 2008, 3:30 doi:10.1186/1750-1172-3-30

Received: 20 March 2008 Accepted: 19 November 2008

This article is available from: http://www.ojrd.com/content/3/1/30 © 2008 Battaglia; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The inv dup(15) or idic(15) syndrome displays distinctive clinical findings represented by early central hypotonia, developmental delay and intellectual disability, epilepsy, and autistic behaviour. Incidence at birth is estimated at 1 in 30,000 with a sex ratio of almost 1:1. Developmental delay and intellectual disability affect all individuals with inv dup(15) and are usually moderate to profound. Expressive language is absent or very poor and often echolalic. Comprehension is very limited and contextual. Intention to communicate is absent or very limited. The distinct behavioral disorder shown by children and adolescents has been widely described as autistic or autistic-like. Epilepsy with a wide variety of seizure types can occur in these individuals, with onset between 6 months and 9 years. Various EEG abnormalities have been described. Muscle hypotonia is observed in almost all individuals, associated, in most of them, with joint hyperextensibility and drooling. Facial dysmorphic features are absent or subtle, and major malformations are rare. Feeding difficulties are reported in the newborn period. Chromosome region 15q11q13, known for its instability, is highly susceptible to clinically relevant genomic rearrangements, such as supernumerary marker chromosomes formed by the inverted duplication of proximal chromosome 15. Inv dup(15) results in tetrasomy 15p and partial tetrasomy 15q. The large rearrangements, containing the Prader-Willi/Angelman syndrome critical region (PWS/ASCR), are responsible for the inv dup(15) or idic(15) syndrome. Diagnosis is achieved by standard cytogenetics and FISH analysis, using probes both from proximal chromosome 15 and from the PWS/ASCR. Microsatellite analysis on parental DNA or methylation analysis on the proband DNA, are also needed to detect the parent-of-origin of the inv dup(15) chromosome. Array CGH has been shown to provide a powerful approach for identifying and detecting the extent of the duplication. The possible occurrence of double supernumerary isodicentric chromosomes derived from chromosome 15, resulting in partial hexasomy of the maternally inherited PWS/ASCR, should be considered in the differential diagnosis. Large idic(15) are nearly always sporadic. Antenatal diagnosis is possible. Management of inv dup(15) includes a comprehensive neurophysiologic and developmental evaluation. Survival is not significantly reduced. Disease name and synonyms: The inv dup(15) or idic(15) syndrome can also be termed "tetrasomy 15q". About 160 patients have been reported in the medical literature [1-5].

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that can be suspected clinically. Molecular studies. particularly in the older age groups. The inv dup (15) or idic (15) is the most common of the heterogeneous group of the extra structurally abnormal chromosomes (ESACs). and the cytogenetic description is dic(15)(q12 or q13).21]. with different phenotypic consequences [11-14]. or by spinning or any glittering objects. even before the cytogenetic confirmation. probably remain undiagnosed. and usually do not develop appropriate social interactions. smaller or similar to a G group chromosome. Age of acquisition of motor milestones are seldom reported in the medical literature. translocations. Recently.000 with a sex ratio of almost 1 [3].Orphanet Journal of Rare Diseases 2008. and walking between 2 and 3 years [17. although exceptions have been recorded [16]. considerable structure heterogeneity has recently been described in a few patients [19]. It includes the PWS/ ASCR [17. epilepsy. They show no interest toward their peers. it seems that sitting is achieved between 10 and 20 months of age. such as microsatellite analysis on parental DNA or methylation analysis on the proband DNA. The latter is characterized by lack of social interaction. and autistic behavior. and is reportedly associated with increased mean maternal age at conception. Epidemiology Although poorly known.22].8]. The distinct behavior disorder shown by children and adolescents has been widely described as autistic or autistic-like. Usually. by the water. this picture constitutes a distinct and recognizable neurogenetic disorder. However. In all such cases. incidence at birth is estimated to be 1 in 30. When thwarted. stare at people as looking through them.18]. One is a metacentric or submetacentric and heterochromatic chromosome. or larger than. stereotypies. inversions and supernumerary marker chromosomes formed by the inverted duplication of proximal chromosome 15.ojrd. Intention to communicate is absent or very poor [21.22]. [29] met the clinical criteria for the diagnosis of autistic disorder by DSM IV (Diagnostic and Statistical Manual – Revision 4). Altogether. Recently. and the cytogenetic description is dic(15)(q11). and some individuals. which constitutes the idic(15) syndrome [20. using probes both from proximal chromosome 15 and from the PWS/ASCR [2. including hand Page 2 of 7 (page number not for citation purposes) . Most children with this aberration show a normal phenotype [15].27]. [28]. Since dysmorphic features are absent or subtle and major malformations are rare.26.21].17. 3:30 http://www. developmental delay and intellectual disability. similar to other aneuploides. Stereotypies are frequently seen.27]. according to parental origin [9]. However. [25]. Expressive language is absent or very poor. a G group chromosome and has 15q euchromatin. which is known for its instability [6] due to the presence of repeated DNA elements [7. and is the most common ESAC accounting for about 70% of all small extra marker chromosomes.2. a higher incidence is plausible due to under-ascertainment. array CGH (array comparative genomic hybridization) has been shown to provide a powerful approach to detect the duplication and its extent [4]. They usually prefer being left alone. it is often echolalic with immediate and delayed echolalia and pronoun reversal. Maternally derived cytogenetic mosaicism with a normal cell line has been described in a small subset of individuals [23. primordial type of exploration. Many rearrangements may occur in the imprinted chromosome region 15q11q13. The rearrangements include deletions associated either with Angelman syndrome (AS) or with Prader-Willi syndrome (PWS). Two cytogenetic types of inv dup (15) marker chromosomes have been identified.13. The vast majority of dic(15)(q12 or q13) derives from the two homologous maternal chromosomes at meiosis. one patient with a mosaic paternally derived inv dup(15). showing a mild PWS phenotype. they can react with outbursts of shouting or with aggressiveness. Comprehension is very limited. The patients reported by Borgatti et al. However. The second type of inv dup (15) is as large as. not containing the PWS/AS critical region (PWS/ASCR). Non-functional use of objects with a primordial type of exploration is also observed. standard cytogenetics must be associated with FISH (fluorescence in situ hybridization) analysis.21. Clinical description Developmental delay and intellectual disability affect all individuals with inv dup (15) and are usually moderate to profound [1. these kids have gaze avoidance from very early on. and poor intention to communicate. dic(15)(q11) can be familial or de novo.24]. The presence of large inv dup (15) results in tetrasomy 15p and partial tetrasomy 15q. triplications and balanced reciprocal translocations are much less frequent [10]. Physically. lying on the back just looking at their fingers and taking bizarre postures. Symbolic play is usually never acquired. They can be fascinated by certain sounds. nonfunctional use of objects.com/content/3/1/30 Background The inv dup(15) or idic(15) syndrome (inverted duplication of proximal chromosome 15 or isodicentric 15 chromosome) displays distinctive clinical findings represented by early central hypotonia. A strong association between autistic features and isodicentric chromosome 15 [idic (15)] was reported by Rineer et al. there are only minor anomalies. limited comprehension. are also needed in order to detect the parent-of-origin of the inv dup (15) chromosome [2. contextual and accompanied by the gesture. absent or very poor echolalic language. has been reported by Saitoh et al. This condition is associated with an abnormal phenotype. Interstitial duplications. chromosome analysis may not be thought to be indicated. shun body contact.

Since only maternally inherited aberrations of chromosome 15q11-13 seem to be pathogenic. tonic-clonic seizures and atypical absences with onset between 4 and 8 years of age. partial 2nd–3rd toe syndactyly [3. characterized by slow sharp element-spike/wave complexes. generalized epilepsy with absence seizures and occasional head drops. Hypogonadism is reported in about 20% [1. such as ventricular septal defects. highly arched palate. and/or by tonic fits. Epilepsy with a wide variety of seizures can occur in these individuals. [21]. Furthermore. dosage effect of genes in this region.13. anteverted nares. and generalized tonic-clonic seizures has also been occasionally reported. spinning him/herself for long periods of time. with joint hyperextensibility and drooling.3].26. on eye closure. hand-wringing. Major malformations. 2) absence or poverty of the rhythmic activities usually elicited over the posterior third of the brain.31]. associated. 2). epicanthal folds. and talipes seem to be rare [13. unilateral renal agenesis. frontal bossing.17.17.26.Orphanet Journal of Rare Diseases 2008. and ill-defined polispike/wave complexes. head turning. Complex partial and myoclonic seizures were observed in a number of other individuals [26]. very little is reported on the EEG characteristics in inv dup (15) syndrome.21]. 3) multifocal discharges with variable hemispheric predominance. 6) disruption of the usual sleep structure. Mean parental/maternal ages at birth of the probands were markedly advanced [2. with a good outcome [33]. prominent mandible in adults. viewing of pleasant or funny events) have been reported in a 9-year-old boy [32]. Hyperactivity has been reported in a number of cases [21. Other physical findings are rather unspecific and may include: minor facial dysmorphisms. lasting 2 to 20 seconds. it is likely that maternal genes.27]. accompanied by tachypnea and/or by an upward rotation of the eyes. Additional EEG abnormalities consist of diffuse spikes.18. Growth is retarded in about 20%–30% of the patients. Battaglia et al. In the medical literature. Brain neuroimaging (CT/MRI) does not show abnormal findings in most cases [21.21. contained in this genomic region. suggests that there is a dosage effect for a gene or genes in this region [5. Five recurrent breakpoints (BP) have been described in most cases and most idic(15) chromosomes arise through BP3:BP3 or BP4:BP5 recombination events (Fig. 3:30 http://www. broad nose.13.35-38].ojrd. Seizures were difficult to control in all. The fact that tetrasomy of the PWS/ASCR is associated with a more severe phenotype than the one observed in trisomy. In 1997. synophrys. 5) frequent generalized bursts of fast rhythms during slow wave sleep in 2 of the 4 patients. Molecular characterization Various genetic mechanisms have been hypothesized to explain clinical heterogeneity. mainly due to the poor description of these findings and a total lack of serial EEG studies [2. Feeding difficulties are reported in the newborn period [5]. cleft palate. tetralogy of Fallot.30]. cryptorchidism. act in a dosagedependent manner and that their copy number is critical for normal brain development and function. A mild.42]. Pregnancies and birth weights are mostly normal. finger biting. [21] described in detail the EEG abnormalities observed in four such individuals.30].17.26. large amplitude.30]. Microcephaly is observed in less than 20% of individuals.5–4 Hz spike-and-wave discharges. Other EEG findings reported in the literature include generalized rhythmic 3. in most of them. 5th finger clinodactyly and unusual dermatoglyphics. including the size of chromosomal duplication. pubertal disorders. have been observed in three girls [40]. associated with some degree of deterioration were also reported by other authors [13. Drug-resistant myoclonic absence-like seizures induced by emotionally gratifying stimuli (kissing.13. umbilical and inguinal hernias. showing: 1) slow background activity. no individual with idic(15) syndrome is known to have reproduced. Infantile spasms associated with an hypsarrhythmic EEG (electroencephalogram) have been reported in several patients [2.21. brachydactyly. polispikes. low-set and/or posteriorly rotated ears. Brachycephaly. adult-onset. and the imprinting mechanism. 4) frequent. All received serial polygraphicvideo-EEG recordings during wakefulness and sleep (overnight sleep in 2 of the 4) over a long period of time. and areas of increased and reduced skin pigmentation can be occasionally observed. lasting 4–6 seconds [33]. deep-set eyes. Benign epilepsy with centro-temporal spikes with a benign evolution has been observed in another inv dup(15) individual [34].26. hypospadias. To the best of our knowledge. 1) [personal observation]. with onset between ages 6 months and 9 years [2. mostly accompanied by atypical absences. generalized paroxysms. The ~4Mb seg- Page 3 of 7 (page number not for citation purposes) . Typical LennoxGastaut syndrome or Lennox-Gastaut-like syndrome was observed in the four inv dup (15) patients reported by Battaglia et al. with the sole exception of one patient [44].41]. These had tonic/atonic (as head drops or drop attacks). gene expression in this critical region is regulated by an imprinting mechanism [43]. such as central precocious puberty or ovarian dysgenesis. Muscle hypotonia is observed in almost all individuals. short philtrum. despite adequate antiepileptic treatment. with variable hemispheric predominance (Fig.27. characterized by downslanting palpebral fissures. Although puberty is reportedly normal in most individuals [39].29]. while macrocephaly in less than 3%. broad nose. hand-clapping over plane surfaces. Difficult to control seizures.com/content/3/1/30 flapping. All EEGs were abnormal.

Amplitude 100 μV/cm.ojrd. The most frequent form of idic (15) is characterized by an asymmetric recombination event between BP4 and BP5. and the ~4 Mb segment that encompasses the PWS/AS critical region. somewhat predominant over the right hemisphere. EEG showing diffuse spikes. Tetrasomy of these genes. ill-defined polispike/wave complexes. Amongst the genes that are known to be located at or near the PWS/ASCR. and the ~4 Mb segment that Schematic Schematic representation of chromosome 15. an interesting relationship has been shown between the α5 and β3 GABA (gamma-aminobutyric acid) receptor subunit genes and the P gene. 3:30 http://www. jerky gait and ataxia [45]. polispikes. showing the five recurrent breakpoints (BP). speed 1 sec/1.Orphanet Journal of Rare Diseases 2008. upon which the major CNS (central nervous system) inhibitory mechanisms Figure 2 representation critical region encompasses the PWS/ASof chromosome 15. as seen in inv dup (15) syndrome. showing the five recurrent breakpoints (BP). This leads to tetrasomy for the interval from the centromere to BP4 and to trisomy from BP4 to BP5 [4]. may alter the GABA receptor activity. ment that encompasses the PWS/ASCR lies between BP2 and BP3. Page 4 of 7 (page number not for citation purposes) . rearrangements of α5 and β3 receptors producing a particular phenotype characterized by seizures.com/content/3/1/30 Figure 1 Inv dup(15) or idic(15) patient at age 12 ys7 m Inv dup(15) or idic(15) patient at age 12 ys7 m. even though these genes are not imprinted. In fact. Slow wave sleep. in the mouse.5 cm. a deletion of both P alleles causes.

combined with additional genetic or environmental influences on epigenetic mechanisms. who subsequently develops hard to control seizures/epilepsy (Table 1). In the Table 1: Frequency of the main clinical characteristics of inv dup(15) or idic(15) syndrome Exceeding 75% Hypotonia. has also been reported [4. gin of the inv dup (15) chromosome [2. suggests that genetic copy number variation. Standard cytogenetics (G-C-banding methods) must be associated with FISH analysis.49]. brachycephaly. but it was problematic. family 12. or amniocentesis. showing the idic(15) chromosome [21]. resulting in partial hexasomy of the maternally inherited PWS/ASCR. A recent study performed on post-mortem brain tissue from two individuals with 15q11-13 hexasomy and 15q11-13 tetrasomy respectively. GABRB3 155CA-2. aggressiveness. Cells obtained by chorionic villus sampling (CVS) at approximately 12 weeks' gestation. 3:30 http://www. the SLC12A6 (solute carrier. and small hands and feet [38]. and has frequently been reported [50]. such as microsatellite analysis on parental DNA or methylation analysis on the proband DNA. behaviour disorder. developmental delay/intellectual disability. and autistic disorder. coding for a cation chloride cotransporter and expressed in the brain. Hypotonia in infancy can be severe and may lead to genetic evaluation for PWS. autism or autistic-like behavior.Orphanet Journal of Rare Diseases 2008. array CGH has been shown to provide a powerful approach to detect the duplication and its extent [4]. This disorder is. minor dysmorphic features. are nearly always sporadic.com/content/3/1/30 rely. Molecular studies. Diagnosis and diagnostic methods Clinicians should suspect this syndrome in any infant or child with early central hypotonia.ojrd. linkage disequilibrium between a marker in the γ-aminobutiric acidA receptor subunit gene. impact clinical heterogeneity and outcome of idic(15) syndrome [48]. Genetic counseling Large SMC(15) (supernumerary marker chromosome). as well. member 6). Of interest. and molecular (methylation analysis) methods.22]. are also needed in order to detect the parent-of-ori- Management The management of inv dup (15) includes a comprehensive neurophysiologic and developmental evaluation. could also potentially be implicated in the pathogenesis of seizures [47]. and autistic disorder has been reported by Cook et al. and developmental status are difficult to assess accurately. hypotonia. An additional gene. usually performed at approximately 15–18 weeks' gestation. A waking/sleeping polygraphic-video-EEG study is recommended in infancy and childhood in order to achieve the best characterization of the seizures. facial dysmorphisms. using probes both from proximal chromosome 15 and from the PWS/ASCR [2. can be analyzed by a combination of cytogenetic (G-Cbanding. In fact. or idic(15). A phenotype-genotype correlation has been attempted. FISH). lax ligaments Developmental delay/Intellectual disability Autistic behavior Epilepsy Minor dysmorphic features (mainly involving the face) From 25% to 50% Brain abnormalities Genitourinary tract defects Growth retardation Below 25% Congenital heart defects Microcephaly Page 5 of 7 (page number not for citation purposes) . component manifestations such as seizure history. which include PWS/ASCR. including severe psychomotor delay. This is of the utmost importance for the first choice pharmacotherapy. Recently. Differential diagnosis Occurrence of double supernumerary isodicentric chromosomes derived from 15. skeletal muscle.22]. hyperactivity. such as seizures. personal observation]. This alteration could represent the biological basis for some clinical manifestations of the inv dup (15) syndrome individuals. Antenatal diagnosis Prenatal diagnosis is possible. and there is also considerable variation in the breakpoints [5. [46]. joint hyperlaxity. heart. located more distally. especially in young children. associated with an abnormal phenotype. and kidney.

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