Abstract
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.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].
Highlights
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 behavior
The rearrangements include deletions associated either with Angelman syndrome (AS) or with Prader-Willi syndrome (PWS), according to parental origin [9]; translocations, inversions and supernumerary marker chromosomes formed by the inverted duplication of proximal chromosome 15
Standard cytogenetics must be associated with FISH analysis, using probes both from proximal chromosome 15 and from the PWS/ASCR
Summary
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, developmental delay and intellectual disability, epilepsy, and autistic behavior. Occurrence of double supernumerary isodicentric chromosomes derived from 15, resulting in partial hexasomy of the maternally inherited PWS/ASCR, has been reported [4,49] This disorder is, as well, associated with an abnormal phenotype, including severe psychomotor delay, hypotonia, joint hyperlaxity, brachycephaly, facial dysmorphisms, and small hands and feet [38]. A recent study performed on post-mortem brain tissue from two individuals with 15q11-13 hexasomy and 15q11-13 tetrasomy respectively, suggests that genetic copy number variation, combined with additional genetic or environmental influences on epigenetic mechanisms, impact clinical heterogeneity and outcome of idic(15) syndrome [48] Clinicians should suspect this syndrome in any infant or child with early central hypotonia, minor dysmorphic features, developmental delay/intellectual disability, autism or autistic-like behavior, who subsequently develops hard to control seizures/epilepsy (Table 1). Abbreviations (AS): Angelman syndrome; (PWS): Prader-Willi syndrome; (ESACs): extra structurally abnormal chromosomes; (PWS/ASCR): PWS/AS critical region; (FISH): fluorescence in situ hybridization; (aCGH): array comparative genomic hybridization; (DSM IV): Diagnostic and Statistical Manual – Revision 4; (EEG): electroencephalogram; (CT/MRI): computerized tomography/magnetic resonance imaging; (BP): breakpoints; (GABA): gammaaminobutyric acid; (CNS): central nervous system; (CVS): chorionic villus sampling; (VPA): valproate; (CBZ): carbamazepine; (LTG): lamotrigine
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