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      Isodicentric Chromosome 15 Syndrome in a Korean Patient With Café-au-lait Spots

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          Abstract

          Dear Editor Isodicentric chromosome 15 [idic(15) or inv dup(15)] syndrome is a rare condition with distinctive clinical features, including developmental delay, hypotonia, epilepsy, and autism or autistic-like behavior [1]. These features can obscure a definitive diagnosis, which can only be obtained by chromosomal analysis. In a review of the types and incidence of marker chromosomes at a university hospital in Korea, there was a report on a patient that presented idic(15) along with various other marker chromosomes [2]. Recently, two additional cases of idic(15) syndrome in Korea were published in reports focusing on their specific phenotypes [3, 4]. We present a Korean patient with delayed development and café-au-lait spots, a novel associated phenotype, who was diagnosed with idic(15) syndrome. A 3-yr-old boy was referred to our hospital for evaluation of delayed development and multiple, large café-au-lait spots. He was born full term by normal vaginal delivery. The patient had no history or family history of seizure. He was a second child, and his older brother showed normal development. He showed developmental delay in speech and motor functions, which were estimated to be one year behind the reference milestones assessed by the Bayley Scales of Infant Development. Physical examination revealed multiple café-au-lait spots (3-10 cm) on the right hemitrunk, upper extremity, lower extremity, and neck (Fig. 1). Minor craniofacial dysmorphisms involving mildly deep-set eyes, downslanting palpebrae, and microcephaly were also observed. Although the first impression was neurofibromatosis (NF) type 1 based on the café-au-lait spots, chromosome analysis using standard trypsin-Giemsa banding showed an abnormal karyotype 47,XY,+idic(15)(q13) (Fig. 2A). To confirm the abnormality, FISH was performed with a locus-specific identifier (LSI) probe set for SNRPN (Abbott Molecular/Vysis, Downers Grove, IL, USA), which is the causal region of Prader-Willi/Angelman syndrome. Two aqua signals and one orange signal indicated the presence of an isodicentric chromosome 15 with region q13 affected (Fig. 2B). Parental chromosome analyses were not available because of their refusal. At publication, no epileptic events had occurred, and conservative care with physical and speech-language therapy has been administered. Epilepsy is considered to be the most significant medical concern in patients with idic(15) syndrome. Therefore, several studies have focused on the types of seizures and treatment options [5]. It is recommended that patients with idic(15) syndrome and clinicians be aware of the increased risk for seizures, which highlights the importance of accurate diagnosis of idic(15) syndrome by medical geneticists. Another interesting clinical phenotype of idic(15) syndrome is autism or autistic-like behavior [6]. Chromosome region 15q11-q13 has been widely investigated for its instability and high susceptibility to genomic rearrangements [1], and there are several reports of autism spectrum disorder in patients with chromosome 15 abnormalities, which supports the notion that the long arm of chromosome 15 is an autism candidate region [6, 7]. Although our patient did not show signs of autistic behavior, the development of autism should be monitored carefully since the emergence of some autistic features may be delayed. The most important clinical presentation in our patient was the multiple, large café-au-lait spots. Café-au-lait spots are traditionally regarded as the definitive sign of NF type 1, and their significance has been continuously validated [8]. Interestingly, there have been recent reports on the spectrum of diseases that can manifest multiple café-au-lait spots, especially in correlation with genetic abnormalities [9]. Our case suggests that café-au-lait spots could be the most remarkable abnormality in idic(15) syndrome, even though it is rarely reported. There was a recent report on a Cuban girl diagnosed as having idic(15) syndrome with a periumbilical café-au-lait spot [10], which supports the opinion that significant, abnormal skin manifestations should be carefully evaluated in relation to idic(15) syndrome. Our finding suggests that idic(15) syndrome should also be considered along with other syndromes currently associated with multiple, large café-au-lait spots [8], such as NF type 1, Noonan syndrome, and McCune-Albright syndrome. This finding also expands the wide phenotypic variability of idic(15) syndrome and supports the importance of accurate diagnosis and early clinical suspicion [1]. To summarize, idic(15) syndrome is highlighted by large phenotypic variability. We report a novel case of idic(15) syndrome with an additional distinctive cutaneous manifestation; multiple, large café-au-lait spots. Clinical attention for appropriate diagnosis of idic(15) syndrome by concise chromosomal analysis and FISH testing is important, as is a detailed understanding of various phenotypic presentations. Attempts to correlate clinical presentations with chromosomal abnormalities will provide an ability to obtain a comprehensive diagnosis of rare genetic diseases, including idic(15) syndrome.

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          Most cited references 10

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          The inv dup (15) or idic (15) syndrome (Tetrasomy 15q)

          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].
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            A survey of seizures and current treatments in 15q duplication syndrome.

            Seizures are common in individuals with duplications of chromosome 15q11.2-q13 (Dup15q). The goal of this study was to examine the phenotypes and treatments of seizures in Dup15q in a large population.
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              Autistic symptoms among children and young adults with isodicentric chromosome 15.

              A standardized assessment of autistic symptomatology was completed for 29 children and young adults with a supernumerary isodicentric chromosome 15 (formerly known as inverted duplication 15). Although there was variability in severity, 20 individuals with an isodicentric chromosome 15 [idic(15)] had a high probability of being autistic. Eight of the 9 remaining children were under age 5 years and were more sociable than the rest of the cohort. Group characteristics such as gender and seizure presence could not explain the observed difference between older and younger individuals in our study. The natural history of isodicentric 15 syndrome remains to be shown through longitudinal work and may include an age-related risk for developing autism.
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                Author and article information

                Journal
                Ann Lab Med
                Ann Lab Med
                ALM
                Annals of Laboratory Medicine
                The Korean Society for Laboratory Medicine
                2234-3806
                2234-3814
                July 2015
                21 May 2015
                : 35
                : 4
                : 474-476
                Affiliations
                [1 ]Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
                [2 ]Department of Pediatrics, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
                Author notes
                Corresponding author: Jong Rak Choi. Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. Tel: +82-2-2228-2441, Fax: +82-2-364-1583, CJR0606@ 123456yuhs.ac
                Article
                10.3343/alm.2015.35.4.474
                4446592
                © The Korean Society for Laboratory Medicine.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Letter to the Editor
                Diagnostic Genetics

                Clinical chemistry

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