Clinical Overview of Chromosome 15q Duplication Syndrome

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Chromosome 15q duplication syndrome (dup15q) is a clinically identifiable syndrome which results from duplications of chromosome 15q11-q13. Chromosome 15q duplications are associated with autism spectrum disorders, developmental delay, learning disabilities/mental retardation, and seizures/epilepsy.

Clinicians should suspect this syndrome in any infant/child with early central hypotonia, minor dysmorphic features, significant developmental delay, autistic behaviors, infantile spasms, or who subsequently develops hard to control seizures/epilepsy¹.

Chromosome 15q duplications most commonly occur in one of two forms, either as an extra isodicentric 15 chromosome or as an interstitial duplication of chromosome 15q.

Isodicentric 15
Isodicentric chromosome 15, abbreviated idic(15), is diagnosed in individuals who have 47 chromosomes (or sometimes more) instead of the typical 46 chromosomes. The extra chromosome is made up of a portion of chromosome 15 that has been duplicated and "inverted," so that there are two copies of part of chromosome 15q attached to one another that appear to be mirror images. Because of this arrangement, idic(15) used to be referred to as "inverted duplication chromosome 15." Most commonly, the region called 15q11-q13 is the portion of chromosome 15 duplicated. Sometimes the duplicated region is larger. The size of the idic(15) varies depending on the size of the region of chromosome 15 that is duplicated.²

Interstitial Duplication 15
People born with the typical 46 chromosomes, but who have a segment of duplicated material within chromosome 15, are said to have an interstitial duplication chromosome 15. Most often this is the same section (15q11-q13) that makes up the extra chromosome in idic(15). For this reason, people with interstitial duplications of 15q and those with idic(15) share similar characteristics. As a group however, people with interstitial duplication 15 tend to have milder symptoms than those with idic(15).

When the extra genetic material comes from the paternal chromosome, a child may have normal development. However, when the duplicated material comes from the maternal chromosome, developmental problems are often the result. In most cases of chromosome 15q duplication syndrome, the chromosome duplication is not inherited, but occurred as a random event during the formation of reproductive cells (eggs and sperm).

Diagnosis
is confirmed by standard cytogenetic techniques and FISH analysis, which confirms the diagnosis by distinguishing the dup15q from other supernumerary marker chromosomes. Interstitial duplications of chromosome 15 can be more difficult to detect on a routine chromosome analysis but are clearly identifiable using a 15q FISH study or clinical microarray/array CGH. Molecular studies, such as microsatellite analysis on parental DNA or methylation analysis on the affected child’s DNA, are required in order to detect the parent-of-origin of the dup15q.¹ Families should always discuss the results of DNA tests, chromosome and FISH studies with a genetic counselor or other genetics professional to ensure accurate interpretation.

Clinical Overview
Although about 100 cases have been reported to date in the scientific literature, limited data are available on the natural history of chromosome 15q duplication syndrome, especially in adulthood.

There is a wide range of severity in the developmental problems experienced by individuals with dup15q syndrome. Two children with the same dup15q chromosome pattern may be very different in terms of their abilities. Reviews of the scientific literature do not show an obvious correlation between the size of the duplication region and the severity of the symptoms. The following sections provide information on physical features, developmental problems, medical issues and treatments for chromosome 15q duplications.

Physical Features
Unlike many other chromosomal syndromes, there are few characteristic physical findings associated with chromosome 15q syndrome. The physical findings are fairly non-specific and may include the following:

• Hypotonia: Babies with dup15q usually have hypotonia (poor muscle tone). They may appear 'floppy' and have difficulty sucking and feeding. Motor milestones such as rolling over, sitting up, and walking are significantly delayed. Older children and adults with hypotonia often tire easily. Hypotonia in dup15q syndrome generally decreases with age and sometimes progresses to hypertonia (tight muscle tone), particularly in the lower legs. 
• Physical Features: Many children with dup15q share similar facial characteristics. These include a flat nasal bridge which gives them a 'button' nose. There may be skin folds, called 'epicanthi', at the inner corners of the eyes, and the eyes may be deep set. Ears may be low-set and/or posteriorly rotated. There may also be noticeable unfolding of the edge of the ears. The palate (roof of the mouth) may be unusually high. The upper lip is often tented, leaving more of the front upper teeth exposed. There are also reports of areas of increased and reduced skin pigmentation.
• Growth: Somatic growth is decreased in about 20 – 30% of individuals with dup15q, but head growth is typically in the normal range.
• Other Abnormalities: Rarely, babies with dup15q may be born with a cleft lip and/or palate or differences in the way their hearts, kidneys, or other body organs are formed. For this reason, it is important for newly diagnosed children with dup15q to be carefully evaluated for the possibility of such structural differences. Hypogonadism (including undescended testicles) is reported in about 20% of affected individuals. Although puberty is reportedly normal in most individuals, pubertal disorders such as central precocious puberty have been observed in girls.¹ A complete genitourinary exam is recommended for children diagnosed with dup15q.

Developmental problems in chromosome 15q duplication syndrome

• Gross Motor Delays: Gross motor delays are very common, probably partly in relationship to hypotonia. In a 2005 scientific review article, sitting was reportedly achieved between 10 and 20 months of age, and walking between 2 and 3 years.¹ A current study of children with dup15q found that kids with isodicentric duplications achieved independent walking at an average of 25.5 months (range 13-54 months), with 3 children (out of 47) who were not ambulatory at the time of testing.³ The vast majority of people with dup15q are able to walk independently although some degree of ataxia (coordination problems) may be apparent.
• Fine Motor Delays: Parent report suggests that fine motor delays are widespread among children with dup15q syndrome. Nonfunctional use of objects with an immature type of exploration has been reported in the scientific literature.¹
• Cognitive Delays: Most individuals with dup15q syndrome show some degree of cognitive delay and learning disabilities, including intellectual disability (mental retardation) at the more involved end of the spectrum.
  
• Autism Spectrum Disorders: Multiple research reports document the risk of autism spectrum disorders in individuals with dup15q, although not all children with duplications develop autism. Two studies that included a total of 226 patients with autism found dup15q in approximately 3-5% of the patients.^{4, 5} Chromosome 15q11 – 13 duplications are the most frequently identified chromosome problem in individuals with autism.
• Speech/Language Delays: Most children with dup15q are affected by speech/language delays. Expressive language may be absent or may remain very poor, and is often echolalic with immediate and delayed echolalia and pronoun reversal.¹ In her study of dup15q, Dr. Carolyn Schanen found 26 of 47 children had some language at the time of their participation in the research study, with the first word achieved at an average of 28.7 months (range 7-84 months) and phrase speech beginning by an average of 44.1m (range 9-114 months). While the majority of children with dup15q experience speech delays, a small subset of children are highly verbal.
• Sensory Processing Disorders: Parent report suggests that sensory processing disorders are widespread in dup15q syndrome. These sensory processing disorders disrupt the affected child’s ability to achieve and maintain an optimal range of arousal and to adapt to challenges in daily life. These disorders are often manifested by an over-responsiveness or under-responsiveness to sensory input (sound, touch, taste, etc) or fluctuations in response to sensory input.
• Behavior Challenges: Many children with dup15q have difficulties of behavior and social communication, with a lack of response to social cues frequently observed. In older individuals, there is some suggestion of improving social awareness with age.⁶

Medical issues in chromosome 15q duplication syndrome

• Seizure Disorders: Seizures represent an important medical feature of dup15q syndrome. Over half of all people with idic(15) will have at least one seizure. The majority of those will experience their first seizure before age 5, but seizure onset may occur as late as young adulthood. There are many different types of seizures experienced by individuals with dup15q. Children can start with one seizure type and other seizure types may emerge as the child ages. The prevalence of infantile spasms among a surveyed group of families was unusually high and suggests that idic(15) could account for a significant percentage of infants experiencing those episodes.⁷ Infantile spasms associated with an hypsarrhythmic (disorganized) EEG have been reported in the scientific literature.⁸ Typical Lennox-Gastaut syndrome or Lennox-Gastaut-like syndrome was observed in the four patients with idic(15) reported by Battaglia et al.⁹ These had tonic/atonic (head drops or drop attacks), tonic–clonic seizures and atypical absences with onset between 4 and 8 years of age. Complex partial and myoclonic seizures have been observed in a number of other affected individuals.¹⁰
  
  Response to treatment is variable. For some children their first presenting seizures are easily controlled with medication. However, there are many reports in the scientific literature and from parents of seizures that are difficult to control, despite adequate antiepileptic treatment. Difficult to control seizures associated with some degree of deterioration have also been reported.^{10, 11}
• Attention Deficit Disorders: Attention Deficit Disorder/Hyperactivity has been reported in a number of cases of children with dup15q syndrome.⁹
• Anxiety Disorders: Parent report of anxiety disorders in children with dup15q syndrome has been noted among IDEAS families. More research in this area is needed.
• Increased Risk for Sudden Death: There is an increased risk of sudden, unexpected and currently unexplained death among children and young adults ages 7 and older with chromosome 15q duplication syndrome. The risk is small, estimated at 0.5-1% per person per year. Physicians should be alert for potentially relevant symptoms and follow up their patients according to their best clinical judgment. Benzodiazepines and barbiturates should only be used if alternatives are not available, given a possible association with sudden death in this chromosomal disorder. For more information, see the Physician Advisory Sudden Death in Chromosome 15q Duplication Syndrome at www.idic15.org
• Other Medical Problems: Other reported medical problems include recurrent respiratory infections in childhood, middle ear effusions requiring tubes, eczema, precocious puberty, other menstrual irregularities, overeating and weight gain.^6,12 Scoliosis is also reported in adolescence.
  

Treatments for chromosome 15q duplication syndrome

At the present time, there is no specific treatment that can directly address the genetic changes seen in people with dup(15)q syndrome. Although the fundamental genetic imbalance cannot be reversed, therapies are available to help address many of the symptoms associated with idic(15). Physical, occupational, speech and music therapy along with special education and adaptive physical education are critical for children with dup(15)q to develop to their full potential.

Medical Management
Clinicians should be aware that individuals with chromosome 15q duplications may tolerate medications differently and may be more sensitive to side effects for some classes of medications.¹³ Thus, medications should be used with caution and any new medication should be instituted in a controlled setting, with slow titration up to the expected therapeutic dose and with a clear endpoint as to what the expected outcome for treatment is. This includes nutritional and homeopathic supplements.

A group at the University of California, Davis, reported three families, which included five people with interstitial duplications of chromosome 15. The children had ADHD, PDD or Autism.¹⁴ 3/5 were treated with methylphenidate (Ritalin) for their ADHD symptoms and responded well. One of these children had also been given a trial of adderall but did not respond as well so was placed back on methylphenidate. Risperidone had mixed effects- for one child it was beneficial and one responded poorly (no details given). Fluoxetine was not beneficial for any of the 3 children treated with it-- two had aggressive behaviors and one was reported as not responding. In other clinical settings, fluoxetine and other SSRIs have been useful for treatment of irritability associated with compulsive behavior, but clinicians should be mindful that many children with duplications of chromosome 15 have mood instability which may need to be treated with a mood stabilizer before use of an SSRI. Although much research remains to be done, oxcarbazine may be more useful for mood stabilization than valproic acid.

This information has been reviewed by IDEAS Professional Advisors Edwin Cook, MD at the University of Illinois at Chicago and Carolyn Schanen, MD, PhD, Head of Human Genetics Research for Nemours Biomedical Research.

Information Last Updated: July 25, 2008

References

1. Battaglia, A: The inv dup(15) or idic(15) syndrome: a clinically recognizable neurogenetic disorder. Brain Dev. 2005. 27:365-369.   
2. What is Autism, Isodicentric Chromosome 15. (2002) Exploring Autism Website sponsored by National Alliance for Autism Research,  http://www.exploringautism.org/autism/iso_chr15.htm
3. Schanen, C: Molecular Investigations of Duplications of Chromosome 15 Update.  Published in MIRROR Newsletter, Fall 2006.
4. Schroer RJ, Phelan MC, Michaelis RC, et al.: Autism and maternally derived aberrations of chromosome 15q American Journal of Medical Genetics. 1998;76:327-336.
5. Wang CH, Villaca-Norat E, Papendick BD: Molecular analysis of the chromosome 15q11-q13 region in children with autism American Journal of Human Genetics. 1998;63.   
6. Dennis NR, Veltman MW, Thompson R, Craig E, Bolton PF, Thomas NS: Clinical findings in 33 subjects with large supernumerary marker(15) chromosomes and 3 subjects with triplication of 15q11-q13. Am J Med Genet A. 2006 Mar 1;140(5):434-41.  
7. Finucane, B.  Results of the IDEAS Seizure Survey.  Poster presentation at the 2004 Annual Meeting, American Society of Medical Genetics.
8. Bingham PM, Spinner NB, Sovinsky L, Zackai EH, Chance PF. Infantile spasms associated with proximal duplication of chromosome 15q. Pediatr Neurol. 1996; 15:163–5.
9. Battaglia A, Gurrieri F, Bertini E, Bellacosa A, Pomponi MG, Paravatou-Petsotas M, et al. The inv dup(15) syndrome: a clinically recognizable syndrome with altered behaviour, mental retardation and epilepsy. Neurology 1997;48:1081–6.  
10. Gillberg C, Steffenburg S, Wahlstrom J, Gillberg IC, Sjostedt A, Martinsson T, et al. Autism associated with marker chromosome. J Am Acad Child Adolesc Psychiatry 1991;30:489–94.    
11. Crolla JA, Harvey JF, Sitch FL, Dennis NR. Supernumerary marker 15 chromosomes: a clinical, molecular and FISH approach to diagnosis and prognosis. Hum Genet 1995;95:161–70.
12. Grosso S, Balestri P, Anichini C, Bartalini G, Pucci L, Morgese G, Berardi R.: Pubertal disorders in inv dup(15) syndrome. Gynecol Endocrinol. 2001 Jun;15(3):165-9  
13. Schanen, C: Research update on chromosome 15 duplications – idic(15) and interstitial duplications: The duplication 15q syndrome.  Presentation at 2005 International Conference on Isodicentric 15 and Related Disorders.  
14. Thomas JA, Johnson J, Peterson Kraai TL, et al.: Genetic and clinical characterization of patients with an interstitial duplication 15q11-q13, emphasizing behavioral phenotype and response to treatment Am J Med Genet A. 2003;119:111-120