Mosaic 15q duplication syndrome (tetrasomy 15q11.1-q13.2) in a child with behavior disorders: case report

Chromosome 15q duplication syndrome, also known as isodicentric chromosome 15, idic(15), or invdup(15) syndrome, is a rare chromosomal disorder characterized by distinctive features such as autism spectrum, epilepsy, and developmental delay.¹ According to the literature, the 15q11.2-q13.1 segment is the most common region of the large idic(15) syndrome that is duplicated.²,³ We report a new case of mosaic isodicentric chromosome 15 with 15q11.1-q13.2 tetrasomy (duplication of the 15q11.1-q13.2 region) in a 4-year-old female referred for medical evaluation due to autistic behavior, anxiety, facial dysmorphism, and developmental delay. Physical examination revealed large, low-set ears, a broad forehead, and malformed pinnae. She also suffered from reflux. The patient exhibited several signs of autistic behavior, including repeated and stereotyped movements (such as rotating objects) and echolalia (repetitive speech patterns). The parents described their daughter as a cheerful and loving child with good eye-to-eye contact. According to medical records, an echocardiogram showed a ventricular septal defect with no significant hemodynamic changes. An organic acids test and electroencephalogram were normal.

Array comparative genomic hybridization (array CGH) analysis of genomic DNA samples (blood) was performed using the Human Genome CGH Microarray technology platform (Agilent), containing 60,000 oligonucleotide probes. Array CGH analysis showed an abnormal female array profile with a gain of three copies in the 15q11.1-q13.2 region (10 Mb, 20,190,682-30,367,656; Build 37/Hg19) (Figure 1A). Cytogenetic analysis was performed on peripheral blood lymphocytes. Analysis of C- and G-banded metaphases showed that 15 chromosomes (30%) had the normal 46,XX karyotype, whereas 35 (70%) had the 47,XX,+mar karyotype (Figure 1B-C). Further analysis showed 47,XX,+mar[35]/46,XX[15] mosaicism. The patient’s parents did not undergo cytogenetic analysis. Due to the presence of chromosomal mosaicism in 30% of normal cells, array CGH identified amplification of only three copies of the 15q11.1q13.2 segment. However, the combination of cytogenetic analysis and array CHG indicated 15q11.1-15q13.2 tetrasomy.

Figure 1
A) Array comparative genomic hybridization analysis showing amplification of the 15q11.1-15q13.2 chromosomal region (10 Mb; 20,190,682-30,367,656; Build 37/Hg19). B) Partial G-banding: ideogram and normal chromosomes 15. C) Partial G- and C-banding: ideogram and marker chromosome 15.

The mosaic form of 15q duplication syndrome is particularly rare, occurring in only 17% of large idic(15) cases.⁴ This is in contrast to most marker chromosomes, which are more frequently observed to be mosaic.⁵ At least half of patients with idic(15) exhibit convulsions and/or spasms during childhood.⁴ The probability of epilepsy is reduced by up to 50% in idic(15) syndrome patients with mosaicism.⁴ In the case reported herein, 70% of cells carried the marker chromosome 15.

At the time of writing, the proband is 7 years old and shows no signs of epilepsy or reflux; weight is 24 kg and height is 1.25 m. Despite developmental and speech delays, she is able to speak in short sentences. She walks without difficulty and is quite active during the day; she can brush her teeth and eats a varied diet, feeding with the help of her parents. Nevertheless, she experiences anxiety, learning difficulties, fine motor impairment, and is unable to write. Our patient is receiving physical therapy, educational psychology interventions, and equine therapy. We hope our report can contribute to the literature by expanding on genotype-phenotype correlations for this syndrome.

References

• ¹
  Battaglia A. The inv dup (15) or idic (15) syndrome (Tetrasomy 15q). Orphanet J Rare Dis. 2008;3:30.
• ²
  Finucane BM, Lusk L, Arkilo D, Chamberlain S, Devinsky O, Dindot S, et al. 15q duplication syndrome and related disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, editors. GeneReviews® [Internet]. Seattle: University of Washington; 2016.
• ³
  Roberts SE, Maggouta F, Thomas NS, Jacobs PA, Crolla JA. Molecular and fluorescence in situ hybridization characterization of the breakpoints in 46 large supernumerary marker 15 chromosomes reveals an unexpected level of complexity. Am J Hum Genet. 2003;73:1061-72.
• ⁴
  Conant KD, Finucane B, Cleary N, Martin A, Muss C, Delany M, et al. A survey of seizures and current treatments in 15q duplication syndrome. Epilepsia. 2014;55:396-402.
• ⁵
  Loitzsch A, Bartsch O. Healthy 12-year-old boy with mosaic inv dup(15)(q13). Am J Hum Genet A. 2006;140:640-3.

Publication Dates

• Publication in this collection
  Jan-Feb 2019

History

• Received
  4 Sept 2018
• Accepted
  24 Oct 2018