Testicular sex cord-stromal tumor in a boy with 2q37 deletion syndrome
© SAKAI et al.; licensee BioMed Central Ltd. 2014
Received: 3 July 2013
Accepted: 6 February 2014
Published: 22 April 2014
2q37 deletion syndrome is a rare congenital disorder that is characterized by facial dysmorphism, obesity, vascular and skeletal malformations, and a variable degree of intellectual disability. To date, common but variable phenotypes, such as skeletal or digit malformations and obesity, have been associated with the deleted size or affected genes at chromosome 2q37. However, it remains elusive whether 2q37 deletion per se or other genetic factors, such as copy number variations (CNVs), may confer the risk for the tumorigenic condition.
We report a two-year-old Japanese boy with 2q37 deletion syndrome who exhibited the typical facial appearance, coarctation of the aorta, and a global developmental delay, while lacking the symptoms of brachydactyly and obesity. He developed a sex cord-stromal tumor of the right testis at three months of age. The array comparative genome hybridization analysis identified an 8.2-Mb deletion at 2q37.1 (chr2:234,275,216-242,674,807) and it further revealed two additional CNVs: duplications at 1p36.33–p36.32 (chr1:834,101–2,567,832) and 20p12.3 (chr20:5,425,762–5,593,096). The quantitative PCRs confirmed the heterozygous deletion of HDAC4 at 2q37.3 and duplications of DVL1 at 1q36 and GPCPD1 at 20p12.3.
This study describes the unique phenotypes in a boy with 2q37 deletion and additional CNVs at 1p36.33–p36.32 and 20p12.3. The data provide evidence that the phenotypic variations and unusual complications of 2q37 deletion syndrome are not simply explained by the deleted size or genes located at 2q37, but that external CNVs may account at least in part for their variant phenotypes. Accumulating the CNV data for chromosomal disorders will be beneficial for understanding the genetic effects of concurrent CNVs on the syndromic phenotypes and rare complications.
Keywords2q37 deletion syndrome Comparative genome hybridization (CGH) Copy number variation (CNV) And testicular sex cord-stromal tumor
2q37 deletion (del2q37) syndrome is a rare chromosomal disorder that is characterized by congenital hypotonia, cardiovascular anomalies, and mild to severe developmental delays [1–8]. The characteristic facial appearance includes a prominent forehead, sparse hair, highly arched eyebrows, deep-set eyes, a flat nasal bridge, a thin upper lip, and minor ear abnormalities . To date, common but variable phenotypes, such as skeletal or digit malformations and obesity, have been associated with the deleted size or affected genes at 2q37 [1, 3, 5–7]; however, it remains unknown whether the segmental loss of 2q37 by itself or additional risk factors may contribute to the development of these phenotypes [2, 3, 9–13]. In this report, we describe the complication of testicular sex cord-stromal tumor as a novel complication of del2q37 syndrome. This study provides a new line of evidence for the presence of diverse genetic backgrounds in rare chromosomal disorders. This finding also supports the theory of multiple copy number variations (CNVs) as a phenotypic modifier of neuro-developmental diseases [10, 14].
Materials and methods
This study was approved by the institutional review board at Kyushu University (#461-00) and conducted in stringent compliance to the guidelines for genetic and clinical studies. Written informed consent was obtained from the parents for publication of this case report and any accompanying images. Array comparative genome hybridization (CGH) was performed as previously described . Standard techniques of quantitative (q) PCR and immunohistochemistry were used [16, 17]. The coordinates of CNV breakpoints were defined according to the UCSC genome assembly, GRCh37/hg19 (http://genome.ucsc.edu/). More details for these methods are described in Additional file 1.
This study provides novel insight into the genotype-phenotype correlations of the rare chromosomal disorder del2q37 syndrome. First, this case manifests typical clinical features of del2q37 syndrome, while the phenotypic presentation because of the 1p36 duplication was less evident except for intelligence disability . This finding suggests that haploinsufficiency of the genes at 2q37, rather than the segmental duplications of 1p36 or 20p12, shows dominant effects on the phenotypic presentation. Specific gene functions of GPCPD1 and the duplication of 20p12 remain to be clarified, structural variations at 20p14.3, wherein this gene is located, were identified in healthy individuals of Korean ethnicity . Therefore, the 20p14.3 duplication spanning the GPCPD1 locus was unlikely to alter the phenotype of del2q37 syndrome and to produce the carcinogenic condition. While the present case did not show profound phenotype of intellectual disability compared to other cases in the literature, we focused on duplication of 1p36.33–p36.32, since the the CNVs in this region was described to confer the risk for neurodevelopmental disorders, such as autism and intellectual disability [20–22].
Recent studies supported the hypothesis that the complex phenotypes of developmental disorders might be associated with second or multiple-hit events in the genome of the affected individuals . In line with this scenario, the prominent phenotype of our case might result from the combination of HDAC4 haploinsufficiency with 1p36 duplication and/or other genetic factors that remain to be uncovered. Notably, dishevelled 1 (DVL1), the gene encoding the regulator of the canonical and non-canonical Wnt pathways, was located in the duplicated region of 1p36. It might be possible that the duplication of DVL1 accelerated tumor formation in our case. Indeed, deregulated Wnt pathways and the overexpression of DVL1 were reported in various cancers [23, 24]. Altogether, we propose that the testicular tumor in our case might be a phenotypic consequence of the haploinsufficiency of HDAC4 and the duplication of DVL1.
The human HDAC4 gene encodes a chromatin remodeling factor, histone deacetylase 4, which cooperatively regulates gene expressions with other transcription factors in the physiological process of development and differentiation of various tissues [25, 26]. Haploinsufficiency of HDAC4 has been implicated as a responsible gene for the phenotypes of brachydactyly and developmental delay since the gene locus (chr2:240016312-240220334) was mapped to the deleted regions in individuals with del2q37.3 syndrome, who presented these phenotypes . Moreover, Williams et al. clearly demonstrated that frame-shift mutations of HDAC4 itself caused brachydactyly mental retardation phenotypes . The deleted region in this study encompassed the HDAC locus, whereas he did not show the brachydactyly at two years of age. Given that brachydactyly and obesity is typically absent in early childhood of those with del2q37 syndrome, the present case may develop such phenotypes later in his life. It is thus likely that HDAC4 works as an essential regulator of gene expressions both in embryonic and postnatal development.
Drake et al.  studied a series of sporadic Wilms tumors and found evidence of a tumor suppressor role for a 360-kb critical region at 2q37 encompassing the DIS3 mitotic control homolog (S. cerevisiae)-like 2 (DIS3L2) locus. More recently, the germline mutations within the DIS3L2 gene were identified to cause Perlman syndrome, a congenital overgrowth syndrome that is predisposed to Wilms tumor . In this report, we verified that this case had a heterozygous deletion of HDAC4, but not DIS3L2 (Figures 2C and 3). DIS3L2 was therefore unlikely to cause the testicular tumor in this case, although it cannot be completely excluded that the DIS3L2 gene expression was deregulated in the affected tissue. Notably, elevated expression of HDAC4 is known to promote tumor formations, whereas its chemical inhibitors and siRNA-mediated knockdown of HDAC4 are associated with regressions of cell growth . Therefore, it is unlikely that haploinsufficiency of HDAC4 contributed per se to the testicular tumor formation in this case, whereas there is little evidence that other genes within the deleted region are associated with carcinogenesis. Concerning various unknown mechanisms underlying the unique phenotypes of this case, further genome-wide analyses to identify the unique genetic backgrounds in this case must be considered for future studies.
On the other hand, one could argue that testicular sex cord-stromal tumor is coincidental just in this case unless other cases of 2q37 deletion syndrome with similar complications are reported in the future. For better convenience in access to the clinical findings of this case, we are currently submitting the content of this report to the open resource, DECIPHER (http://decipher.sanger.ac.uk/). Also, since genome-wide data in this case are limited to the conventional CGH analysis, we must continue our efforts to identify the parental origin of accompanying CNVs, co-existence of single-nucleotide variations and their associated epigenetic as well as signaling effects  through genome-wide scans in future studies.
In conclusion, this study raised the concept that the clinical severity and the phenotypic variety of del2q37 syndrome may not be simply associated with the size of the deletion or the genes in the affected region; rather, they might also be associated with their combination with other genetic variations, such as rare CNVs. Future studies using genome-wide scanning techniques will warrant the biological basis for phenotypic variations in affected individuals.
Written informed consent was obtained from the parents for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Comparative genome hybridization
- CNV (s):
Copy number variation (s).
We thank S.W. Cheung and staff at Baylor MGL for CGH analysis. This study was supported by JSPS KAKEN #24650199 (Y.S.), Life Science Foundation of Japan (Y.S.), Mother and Child Health Foundation (Y.S.) and Takeda Science Foundation, Japan (Y.S.).
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