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Abstract
20p chromosome inverted duplication deletion syndrome is a rare chromosomal disorder in which the short arm segment 20p11.2–p13 and the deleted subtopic region 20p13–20 replicate simultaneously. Patients with this syndrome are mainly presented with intellectual disability and motor development delay. We report here a middle childhood case of this syndrome characterised by intellectual disability, backward movement, unique facial features, congenital heart disease: ventricular septal defect, patent foramen ovale, pulmonary hypertension and congenital anorectal malformation. The patient’s chromosome karyotyping analysis showed a short arm duplication on chromosome 20, described as 46, XY, 20p+?; his parents’ karyotyping analysis is normal. Later genotype analysis by array-single nucleotide polymorphisms identified a total of 107 genome-wide copy number variations and we detected a new 1.3 Mb deletion (chr20:63 244–1 349 002) and 20.2 Mb duplication (chr20:1 608 108–24 174 965) from 20p13 to 20p11.2 using infinium asian screening array-24 V1.0 BeadChip (Illumina Inc., San Diego, USA).
- Genetic screening / counselling
- Pediatrics
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Background
Chromosome 20p harbours 535 identified genes, some of which have been associated with critical aspects of human development and health. Chromosome 20p inverted duplication deletion (20 p inv dup del) syndrome1 2 is another complex genetic disorder of chromosome 20p first documented by Leclercq et al.3 The characteristics of this syndrome include typical facial features and significant neurodevelopmental abnormalities,4 resembling 20p13 deletion, which is linked to delayed motor and language development, intellectual disability, epilepsy and mild facial deformities.5 6
In this report, we present a case of 20p inv dup del syndrome accompanied with duplication of a specific segment on the short arm of chromosome 20 (20p11.2–p13) and the deletion of the subtelomeric region (20p13-pter).
Case presentation
A male term neonate was admitted due to lack of anus on the day of birth. He was then diagnosed with congenital anorectal malformation (ARM; in this case, high anal atresia), congenital heart disease (CHD): ventricular septal defect (VSD), patent foramen ovale (PFO), pulmonary hypertension (PH) and toe deformity. He was the second child of his mother’s fourth pregnancy who was naturally born at 36 weeks 4 days of gestation without special family history and abnormal prenatal examinations. The patient was born without hypoxia or asphyxia. During the neonatal period, he underwent sigmoid-colostomy surgery for the high anal atresia. After the surgery, he developed severe hyperbilirubinemia and received blood exchange treatment after surgery. At infancy, he underwent open-heart repair for VSD. Later on, he underwent anal plasty and the subsequent surgery to close the fistula. The patient in his early childhood is not yet able to walk independently, mentally retarded and with delayed language development (not yet able to say ‘daddy’ or ‘mommy’) at the moment of examination. MRI of his head showed mild hypoplasia of the anterior pituitary. His hearing was normal by the test of brainstem auditory evoked potential. He had intractable constipation and could not control or resolve his stools; he was then diagnosed with congenital megacolon via intestinal-mucosal biopsy and will need surgery again.
Moreover, the child had facial features typical of his condition: round face, prominent cheeks, midfacial hypoplasia, raised forehead, flared nose with wide bridge, relative macroglossia and arched eyebrows. As he grew older, these facial features became more apparent.
Investigations
Karyotype analysis showed that the patient had a short arm duplication of chromosome 20, described as 46, XY, 20p+? (figure 1). His parents received also the karyotype analysis, which showed normal chromosomes. Later on, we went further to identify the exact genomic lesion by analysing the whole genome copy number variations (CNV) with array-single nucleotide polymorphisms (Array-SNP) (a high-resolution oligonucleotide comparative genomic hybridisation array analysis using Infinium Asian Screening Array-24 V1.0 BeadChip (Illumina Inc., San Diego, USA)). A total of 107 CNVs were discovered and we detected a de novo 1.3 Mb deletion in 20p13 (chr20: 63 244–1 349 002) and a de novo 20.2 Mb repeation from 20p13 to 20p11.2 (chr20: 1 608 108–24 174 965; figure 2). None of his parents carried any chromosomal karyotype abnormalities.
Chromosomal analysis of the patient. (A) Chromosomal analysis of the patient revealed a duplication of the short arm of chromosome 20, described as 46, XY, 20p+?. (B) Chromosomal anomalies were found in different stages of chromosome division.
The results of microarray analysis. The SNP array system showed a de novo 1.3 Mb deletion in 20p13 (chr20: 63 244–1 349 002) and a de novo 20.2 Mb duplication ranging from 20p13 to 20p11.2 (chr20: 1 608 108–24 174 965). SNP, single nucleotide polymorphisms.
Discussion
Leclercq et al reported the world’s first case of 20p chromosome inverted duplication (inv dup del) syndrome.3 The patient was a toddler boy who was the second child of this family with healthy, intellectually normal parents and had an early childhood sister with normal development and good health. Trachoo et al 4 and Kwon et al6 each reported one case of 20p microduplications with inversion complex mutation. Trachoo et al4 summarised the list of genes included in this region. The present case has 20p abnormality via karyotype examination and performed further to find 18.16 Mb repeats in the 20p11–22p13 interval and 2.02 Mb ends in 20p13 telomere deletion by array-SNP. The general phenotypes of these cases were similar, such as facial features, developmental delay, intellectual disability and speech disorders. These are considered to be 20p trisomy-specific manifestations, suggesting that they are a direct consequence of abnormal gene coding in the affected chromosomal region. We summarise the phenotypes of all cases in table 1. The present case is the first case also presented with CHD, ARM and congenital megacolon.
Comparison of the main phenotypic characteristics found in reported cases of 20p (inv dup del) syndrome
The JAG1 gene (online mendelian inheritance in man (OMIM) #601 920) is located at 20p12.2 and encodes jagged canonical notch ligand 1. Variations in this gene have been previously associated with Alagille syndrome 1 (ALGS1; OMIM #118 450).7–9 This is an autosomal-dominant genetic syndrome, traditionally defined as intrahepatic bile duct deficiency associated with five main clinical abnormalities: cholestasis, CHD, characteristic facial phenotype, eye abnormalities and skeletal abnormalities.10 Cholestasis is caused by a lack of intrahepatic bile ducts; renal malformations (mainly renal dysplasia) exist in approximately 39% of these patients.11 Rodriguez et al12 first reported the ARM phenotype of Alagille syndrome in a male at late adolescence with signs of embryonic tail dysplasia: anal atresia, rectourethral fistula, lumbosacral abnormalities and right renal dysplasia. More than 95% of patients with ALGS1 have heart defects, especially in the right-ventricular system (from mild peripheral pulmonary stenosis to severe tetralogy of fallot involving the right ventricle and pulmonary artery). The JAG1 gene is involved in the notch signalling pathway, regulation of which is essential for the formation of ventricular-outflow tracts and ventricular trabeculae in the embryonic heart.13 Our patient’s severe jaundice in the neonatal period and CHD (especially VSD) might be strongly related to the JAG1 gene.
Bone morphogenetic protein 2 (BMP2; OMIM #112 261),14 located at 20p12.3, is a gene encoding the transforming growth factor beta (TGF-β) superfamily. The TGF-β signalling pathway constitutes a large cytokine superfamily that plays an important role in regulating the growth, migration, proliferation, differentiation and apoptosis of cells in a series of processes relating to cell differentiation and growth. Variations of BMP2 are associated with the disease brachydactyly type A2 (OMIM #112 600), facial dysmorphism, short stature and skeletal anomalies with or without cardiac anomalies (SSFSC1; OMIM #617 877). This child’s toe and cardiac abnormalities might also be related to this gene.
In addition, sex-determining region Y-related 3-hydroxy-3-methylglutaryl box 12 (SOX12; OMIM #609 147) and neurensin 2 (NRSN2; OMIM #610 666), which are located in the 20p subtelomere region, are associated with developmental delay, especially of language.15 Although the present case has language delay, no abnormalities were found with this region of SOX12 and NRSN2. Similarly, no abnormalities were shown with Syntaphilin (OMIM #604 942) and signal regulatory protein (SIRP1; OMIM #603 889) whose deletion in the 20p chromosome causes congenital neurodevelopmental defect.16 17
Recent reports indicate that the sizes of deletions and duplications of 20p might be related to the severity of clinical symptoms.6 The present case has the deletion interval of 20p13 (20:63 244–1 349 002) (1.3 Mb) and the repeat interval of −20p11.2 (20:1 608 108–24 174 965) (20.2 Mb). The repeat interval is longer than previously reported cases. Perhaps, these longer repeat intervals in −20p11.2 contain pathogenic genes leading to ARM and congenital megacolon.
Conclusion
We report a case of 20p inv dup del syndrome presented with intellectual disability, motor development delay, unique facial features, CHD (VSD and PFO) with PH and ARM. Array-SNP showed a new 1.3 Mb deletion (chr20:63 244–1 349 002) and 20.2 Mb duplication (chr20:1 608 108–24 174 965) from 20p13 to 20p11.2.
Patient’s perspective
The patient’s parents said: this is our second child diagnosed with congenital heart disease: ventricular septal defect during pregnancy. The doctor suggested performing amniocentesis for prenatal examination, but we did not follow the doctor’s advice because the first child was normal. Even more surprisingly, this child also suffers from congenital anorectal malformation, intellectual and motor disabilities, which have placed a heavy burden on himself and our family. If we can detect chromosomal problems in the fetus during pregnancy and induce labour early, it will not put such a serious burden on our families.
Learning points
20p inverted duplication syndrome is a complex and rare chromosomal disorder, and we report the case of this syndrome in a patient with congenital heart disease, congenital anorectal malformation (ARM) and congenital megacolon.
This patient’s genetic repeat length is longer than those of previously reported cases. Possibly, these long genetic fragments contain pathogenic genes related to ARM and congenital megacolon.
If we can detect chromosomal abnormalities through amniocentesis, early intervention can prevent the birth of severely defective fetuses in early pregnancy.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: WF and GY. Guarantor is GY. The following authors gave final approval of the manuscript: NY and ZT.
Funding This study was funded by Hunan Provincial Natural Science Foundation (2021JJ70082, 2021JJ70132).
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.