A 2-month-old female infant presents with anal atresia requiring urgent surgical intervention. On examination, she has a vertically elongated pupil with iris coloboma and bilateral preauricular skin tags. Cardiac evaluation reveals total anomalous pulmonary venous return (TAPVR). Karyotype analysis shows the presence of a small bisatellited supernumerary chromosome in addition to the normal chromosome 22 pair (47,XX,+mar). The structure marked **A** in the diagram represents this marker chromosome. Which of the following best describes the chromosomal composition and pathogenic mechanism underlying this patient's condition?

Explanation

## Why tetrasomy of chromosome 22q11.2 due to an inverted duplicated marker is right Cat eye syndrome (CES) is caused by the presence of a supernumerary bisatellited marker chromosome that is an inverted duplication of the proximal 22q11.2 region. This marker chromosome, in addition to the normal pair of chromosome 22s, results in four copies (tetrasomy) of the 22q11.2 region, particularly the cat eye critical region (CECR) containing genes such as CECR1/ADA2, CECR2, and ATP6V1E1. The gene dosage imbalance from this tetrasomy causes the characteristic clinical triad of coloboma (iris), anal atresia, and preauricular pits/tags, along with congenital heart disease (TAPVR in this case). The karyotype notation is 47,XX or XY,+mar, indicating the presence of an extra marker chromosome. This is the pathognomonic finding in CES (Robbins 10e Ch 5; Nelson Pediatrics 21e Ch 98). ## Why each distractor is wrong - **Monosomy of chromosome 22q11.2 with deletion of CECR1, CECR2, and ATP6V1E1**: This describes 22q11.2 deletion syndrome (DiGeorge syndrome), which is caused by loss of genetic material, not duplication. DiGeorge presents with thymic hypoplasia, hypocalcemia, and cardiac defects (conotruncal abnormalities), but does NOT present with the classic triad of coloboma, anal atresia, and preauricular tags that define CES. The mechanism is opposite — haploinsufficiency rather than gene dosage excess. - **Trisomy 22 with a balanced translocation between chromosomes 21 and 22**: Trisomy 22 is rare and embryonic lethal; it does not present with the clinical features of CES. A balanced translocation would not cause the tetrasomy of 22q11.2 seen in this patient. The karyotype in CES is 47,XX/XY,+mar, not a translocation. - **Mosaic tetrasomy of chromosome 21 with a supernumerary marker chromosome, leading to Down syndrome phenotype**: This conflates CES with Down syndrome (trisomy 21). The marker chromosome in CES is derived from chromosome 22, not chromosome 21. The clinical features (coloboma, anal atresia, preauricular tags, TAPVR) are specific to CES and do not match the Down syndrome phenotype (which includes intellectual disability, characteristic facies, cardiac defects like endocardial cushion defects, but not coloboma or anal atresia as primary features). **High-Yield:** CAT eye syndrome = **C**oloboma + **A**nal atresia + **T**ags (preauricular) + Tetrasomy 22q11.2 from an inverted duplicated marker chromosome; differentiate from 22q11.2 deletion (DiGeorge) by the presence of a supernumerary marker rather than a deletion. [cite: Robbins 10e Ch 5; Nelson Pediatrics 21e Ch 98]