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At a glance

An inherited neurodevelopmental disorder with large phenotypic variability, ranging from nearly normal to severe malformations of many organs.

Synonyms

Schmid-Fraccaro Syndrome; Partial Tetrasomy of Chromosome 22; Coloboma Anal Atresia Syndrome; Ocular Coloboma Imperforate Anus Syndrome; Chromosome 22 Partial Tetrasomy Syndrome; Inverted Duplicated 22q11 Syndrome.

History

In 1879, the Swiss ophthalmologist Otto Haab (1850-1931) was the first to describe a syndrome of anal atresia combined with coloboma. However, the extra chromosome 22 responsible for the syndrome was detected in 1965 by Getrud Schachenmann (1910-1997) and Werner Schmid (1930-2002) from Zurich, Switzerland, and Marco Fraccaro (1926-2008) from Pavia, Italy, who named it Cat Eye Syndrome (CES) because of the inferior coloboma resulting in a vertical, cat-like pupil, and the downslanting palpebral fissures, although approximately 40% of patients have no signs of coloboma. (Where G. Schachenmann’s name got lost in the synonym Schmid-Fraccaro Syndrome, remains to be elucidated.)

Incidence

In Switzerland, the incidence has been estimated to be 1 in 50,000-150,000 live births. This most likely is representative of other countries, as no racial predilection has been reported. Due to the wide clinical spectrum, CES might be underdiagnosed.

Genetic inheritance

Autosomal dominant. CES results from a duplication or triplication of a part of chromosome 22. Typically, a bisatellited small isodicentric supernumerary chromosome is present, that consists of a duplication (or triplication) of the chromosome 22pter to proximal 22q11.21 fragment. Depending on the breakpoint location, two types of the supernumerary bisatellited marker chromosome can be distinguished; the more frequent Type 1 only affects the CES critical region, while Type 2 also involves the ☞DiGeorge Syndrome critical region. The additional chromosome 22 generally arises de novo from one of the parents. There is considerable phenotypic variability in CES patients, even among affected family members. Increased parental age in patients with noninherited aberrations has been reported when compared to mean population values.

Diagnosis

Clinical features (mainly coloboma, anal atresia, and preauricular pits/tags) may lead to the diagnosis. However, due to the wide clinical spectrum of this disorder, neither coloboma nor anal atresia are mandatory features for CES and the final diagnosis is confirmed by fluorescent in situ hybridization (FISH), which shows the presence of an extra marker chromosome derived from chromosome 22 (partial extra chromosome or duplication) containing two copies of the CES region.

Clinical aspect

The clinical variability is remarkable, with the spectrum of features ranging from only minimally affected individuals to those with the full picture of malformations and lethal outcome. Minimally affected patients may show only downslanting palpebral fissures and preauricular pits or tags. However, CES is classically characterized by the combination of ocular coloboma (present in approximately 60% of patients; either uni- or bilateral; iris coloboma, total or partial coloboma ...

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