cation in the chromosome 22q11.1q11.21 regions, consistent with a diagnosis of cat eye syndrome( CES).
DISCUSSION
CES is a rare genetic condition with variable phenotypic expression, including mild intellectual disability, dysmorphic craniofacial features, coloboma of the iris, congenital heart defects, anal atresia, and urogenital anomalies. 1 Additional eponyms for the condition include Schmid-Fracarro Syndrome 2 and Coloboma of Iris-Anal Atresia Syndrome. 3 There are no population estimates of the incidence of CES. However, it has been estimated at 1 in 50,000 to 1 in 150,000 based on reported observations in patients in Northern Switzerland over the past two decades. 4 The hallmark features of this condition are considered to be coloboma of the irises and anal atresia; however, this combined presentation is present in only 9-41 % of confirmed cases. 4-7 The patient described in our case presented with an imperforate anus as a critical diagnostic sign, and while his eyelids had dysmorphic features, including down-slanting palpebral fissures and epicanthus inversus, no coloboma of the irises were present. Cardiac anomalies are found in more than one-third of affected individuals, including atrial and ventricular septal defects, the persistence of the left superior vena cava, and total anomalous pulmonary venous return. Frequently described craniofacial features include down-slanting palpebral fissures, preauricular pits, hypertelorism, and micrognathia. Urogenital anomalies such as hypospadias, renal agenesis, hydronephrosis, and vesicoureteral reflux are also commonly reported. Affected individuals may have mild intellectual disability or emotional immaturity. 5, 6
The proband described in this case presented with several congenital anomalies, including TOF, imperforate anus, and dysmorphic craniofacial features. Our findings support those described by Jedraszek et al., further emphasizing that clinicians require a high degree of clinical suspicion to identify and confirm the diagnosis of CES, and most cases present without classically described hallmark features. 7 There are no well-accepted clinical criteria for diagnosis. Therefore, for patients with clinical suspicion of the condition, demonstrating a molecular correlate of a marker chromosome 22 consisting of two copies of the CES critical area in 22q11 or other chromosome 22 imbalance consistent with CES is sufficient to confirm the diagnosis. 3
Due to the clinical variability of CES, the differential diagnosis may be quite broad and includes conditions such as CHD7- related disorders( previously known as CHARGE syndrome), 22q11.2 microdeletion disorder( DiGeorge Syndrome), and other copy number variants that may present with congenital heart disease and craniofacial dysmorphisms. Additionally, conditions known to present with anal atresia, such as Townes-Brocks Syndrome and VACTERL-spectrum disorders, 8 can be considered.
The cytogenetics of CES varies and may arise as either a supernumerary inv dup( 22)( q111.21) order( 22)( q11.1q11.21) but also as an intrachromosomal duplication or triplication. 6 The additional chromosome 22 segments characteristic of CES arise most often as a de novo duplication rather than by familial transmission. However, both the intrachromosomal and supernumerary forms can be familial; thus, the clinician must offer familial testing to both parents. 6 Inherited cases of CES have been documented in at least 23 % of probands in a recent case series of 43 individuals with a molecular diagnosis of CES. 9 It has been demonstrated that the supernumerary bisatellited dicentric marker chromosome is typically stable but can exhibit mosaicism. 8 The CES chromosomal abnormality is shown to arise from two possible breakpoint locations. 1, 3 These breakpoints begin in the low copy repeat regions surrounding the DiGeorge syndrome / velocardiofacial syndrome deletion area. In this case, the proband had a significant family history of maternal imperforate anus with rectovaginal fistula and bilateral ear pits, which emphasized the need for parental testing. Karyotype analysis revealed the presence of an inv dup( 22)( q11) chromosome in the proband’ s mother. The father had a normal male karyotype. Genetic counseling for affected families is important in all cases. For affected individuals without evidence of reduced fertility, the recurrence risk is estimated at 50 % for every future offspring. Due to the risk for germline mosaicism, a slight risk for recurrence exists even when both parents are demonstrated to have normal non-mosaic lymphocyte karyotypes and are clinically unaffected. 3
The management of individuals with CES varies but is most often focused on surgical correction of physical differences such as cardiac defects, anal atresia, urogenital malformations, or other anatomical abnormalities. 1 The proband, in this case, had undergone successful complete cardiac repair of his TOF at six months of age and anal dilation to correct the bucket-handle type anorectal malformation. His neurodevelopment is being monitored, and he is enrolled in Birth-to- Three early intervention services. He was referred to pediatric ophthalmology and was diagnosed with bilateral Duane syndrome. Duane syndrome is a congenital and non-progressive form of strabismus( most commonly esotropia) in which horizontal eye movements are limited and associated with globe retraction, which results in narrowed palpebral fissures on adduction. 10 Amblyopia may also occur as a result of this motility disorder.
CONCLUSION
In summary, this case report illustrates the phenotypic variation in individuals with CES, including members of the same family. It is essential to recognize that, while CES most often results from a de novo variant, it can also result from familial transmission, and parental genetic testing is necessary. Additionally, while the hallmark characteristics of CES are coloboma of the irises and anal atresia, these features are not present together in the majority of affected individuals, nor are both required to raise clinical suspicion for the condition. Due to variable expressivity, diagnosis of this condition may be missed. Genetic testing is essential for diagnosis, and appropriate genetic counseling is important in regard to risk for other current or future family members.
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