Some characteristics of CHARGE syndrome overlap with those of other conditions including: VACTERL association, DiGeorge sequence [42], Velo-cardio-facial syndrome (VCFS), Cat Eye syndrome, retinoic acid embryopathy, and PAX2 abnormalities (The PAX2 gene is expressed in primitive cells of the kidney, ureter, eye, ear and central nervous system). Furthermore, several different structural chromosome abnormalities have been reported in children with coloboma, choanal atresia, and/or heart defects (some examples are: deletion 18q22.3-qter, duplication 2q37.3-qter, deletion 3p25.1-pter, deletion 22q11.1-qter, duplication 14q22-q24.3 and duplication 8q22-qter). Although still very rare, since the discovery of the CHD7 gene mutation, several patients with a submicroscopic deletion of 8q12 that includes the CHD7 gene have been reported [42].
It is important to rule out a submicroscopic chromosomal deletion of 22q11 with FISH analysis in all patients suspected of CHARGE syndrome, especially those with thymic hypoplasia and hypocalcemia. PAX2 abnormalities can lead to renal problems and ocular coloboma but few of the other features of CHARGE syndrome have been observed in such children [43].
The syndrome with hypoplasia of the depressor anguli oris muscle and cardiac defects also overlaps with both CHARGE syndrome and Velo-cardio-facial syndrome (VCFS). Retinoic acid embryopathy can produce ear, face, heart and cranial nerve defects similar to CHARGE syndrome, however, brain malformations resulting from retinoic acid embryopathy are usually much more severe. Exposure to retinoic acid during critical periods of morphogenesis has not been reported in children with CHARGE syndrome.
Genetic counseling
Most cases of CHARGE syndrome are sporadic, occurring in an otherwise normal family. The presence of CHARGE syndrome like features should prompt a detailed evaluation of the family members including parents. There are a number of overlapping features with other conditions such as DiGeorge syndrome, VATER, Oculo-auriculo-vertebral syndrome thus all children/adults suspected with CHARGE syndrome should have a formal genetics consultation. The discovery of the CHD7 gene has led to the conclusion that most patients with CHARGE syndrome have a de novo autosomal dominant mutation. The first parent-to-child transmissions of CHD7 mutations, as well as germ line mosaicism, have already been identified by the Baylor group [25] and independently by the Vissers group [36]. The documented empiric recurrence risk is around 2%. Two separate studies have revealed that advanced paternal age is associated with sporadic cases of CHARGE syndrome [44,45]. The recent gene discovery will impact on genetic counseling and prenatal diagnosis issues.
Antenatal diagnosis
Most of the abnormalities associated with CHARGE syndrome are difficult to diagnose antenatally through ultrasound unless there is a high index of suspicion with the presence of polyhydramnios. However, focused ultrasound for detection of external ear anomalies, choanal atresia, semicircular canal agenesis and arhinencephaly should lead to a higher prenatal defection rate. Moreover, arhinencephaly and semicircular canal agenesis were two constant features in fetuses with CHARGE syndrome and CHD7 mutations [35]. If the CHD7 mutation is discovered in the index CHARGE individual, then reliable prenatal diagnosis is possible by chorionic villus sampling or amniocentesis.
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