Updated diagnostic criteria for CHARGE syndrome: A proposal

Abstract

“CHARGE association” is a well-known entity of unknown origin. It was originally delineated by Bryan Hall [1979] in 17 children with multiple congenital anomalies (MCA) including choanal atresia and, independently by Hittner et al. [1979] in 10 MCA patients with coloboma, hence the eponymic Hall–Hittner syndrome which is sometimes used for it Graham, 2001. Pagon et al. [1981] coined “CHARGE,” an acronym summarizing the five cardinal clinical features: ocular Coloboma, Heart defects of any type, Atresia of the choanae, Retardation (of growth and/or of development), Genital anomalies, and Ear anomalies (abnormal pinnae or hearing loss). Classically, to make a diagnosis of CHARGE complex, 4/7 signs need to be present [Oley et al., 1988], and one should be either choanal atresia or a coloboma [Pagon et al., 1981]. Many other developmental anomalies have been reported in CHARGE beyond the acronymic components [Pagon et al., 1981; Oley et al., 1988; Blake et al., 1998; Tellier et al., 1998; Gorlin et al., 2001]. Among those, otic malformations, anomalies of the cranial and CNS midline structures, hypophyseal disorders, and brainstem dysfunctions have to be stressed as emerging problems hidden beyond the historical cardinal features. An association is the nonrandom cluster of developmental anomalies that results from early teratogenic events that overlap in time and space. Whereas the term association is appropriate for VATER, which is a generalized blastogenic defect, CHARGE is characterized by very specific developmental anomalies of the optic vesicle, otic capsule, midline CNS structures, and upper pharynx. CHARGE is supposed to result from abnormal differentiation of cephalic mesoderm and ectoderm (otic placode and 1st branchial cleft), abnormal setting (differentiation, migration, survival) of neural crest cells, abnormal interaction of neural crests (forming e.a. 1st and 2nd arch) with the cephalic mesoderm and the developing forebrain, and concomitant disorder in the development of the rhombencephalon out of which the neural crest cells have migrated. CHARGE is thus a complex neurocristopathy, the timing of which extends from blastogenesis (3rd week) to after the 9th week of gestation [Siebert et al., 1985; Kirby and Waldo, 1990; Lin et al., 1990]. Even though the cause is not known, the term “CHARGE syndrome” [Lubinsky, 1994; Amiel et al., 2001] is probably more appropriate, and the term “association” should be dropped. Cochleovestibular abnormalities have recently been shown to be an important additional dysplasia in CHARGE syndrome [Morgan et al., 1993; Murofushi et al., 1997; Dhooge et al., 1998; Amiel et al., 2001] In CHARGE, semicircular canals can be aplastic and vestibular functions may be severely reduced. Cranial imaging frequently reveals absence or abnormality of the semicircular canals and, less frequently, hypoplasia of the upper turn of the cochlea or, in more severe cases, Mondini anomaly. In middle ear, hypoplastic long process of the incus, abnormal/absent oval window, and absence of stapedius muscle are described. Facial nerve may show aberrant course in the temporal bone, sometimes related with facial palsy. From an embryological point of view, inner ear develops from the ectodermally-derived otic placode, whereas middle and outer ear develop between the 5th and the 9th week from the ectodermally-derived 1st branchial cleft and from the mesenchyme (of neural crest origin) of the 1st and 2nd arches. Anatomical anomalies of middle and inner ear were not directly considered at the time where CHARGE was coined, probably because technical limits of medical imaging did not allow evaluation of these signs. Anomalies of the semicircular canals are present in more than 80% of scanned CHARGE children [Morgan et al., 1993]. In another recent review of congenital aplasia of semi-circular canals with “relatively well-formed cochlea” retrospectively selected in a population of children candidate for inner ear implant electrode, Satar et al. [2003] presented a series of 15 patients. Ten of them were diagnosed as CHARGE syndrome. Among those, 85% of the cochleas were mildly or moderately dysplastic. Combined, those two series illustrate the high frequency and the high specificity of canalar anomalies in CHARGE, a point further stressed in a recent review [Stjernholm, 2003]. Although the importance of inner ear anomalies has been stressed, the practical conclusions have not been completely drawn in terms of diagnostic rules and syndrome definition. CHARGE was coined 22 years ago and has been shown to be a successful acronym giving a simple rule of the thumb for making or rejecting a diagnosis. Nevertheless, any dysmorphologist knows how often he/she is led to the diagnosis of “partial” or “atypical” CHARGE in patients who, usually, presents only with choanal atresia and some other signs. Curiously, this point has never been adequately discussed in the literature, and the definition of “partial” CHARGE ha