“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 has not been formalized. The reason is probably that diagnosis of “incomplete CHARGE” is widely and universally used as an ancillary diagnosis when a “possible CHARGE case” do not fit with the definition. This has led to my sense to an excess of “near-CHARGE” in our files, those near-CHARGE being grouped in 2 bins: (a) the children with C AND A who cannot be diagnosed as CHARGE despite the presence of the two most relevant criteria, and (b) those with C OR A and an insufficient number of other elements (the latter bin being in my experience much more heterogeneous). Pagon proposed a simple diagnostic rule (4/7 criteria) and stated that coloboma or choanal atresia were mandatory, a concept that, from the beginning, linked phenotypic recognition with an etiopathogenic mechanism. Davenport et al. [1986] delineated the facial Gestalt (square face, pinched nose, prominent columella). Oley et al. [1988] added three further anomalies: central (hypothalamic or hypophyseal) hypogonadism, renal malformations, and facial palsy. Dhooge et al. [1998] and Tellier et al. [1998] stressed the importance of inner ears abnormalities. The latter, in a review of 47 cases, pointed to the involvement of brainstem, the high frequency of cranial nerve palsies, and inner ear malformations. Moreover, Amiel et al. [2001] suggested that semi-circular canal anomalies should be considered as a major criteria for CHARGE. They suggested wisely not to take in account the cochlear anomalies, which are much less characteristic of CHARGE by themselves. Unfortunately, no rules were given on how to use these “new” findings in making a diagnosis. Based on previous literature, Blake et al. [1998] proposed a renewed definition of CHARGE based on 11 criteria. A diagnosis of CHARGE is possible in the presence of the 4 major criteria or 3 major + 1 minor. Blake's major criteria are coloboma, choanal atresia, typical ears anomalies (inner, middle, or outer), and cranial nerve dysfunction. The minor criteria are genital hypoplasia, developmental delay, cardiovascular malformations, growth deficiency, orofacial cleft tracheoesophageal fistula, and distinctive face. They further pointed to six occasional findings (thymic/parathyroid hypoplasia, renal, abdominal wall, spinal, or digital anomalies). This renewed definition is clearly a progress compared to the original rules, as brainstem dysfunctions are now a major component of CHARGE, but labyrinthine anomalies are not even mentioned. Deafness is somewhat ambiguously used, as sensorineural deafness are compatible with two criteria: characteristic ear anomaly (“mixed deafness/cochlear defect”) and cranial nerve dysfunction (“sensorineural deafness”). Among the minor criteria, Blake keeps genital anomalies, a disputable key, in my sense: cryptotchidism is nonspecific, hypoplastic labiae are very subjective, and micropenis or pubertal delay probably secondary, as does growth retardation (at least in those who have GH deficiency). In my opinion, an updated definition of CHARGE must reinforce the weight of the very specific embryological defects (thus of the pathogenesis), avoid as far as possible inclusion of nonspecific or secondary anomalies and dismiss sex-dependent criteria. Eight key features are proposed, three major (the three “C:” Coloboma, Choanal atresia, semicircular Canals anomalies) and five minors (rhombencephalic anomalies, hypothalamo-hypophyseal dysfunction, external/middle ear malformations, malformation of mediastinal viscera, and mental retardation). The eight clinical items are grouped in major and minor criteria (Tables I and II). The three major criteria I suggest here are the three most prominent noncontiguous cranial malformations. They refer to three non-overlapping embryological territories: otic placode, optic vesicle, and midcranial medial structures. They are independent of functional criteria as facial palsy or mental handicap and can thus be assessed by fetal pathologists. As previously suggested by Amiel et al. [2001] and Stjernholm [2003], the key sign in inner ear is semicircular canal anomalies, which show a high specificity, and not cochlear anomalies, which are encountered in many CHARGE cases but also in a host of unrelated syndromes and in non syndromic deafness. By contrast, hypoplastic canals are observed in very few entities, most of them resulting from 1st and 2nd arch defects (Wildervank, Goldenhar,…). For that reason (specificity and sensitivity), I propose that labyrinthine anomalies are at the same level of diagnostic significance that coloboma and choanal atresia. The five minor criteria are selected as an attempt to define CHARGE by primary, nonoverlapping disturbances, rather than by secondary features. These five criteria point to topographically distinct areas. Most of the clinical features proposed by Blake et al. [1998] are present in some way in this proposal, although their weight and interdependencies are different. Rhombencephalic anomalies (i.e. brainstem and cranial nerve VII to XII dysfunctions). This criterion allows consideration of facial palsy, swallowing difficulties, and sensorineural deafness (including deafness related to abnormal development of the organ of Corti). Hypophyseal and/or hypothalamic dysfunction. This key which encompass GH or gonadotrophin deficiencies replaces to a large extend the ancient G and R criteria. Delayed growth was unspecific. Now, it is only counted if it results from GH deficiency. Genital anomalies are considered only when sustained by demonstrable central-onset endocrine disturbance. This allows elimination of the irritating sex-dependence that classically makes CHARGE more easily diagnosed in male patients. Middle/external ear. This item is set for anomalies of the branchial derivatives: typical, small, simple, cup-shaped, lop pinna, and malformations of the ossicles and windows (leading to conductive deafness). Inner ear malformations are excluded here. Malformations of the intrathoracic viscera Mediastinal anomalies (heart defect and esophageal atresia) are counted once. They are relatively nonspecific blastogenic defects, but they are the most common noncephalic malformations in patients with the three major criteria, and they cannot be replaced by a more central defect. Upper CNS functioning. Mental retardation is the less developmentally founded criterion. Nevertheless, this is the only way to take account of functional forebrain anomalies, which are commonly observed in CHARGE, but poorly explained on an anatomical or histological basis. The presence of the three major criteria is necessary and sufficient to make a diagnosis of CHARGE, even if no other features are present. To allow recognition or rejection of CHARGE in patients who have only one or two major criteria, no simple scientific system could be advocated: we have to count on some rules of the thumb. If 2/3 major elements are present, CHARGE can be diagnosed if at least 3/5 minor traits are present. Patients with “borderline phenotypes” are classified in two groups: partial (or incomplete) CHARGE and atypical CHARGE. Partial CHARGE are those who have two major signs but only one minor, whereas atypical CHARGE are those who have two major and no minor, or one major sign and at least three minors. I propose here updated diagnostic criteria for CHARGE syndrome. The major criteria keep largely on with the previous ones: roughly speaking, these updated rules will not alter the diagnosis in most typical cases, and will make diagnosis easier in fetuses. For less typical patients, the new rules may lead to a different classification. The definition of partial and atypical CHARGE, as defined here, should allow diagnosis of CHARGE in a larger number of unclassifiable, borderline, and mild cases: many patients that do not fall anymore in the typical CHARGE bin (in the sense defended here) will probably fit with my definition of incomplete CHARGE. With the atypical category, I expect a diagnosis in many cases that are now ancillary classified as “possibly CHARGE” as they do not fit the more restrictive criteria imposed by Pagon's or Blake's dichotomic system.
