CHARGE association in a child with de Novo chromosomal aberration 46, X,der(X)t(X;2)(p22.1;q33) detected by spectral karyotyping.

EDITOR—The CHARGE association is an increasingly recognised pattern of congenital anomalies comprising colobomata, heart defects, choanal atresia, retarded growth and development, hypoplastic genitalia, and ear abnormalities/deafness. We report a case of CHARGE association with a de novo chromosomal aberration, 46,X,+der(X)t(X;2), which was detected by spectral karyotyping. The proband, an 11 year old girl, was the term product of a normal pregnancy and delivery to healthy and unrelated parents. She has a healthy younger brother. The family history is unremarkable for mental retardation and congenital malformations. Birth weight was 2870 g and Apgar scores were 7 and 7 at one and five minutes, respectively. Bilateral choanal atresia was diagnosed at birth and she was admitted to hospital with an airway for two months. At the age of 8 months, she underwent a surgical repair but left choanal stenosis persisted. At the age of 5 years, after recurrences of purulent otitis media, she underwent an adenoidectomy. At the age of 8 years, a heart murmur was heard and an echocardiogram and cardiac catheterisation showed minimal valvar pulmonary stenosis and partial anomalous venous return. Renal ultrasound showed mild enlargement of the left kidney with calculi. Because of additional growth and developmental delay, a chromosome analysis was performed on blood lymphocytes at the age of 6 years and showed 46,X,add(X)(p?) (fig 1). FISH studies using X chromosome paint probe showed that the derivative chromosome came from an autosomal chromosome. The parents’ karyotypes were normal. On present examination at 11 years, the patient’s OFC is 44 cm (−6 SD) and her height is well below the 5th centile. She functions in the mild mental retardation range. Her eye examination showed exotropia and esophoria and she has posterior embryotoxon. She exhibits a number of minor anomalies including a high nasal bridge, short columella, bulbous nasal tip, hypertelorism, simple auricles with small ear lobes, mild prognathism (figs 2 and 3), clinodactyly, and a hypertrophic clitoris with normal labia. A CT scan performed when she was 8 years old showed mild cerebral atrophy. Auditory tests and tympanometry indicated partial conductive and sensorineural hearing loss. In order to determine the origin of the derivative chromosome, spectral karyotyping analysis (SKY) was performed, as previously described. Briefly, chromosome specific libraries generated by PCR from flow sorted human chromosomes were directly labelled with nucleotides conjugated to four diVerent dyes (FITC, Rodamine, Texas Red, Cy5). All 24 chromosome libraries were hybridised simultaneously to the metaphases. Slides were washed and stained with 4'6-diamidino-2 phenylinodole (DAPI) in antifade medium. Discrimination between the diVerent spectra was done using the SD200 spectral bioimaging system (Applied Spectral Imaging Ltd, Migdal Ha’emek, Israel) and showed the correct karyotype: 46,X,+der(X)t(X;2) (fig 4). Only after re-examination of the G banded chromosomes were the breakpoints in chromosomes 2 and X assigned, and it appeared that the breakpoints were at Xp22.1 and 2q33 and the karyotype was 46,X,add(Xp?)ish. der(X)t(X;2) (p22.1;q33)(wcpX+,wcp2+). The combination of anomalies (bilateral choanal atresia, congenital heart defect, short stature, external ear anomalies with conductive hearing loss, mental retardation, and minor anomalies) found in our patient is consistent with the diagnosis of CHARGE association. Colobomata were not found in our patient. In a recent evaluation of 47 patients with CHARGE syndrome for the frequency of major anomalies, coloboma was found only in 79% of them. The cause of the CHARGE association remains