CHARGE syndrome includes hypogonadotropic hypogonadism and abnormal olfactory bulb development

Context: CHARGE ( coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear abnormalities, and/or hearing loss defect) syndrome consists of a combination of congenital malformations including genital hypoplasia and retarded growth. Objective: The objective of the study was to study gonadotropic axis function and growth parameters in CHARGE syndrome. Design: This was a retrospective study. Patients: The study included 32 children with CHARGE syndrome. Results: Nineteen of 20 affected boys had micropenis and/or cryptorchidism, consistent with hypogonadotropic hypogonadism during fetal life. None of the boys was of pubertal age. Seven of nine boys tested before the age of 5 months during the neonatal peak period had extremely low testosterone levels. LH response to GnRH stimulation was variable during the first year of life and not correlated with existing clinical abnormalities. None of the girls over the age of 12 yr (n = 7) had begun puberty spontaneously, and a lack of response to GnRH stimulation was documented in five of them. Olfactory evaluation (n = 10) and magnetic resonance imaging (n = 18) of the forebrain revealed defective sense of smell and abnormal olfactory bulbs in all cases. Cardiorespiratory and nutritional problems were corrected, but the mean height of the 25 children who had reached 5 yr of age was -2 +/- 0.2 SD score. Height was not correlated with birth length or body mass index. GH deficiency was diagnosed in only three children. Conclusion: These findings suggest that CHARGE syndrome includes the main features of Kallmann syndrome, which is defined by hypogonadotropic hypogonadism combined with a defective sense of smell and abnormal olfactory bulb development. This forebrain abnormality, if confirmed in a larger group of patients, could serve as a major new criterion for the diagnosis of CHARGE syndrome.