CHARGE syndrome is a multiple malformation syndrome caused by pathogenic variants in the CHD7 gene (8q12.2). It was first reported by Hittner and Hall in 1979, and in 1981 Pagon coined the acronym “CHARGE” from the initial letters of the major features.
The incidence is reported to be approximately 1 in 10,000 to 17,000 births, 5) and it is designated as an intractable disease in Japan. CHD7 gene mutations are identified in 70–90% of patients. 1)3) Most mutations are de novo, but autosomal dominant inheritance has been observed in some families.
Mortality before age 5 is high, at about 30%, 5) with major causes being heart malformations, choanal atresia, and aspiration.
QHow often does CHARGE syndrome occur?
A
It occurs in about 1 in 10,000 to 17,000 births. 5) The mortality rate before age 5 is about 30%, and severe heart malformations and choanal atresia affect prognosis. It is eligible for medical expense subsidies as a designated intractable disease.
Visual impairment: Severity varies depending on the extent and location of coloboma. Involvement of the optic nerve or macula leads to severe visual impairment.
Photophobia: Caused by abnormal pupillary function due to iris coloboma.
Hearing loss: Sensorineural hearing loss is present in 90–95% of patients. 1) Mixed hearing loss associated with semicircular canal hypoplasia is also common. When both hearing and visual impairments are severe, communication becomes extremely difficult, requiring early specialized habilitation and education.
Balance dysfunction: Hypoplasia or aplasia of the semicircular canals delays development of walking and sitting.
Feeding difficulties: Cranial nerve dysfunction and choanal atresia cause difficulty with sucking and swallowing.
CHARGE syndrome presents with multiple congenital anomalies affecting various organs.
Eyes (75-90%)
Coloboma: Most common in the choroid, retina, and optic nerve. Also occurs in the iris and lens. Prevalence 80-90%. 1)5) The severity of visual impairment depends on the size of the choroidal defect; large choroidal defects are associated with superior visual field defects and visual impairment, requiring low vision care.
Microphthalmia/Microcornea: Underdevelopment of the entire eyeball.
Cataract, Strabismus, Nystagmus: High frequency of association. Refractive errors and strabismus are also commonly seen. 3)
The impact of coloboma depends on its extent and location. Isolated iris coloboma often causes only mild visual impairment. Chorioretinal coloboma or optic nervecoloboma can lead to severe visual loss. Additionally, the retina around the coloboma is thin and prone to detachment, so regular fundus examinations are necessary.
The CHD7 gene (8q12.2) encodes chromodomain helicase DNA-binding protein (2,997 amino acids).3) CHD7 regulates the expression of numerous genes through chromatin remodeling and plays an essential role in the migration and differentiation of neural crest cells during early embryonic development.1)
The most common types of mutations are nonsense mutations (41%) and frameshift mutations (32%),4) both leading to loss of function (haploinsufficiency).3) Missense mutations are strongly associated with isolated hypogonadotropic hypogonadism (IHH), while nonsense/frameshift mutations tend to be associated with the full CHARGE syndrome phenotype.5) However, the genotype-phenotype correlation is not always clear.5)
Most mutations occur de novo. Familial recurrence due to parental mosaicism is rare but possible, so genetic counseling is recommended.
QIs CHARGE syndrome inherited?
A
Most cases are de novo, with the mutation occurring only in the child and neither parent affected. Rarely, familial recurrence occurs due to parental mosaicism. If an affected individual has children, there is a 50% chance of passing the mutation to each child. Genetic counseling is recommended.
CHD7 sequence analysis + deletion/duplication analysis: First-line test. 3) If negative, proceed to multi-gene panel or exome analysis.
Genome-wide methylation analysis (GMA): A new method to detect CHD7-specific epigenetic signatures. 3) Useful for diagnosis even when standard tests are negative.
RNA analysis / Mini-gene assay: Used to evaluate variants with unknown functional impact, such as intronic variants. 3)5)
Due to its diverse phenotypes, CHARGE syndrome requires differentiation from other syndromes. A case of misdiagnosis as Noonan syndrome for 8 years has been reported. 1)
Treatment of CHARGE syndrome is based on a multidisciplinary team approach for each organ malformation. Ophthalmology, cardiac surgery, otolaryngology, endocrinology, and rehabilitation departments collaborate.
Ophthalmologic management
Coloboma itself: No treatment exists. The focus is on correction of refractive errors and amblyopia therapy.
Retinal detachment prevention: Prophylactic laser photocoagulation may be performed at the border of a large coloboma (selected cases).
Retinal detachment treatment: Vitrectomy (with silicone oil tamponade if necessary).
Photophobia management: Use of tinted glasses.
Strabismus surgery: Surgical correction is performed in indicated cases. 3)
Systemic management
Heart malformations: Surgical repair according to each malformation (BT shunt, coarctation repair, PDA ligation, etc.). 2)5)
Choanal atresia: After emergency airway management in the neonatal period, surgical fenestration is performed. 1)
Endocrine: Testosterone replacement therapy is performed for hypogonadotropic hypogonadism. 3)4)
Hearing: Evaluate the indication for hearing aids or cochlear implants. 5)
Developmental support: Early intervention with speech therapy (ST), physical therapy (PT), and occupational therapy (OT) is important. If feeding difficulties are severe, tube feeding via gastrostomy or jejunostomy is performed.
QIs there a way to prevent retinal detachment associated with coloboma?
A
There is no treatment for coloboma itself, but laser photocoagulation may be performed at the border of a large coloboma to prevent retinal detachment (considered in selected cases). If retinal detachment occurs, vitrectomy is necessary. Regular ophthalmologic examinations for early detection are important.
The CHD7 gene encodes a chromodomain helicase DNA-binding protein consisting of 2,997 amino acids. 3) The CHD7 protein is incorporated into chromatin remodeling complexes and regulates histone modifications and RNA polymerase recruitment at enhancer and super-enhancer regions. 1)
The mechanism by which CHD7 haploinsufficiency (one allele nonfunctional) causes multiple malformations is as follows. 1)3)
Effect on neural crest cells: CHD7 deficiency impairs chromatin remodeling, disrupting gene expression involved in the development of the heart (conotruncal region), face, and ears. Effects on neural crest-derived structures have been confirmed in zebrafish and Xenopus experimental models. 1)
Effect on GnRH neurons: CHD7 deficiency impairs the formation and migration of GnRH (gonadotropin-releasing hormone)-producing neurons, leading to decreased FSH/LH secretion. This is the mechanism of hypogonadotropic hypogonadism. 4)
Complication of primary hypogonadism (new finding): In some cases, decreased expression of Leydig cell steroidogenic enzymes (P450scc, P450 17α, 3β-HSD, 17β-HSD) has been reported, also complicating primary hypogonadism. The transcription factor Ad4BP/SF-1 is normal, suggesting selective impairment at the enzyme level. Furthermore, spermatogenesis arrest and GCNIS (germ cell neoplasia in situ) have also been confirmed. 4)
Regarding the relationship between codon mutation types and phenotypes, nonsense/frameshift mutations tend to correlate with the typical CHARGE syndrome phenotype, while missense mutations have been reported to be associated with isolated IHH and mild cases. However, the genotype-phenotype correlation is not always clear. 5)
7. Latest Research and Future Perspectives (Investigational Reports)
Granadillo et al. (2021) discovered a CHD7 intronic mutation (intron4 c.2239-20_2239-6del) that could not be detected by conventional genetic analysis, using an integrated omics approach combining genome-wide methylation analysis (GMA), whole genome sequencing (WGS) reanalysis, and RNA analysis. 3) GMA confirmed a CHD7-specific epigenetic signature, and RNA analysis supported haploinsufficiency.
This approach may improve the diagnostic rate in patients for whom standard genetic testing fails to identify a causative mutation.
Continuous Spectrum Hypothesis of IHH and CHARGE Syndrome
Wu et al. (2025) conducted a literature review of 7 cases in which patients diagnosed with isolated IHH (idiopathic hypogonadotropic hypogonadism) were re-diagnosed with CHARGE syndrome, showing that CHD7 mutations can be a common genetic basis for CS and IHH. 5) It has been proposed that IHH and CHARGE syndrome may form a continuous spectrum.
Traisrisilp et al. (2021) showed that subtle prenatal ultrasound findings (ear abnormalities, renal rotation abnormalities, lack of response to acoustic stimulation) can be sonographic markers for CHARGE syndrome. 2) Combined with fetal MRI for CNS evaluation, this is expected to improve the accuracy of prenatal diagnosis.
Saenz Hinojosa S, Reyes C, Romero VI. Diagnosis challenges in CHARGE syndrome: A novel variant and clinical description. Heliyon. 2024;10:e28024.
Traisrisilp K, Chankhunaphas W, Sittiwangkul R, Phokaew C, Shotelersuk V, Tongsong T. Prenatal sonographic features of CHARGE syndrome. Diagnostics. 2021;11:415.
Granadillo JL, Wegner DJ, Paul AJ, et al. Discovery of a novel CHD7 CHARGE syndrome variant by integrated omics analyses. Am J Med Genet A. 2021;185(2):544-548.
Yoshida Y, Ogawa S, Meguro S, et al. CHARGE syndrome with both primary and secondary hypogonadism. IJU Case Rep. 2024;7:197-200.
Wu J, Huang Z, Zhu B, et al. De novo CHD7 variant in a CHARGE syndrome preterm infant initially diagnosed as idiopathic hypogonadotropic hypogonadism: a case report and literature review. BMC Pediatr. 2025;25:926.
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