Autosomal Dominant
Principles
• Pleiotropy
• Haploinsufficiency
• Association versus syndrome
Major Phenotypic Features
• Coloboma of the iris, retina, optic disc, or optic nerve
• Heart defects
• Atresia of the choanae
• Retardation of growth and development
• Genital abnormalities
• Ear anomalies
• Facial palsy
• Cleft lip
• Tracheoesophageal fistula
History and Physical Findings
Baby girl E.L. was the product of a full-term pregnancy to a 34-year-old gravida 1, para 1 mother after an uncomplicated pregnancy. At birth, it was noted that E.L.'s right ear was cupped and posteriorly rotated. Because of feeding difficulties, she was placed in the neonatal intensive care unit. Placement of a nasogastric tube was attempted but was unsuccessful in the right naris, demonstrating unilateral choanal atresia. A geneticist determined that she might have the CHARGE syndrome. Further evaluation included echocardiography, which revealed a small atrial septal defect, and ophthalmological examination demonstrating a retinal coloboma in the left eye. The atrial septal defect was repaired surgically without complications. She failed the newborn hearing screen and was subsequently diagnosed with mild to moderate sensorineural hearing loss. Testing for mutations in the gene associated with CHARGE syndrome, CHD7, demonstrated a 5418C>G heterozygous mutation in exon 26 that results in a premature termination codon (Tyr1806Ter). Mutation analyses in E.L.'s parents were negative, indicating that a de novo mutation had occurred in E.L. Consequently, the family was advised that the recurrence risk in future pregnancies was low but still possible due to parental germline mosaicism. At 1 year of age, E.L. was moderately delayed in gross motor skills and had speech delay. Her height and weight were at the 5th percentile, and head circumference was at the 10th percentile. Yearly follow-up was planned.
Background
Disease Etiology and Incidence
CHARGE syndrome (MIM 214800) is an autosomal dominant condition with multiple congenital malformations caused by mutations in the CHD7 gene in the majority of individuals tested. Estimated birth prevalence of the condition is 1 in 3000 to 1 in 12,000. However, the advent of genetic testing may reveal CHD7 mutations in atypical cases, leading to recognition of a higher incidence.
Pathogenesis
The CHD7 gene, located at 8q12, is a member of the superfamily of chromodomain helicase DNA-binding (CHD) genes. The proteins in this family are predicted to affect chromatin structure and gene expression in early embryonic development. The CHD7 gene is expressed ubiquitously in many fetal and adult tissues, including the eye, cochlea, brain, central nervous system, stomach, intestine, skeleton, heart, kidney, lung, and liver. Over 500 heterozygous nonsense and missense mutations in the CHD7 gene, as well as deletions in the 8q12 region encompassing CHD7, have been demonstrated in patients with CHARGE syndrome, indicating that haploinsufficiency for the gene causes the disease. Most mutations are novel, although a few hot spots for mutations in the gene exist. Some patients with CHARGE syndrome have no identifiable mutation in CHD7, suggesting that mutations in other loci may sometimes underlie the condition.
Phenotype and Natural History
The acronym CHARGE (coloboma, heart defects, atresia of the choanae, retardation of growth and development, genital abnormalities, ear anomalies), encompassing the most common features of the condition, was coined by dysmorphologists as a descriptive name for an association of abnormalities of unknown etiology and pathogenesis seen together more often than would be expected by chance. With the discovery of CHD7 mutations in CHARGE, the condition is now considered to be a dysmorphic syndrome, a characteristic pattern of causally related anomalies (see Chapter 14). The current major diagnostic criteria are ocular coloboma (affecting the iris, retina, choroid, or disc with or without microphthalmia), choanal atresia (unilateral or bilateral; stenosis or atresia), cranial nerve anomalies (with unilateral or bilateral facial palsy, sensorineural deafness, or swallowing problems), and characteristic ear anomalies (external ear lop or cup-shaped ear, middle ear ossicular malformations, mixed deafness, and cochlear defects). A number of other abnormalities are found less often, such as cleft lip or palate, congenital heart defect, growth deficiency, and tracheoesophageal fistula or esophageal atresia. CHARGE syndrome is diagnosable if three or four major criteria or two major and three minor criteria are found (Fig. C-9).
FIGURE C-9 Ear and eye anomalies in patients with CHARGE syndrome. See Sources & Acknowledgments.
Perinatal or early infant mortality (before 6 months of age) is seen in approximately half of affected patients and appears to be most highly correlated with the most severe congenital anomalies, including bilateral posterior choanal atresia and congenital heart defects. Gastroesophageal reflux is a significant cause of morbidity and mortality. Feeding problems are also common; as many as 50% of adolescent and adult patients require gastrostomy tube placement. Delayed puberty is found in the majority of patients with CHARGE syndrome. Developmental delay or mental retardation can range from mild to severe in the majority of individuals, and behavioral abnormalities (including hyperactivity, sleep disturbances, and obsessive-compulsive behavior) are frequent. As CHD7 mutation testing delineates more individuals with CHARGE, the features of the condition may become better defined and the phenotypic spectrum widened.
Management
If CHARGE syndrome is suspected, thorough evaluation is warranted for possible choanal atresia or stenosis (unilateral), congenital heart defect, central nervous system abnormalities, renal anomalies, hearing loss, and feeding difficulties. Management consists of surgical correction of malformations and supportive care. Developmental evaluation is an important component of follow-up. With the availability of testing for CHD7 mutations, a molecular diagnosis can be made in at least 50% of patients. SEMA3E mutations are another rare cause of the syndrome.
Inheritance Risk
Almost all cases of CHARGE syndrome are due to new dominant mutations, with the majority of mutations occurring in the paternal germline. Recurrence risk is therefore low for future offspring. There has been one known reported instance of monozygotic twins having CHARGE, as well as one family with two affected siblings (male and female). The latter situation suggests that germline mosaicism may be present with this condition. If a mutation in CHD7 is found in an affected individual and both parents test negative for the mutation, the recurrence risk for future offspring would be less than 5%. An affected individual has a 50% recurrence risk to his or her offspring.
Questions for Small Group Discussion
1. Explain the difference between an association and a syndrome. Give an example of a common association.
2. By what mechanism could haploinsufficiency for a chromodomain protein cause the pleiotropic effects of CHARGE syndrome?
3. Why would you counsel the parents of a child with a proven de novo mutation in CHD7 of a 5% recurrence risk? Would the risk change if their next child were affected?
References
Hus P, Ma A, Wilson M, et al. CHARGE syndrome: a review. J Paediatr Child Health. 2014;50:504–511.
Janssen N, Bergman JE, Swertz MA, et al. Mutation update on the CHD7 gene involved in CHARGE syndrome. Hum Mutat. 2012;33:1149–1160.
Lalani SR, Hefner MA, Belmont JW, et al. CHARGE syndrome. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1117/.
Pauli S, von Velsen N, Burfeind P, et al. CHD7 mutations causing CHARGE syndrome are predominantly of paternal origin. Clin Genet. 2012;8:234–239.