Chd7 Disorder

Clinical characteristics.

CHD7 disorder encompasses the entire phenotypic spectrum of heterozygous CHD7 pathogenic variants that includes CHARGE syndrome as well as subsets of features that comprise the CHARGE syndrome phenotype. The mnemonic CHARGE syndrome, introduced in the premolecular era, stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness). Following the identification of the genetic cause of CHD7 disorder, the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies. Life expectancy highly depends on the severity of manifestations; mortality can be high in the first few years when severe birth defects (particularly complex heart defects) are present and often complicated by airway and feeding issues. In childhood, adolescence, and adulthood, decreased life expectancy is likely related to a combination of residual heart defects, infections, aspiration or choking, respiratory issues including obstructive and central apnea, and possibly seizures. Despite these complications, the life expectancy for many individuals can be normal.

Diagnosis/testing.

The diagnosis of CHD7 disorder is established in a proband with suggestive clinical and imaging findings and a heterozygous pathogenic variant in or deletion of CHD7 identified by molecular genetic testing.

Management.

Treatment of manifestations: Management of the manifestations of CHD7 disorder can be complex and require a multidisciplinary approach involving clinicians, therapists, and educators.

Surveillance: Requires routine follow up of manifestations identified in infancy/childhood, as well as ongoing monitoring of growth, development, educational progress, behavior, and possible endocrine issues.

Agents/circumstances to avoid: Because of the increased risk of post-anesthesia airway complications, procedures requiring anesthesia should be minimized and combined whenever possible.

Genetic counseling.

CHD7 disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant. In rare instances, an individual with CHD7 disorder inherits a pathogenic variant from a heterozygous parent. The risk to the sibs of the proband depends on the genetic status of the proband's parents: (1) If a parent of the proband has a CHD7 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%; (2) If the CHD7 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs of a proband is approximately 1%-2% because of the possibility of parental germline mosaicism. Although many individuals with CHD7 disorder are not able to reproduce, each child of an individual with CHD7 disorder has a 50% chance of inheriting the pathogenic variant. Once the CHD7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

CHD7 disorder should be suspected in individuals with combinations of the following findings and family history.

Clinical and imaging findings

• Coloboma of the iris, retina, choroid, and/or disc, and/or anophthalmos or microphthalmos
• Choanal atresia or stenosis: unilateral or bilateral, bony or membranous, confirmed by axial sections of non-enhanced axial CT scan
• Cleft palate with or without cleft lip (Note: Choanal atresia is rare in the presence of a cleft palate.)
• Cranial nerve dysfunction or anomaly
  • Cranial nerve I. Hyposmia or anosmia
  • Cranial nerve VII. Facial palsy (unilateral or bilateral)
  • Cranial nerve VIII. Sensorineural hearing loss and/or balance problems, hypoplasia or aplasia on imaging
  • Cranial nerve IX/X. Difficulty with sucking/swallowing and aspiration, gut motility problems
• Ear malformations (most characteristic of CHD7 disorder)
  • Auricle. Short, wide ear with little or no lobe, "snipped-off" helix, prominent antihelix that is often discontinuous with tragus, triangular concha, decreased cartilage; often protruding and usually asymmetric (see Figure 1)
  • Middle ear. Ossicular malformations (resulting in a typical wedge-shaped audiogram due to mixed sensorineural and conductive hearing loss)
  • Temporal bone abnormalities (most commonly determined by temporal bone CT scan). Mondini defect of the cochlea (cochlear hypoplasia), absent or hypoplastic semicircular canals
• Tracheoesophageal fistula or esophageal atresia
• Cardiovascular malformation, including conotruncal defects (e.g., tetralogy of Fallot), AV canal defects, and aortic arch anomalies [Corsten-Janssen & Scambler 2017]
• Hypogonadotropic hypogonadism
  • Males at birth. Micropenis and cryptorchidism
  • Females at birth. Hypoplastic labia, abnormal or (rarely) absent uterus
  • Males and females. Delayed or absent puberty, often in combination with anosmia [Bergman et al 2011a]
• Developmental delay / intellectual disability, delayed motor milestones, often secondary to sensory and balance deficits
• Growth deficiency. Short stature, usually postnatal with or without growth hormone deficiency
• Other clinical features
  • Face. Square-shaped with broad forehead, broad nasal bridge, prominent nasal columella, flattened malar area, facial palsy or other asymmetry, cleft lip, and small chin (gets larger and broader with age) (See Figure 2.)
  • Neck. Short and wide with sloping shoulders [O'Grady et al 2016] (See Figure 2.)
  • Hands. Typically, short, wide palm with hockey-stick crease, short fingers, and finger-like thumb (see Figure 3); polydactyly and reduction defects in a small percentage [Van de Laar et al 2007]
• Brain MRI. Clivus hypoplasia [de Geus et al 2018], hypoplasia of cerebellar vermis [Donovan et al 2017]

Figure 1.

Ears 1a. Clipped-off helix, prominent antihelix that extends to the outer helical rim, antihelix discontinuous with the antitragus; absent lobe

Figure 2.

Face 2a. Female age 2.5 years; square face, round eye, straight nose with broad nasal root, unilateral facial palsy

Figure 3.

Hand Typical CHARGE hand: square hand, short fingers, finger-like thumb, hockey-stick palmar crease

Family history consistent with autosomal dominant inheritance. While the majority of individuals with CHD7 disorder are simplex cases (i.e., a single occurrence in a family resulting from a de novo CHD7 pathogenic variant), familial occurrences consistent with autosomal dominant inheritance and germline mosaicism have been reported [Bergman et al 2011b, Legendre et al 2017]. Note: Absence of a family history of features consistent with CHD7 disorder does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of CHD7 disorder is established in a proband with suggestive clinical and imaging findings and a heterozygous pathogenic variant in CHD7 identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous CHD7 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (CHD7 single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas genomic testing does not. Individuals with suggestive findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical findings are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

In the premolecular era, the acronym CHARGE was proposed for the combination of the clinical features coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness) of unknown cause [Pagon et al 1981]. Clinical diagnostic criteria were refined for what became called CHARGE association [Blake et al 1998, Verloes 2005]. Following the discovery that heterozygous CHD7 variants and deletions cause CHARGE syndrome [Vissers et al 2004], molecular genetic testing of family members of probands with CHARGE syndrome expanded the phenotypic spectrum to include phenotypes that do not fulfill the previously proposed CHARGE syndrome clinical diagnostic criteria [Lalani et al 2006, Delahaye et al 2007, Jongmans et al 2009, Bergman et al 2011b, Hale et al 2016]. Thus, CHD7 disorder exhibits a high degree of clinical variability even among individuals in the same family and among individuals from different families with the same pathogenic variant [Jongmans et al 2008].

This section discusses only those reports in which a CHD7 pathogenic variant has been confirmed in affected individuals. To date reports of isolated manifestations of CHD7 disorder have been rare – many of which did not document a clinical workup sufficient to identify other features in the CHD7 disorder phenotypic spectrum. Thus, the percentages in Table 2 (based on persons with molecularly confirmed CHARGE syndrome [van Ravenswaaij-Arts & Martin 2017]) are likely to change over time as individuals with a CHD7 pathogenic variant ascertained through use of a multigene panel or genomic testing undergo a complete clinical evaluation (see Table 5).

Because the majority of individuals with a pathogenic CHD7 variant have a typical CHARGE syndrome or CHARGE syndrome-like phenotype, the clinical features described below are relevant for most individuals with CHD7 disorder. In contrast, isolated hypogonadotropic hypogonadism with or without anosmia due to a pathogenic CHD7 missense variant appears to be rare [Xu et al 2018].

Genotype-Phenotype Correlations

While no clear genotype-phenotype correlations exist for CHD7-related CHARGE syndrome [Legendre et al 2017], in general, but not as a rule, missense variants are associated with a less severe phenotype [Bergman et al 2012].

CHD7-related hypogonadotropic hypogonadism with or without anosmia is more likely to be due to missense variants than nonsense variants.

Prevalence

Because of the more widespread use of genomic testing, it is currently difficult to assess the prevalence of CHD7 disorder.

In the past, when the diagnosis of CHARGE syndrome was based on clinical features or gene-specific molecular testing, its estimated prevalence ranged from one in 15,000 newborns in the Netherlands [Janssen et al 2012] to one in 8,500 in Canada [Issekutz et al 2005].