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CHD8-Related Neurodevelopmental Disorder with Overgrowth

, MS, CCC-SLP, , MD, , ScM, CGC, , PhD, , PhD, , PhD, , PhD, , PhD, , PhD, , PhD, FACMG, , PhD, FACMG, and , PhD.

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Estimated reading time: 30 minutes

Summary

Clinical characteristics.

CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is characterized by generalized overgrowth, developmental delay / intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, sleep disturbance, and gastrointestinal issues The most common findings are the development of macrocephaly (most often during infancy) and tall stature (most typically during puberty), which is often accompanied by ASD and/or DD/ID. Most, if not all, affected individuals have some degree of DD, most commonly speech and motor delays. When present, ID is most often in the mild-to-moderate range. Sleep disturbance is characterized by difficulty with both initiation (delayed sleep onset) and maintenance (frequent night awakenings) of sleep. The most common gastrointestinal issue is constipation with or without periods of diarrhea. Less common features are hypotonia (about 30% of affected individuals), seizures (10%-15%), dystonia (rare), and Chiari I malformation (rare).

Diagnosis/testing.

The diagnosis of CHD8-NDD is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in CHD8 by molecular genetic testing.

Management.

Treatment of manifestations: Sleep disturbance may be addressed through behavioral interventions and/or pharmacologic treatment; if Chiari I malformation is present, surgical treatment may be required; standard treatment for DD/ID, seizures, and bowel dysfunction.

Surveillance: At each visit: measurement of growth parameters (including head circumference); assessment of developmental progress and educational needs; monitor for signs and symptoms of anxiety, attention-deficit/hyperactivity disorder, and aggressive or self-injurious behavior; assess for new manifestations, such as seizures, changes in tone, and signs/symptoms of cerebrospinal fluid obstruction and/or spinal cord dysfunction; screen for signs/symptoms of sleep disturbance; monitor for constipation. Consider serial imaging for asymptomatic or minimally symptomatic Chiari I malformation as clinically indicated.

Genetic counseling.

CHD8-NDD is inherited in an autosomal dominant fashion. However, most probands reported to date whose parents have undergone molecular genetic testing have the disorder as the result of a de novo CHD8 pathogenic variant. Each child of an individual with CHD8-NDD has a 50% chance of inheriting the CHD8 pathogenic variant. Once the CHD8 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) have been published.

Suggestive Findings

CHD8-NDD should be considered in individuals with the following clinical and family history findings.

Clinical findings

  • Developmental delay (DD) and/or intellectual disability (ID) (typically in the mild-to-moderate range)
  • Neuropsychiatric disorders, including autism spectrum disorder (ASD)
  • Generalized overgrowth, including tall stature and macrocephaly
  • Sleep disturbance
  • Gastrointestinal problems, especially constipation

Family history. The majority of cases of CHD8-NDD are due to a de novo pathogenic variant, and most probands represent a simplex case (i.e., a single occurrence in a family). A minority of cases of CHD8-NDD are inherited in an autosomal dominant manner (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of CHD8-NDD is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in CHD8 by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of a heterozygous CHD8 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with DD/ID and/or ASD with macrocephaly may include FMR1 analysis (molecular genetic testing for fragile X syndrome), chromosomal microarray analysis (CMA), multigene panels, and exome/genome sequencing. Note: Single-gene testing (sequence analysis of CHD8, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

  • Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including CHD8) that may not be detected by sequencing.
  • An ID, ASD, and/or overgrowth multigene panel that includes CHD8 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Further comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used. Genome sequencing may also be performed and yields results similar to an ID multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing ID, ASD, and/or overgrowth, whereas some multigene panels may not.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
  • Epigenetic signature analysis / methylation array. A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with CHD8-NDD [Aref-Eshghi et al 2020, Levy et al 2021]. Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample can therefore be considered to clarify the diagnosis in individuals with: (1) suggestive findings of CHD8-NDD but in whom no pathogenic variant in CHD8 has been identified via sequence analysis or genomic testing; or (2) suggestive findings of CHD8-NDD and a CHD8 variant of uncertain clinical significance identified by molecular genetic testing. For an introduction to epigenetic signature analysis click here.

Table 1.

Molecular Genetic Testing Used in CHD8-Related Neurodevelopmental Disorder with Overgrowth

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
CHD8 Sequence analysis 3~45%-50% 4
Gene-targeted deletion/duplication analysis 5~50%-55% 4
Chromosomal microarray 6See footnote 7.
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Prontera et al [2014], Terrone et al [2014], and Yasin et al [2019]) may not be detected by these methods.

6.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including CHD8) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 14q11.2 region. CMA designs in current clinical use target the 14q11.2 region.

7.

The vast majority of exon-level deletions/duplications in CHD8 can be detected by BOTH CMA and gene-targeted deletion/duplication analysis.

Clinical Characteristics

Clinical Description

To date, 115 individuals have been identified with a pathogenic heterozygous sequence variant in CHD8 for whom some phenotypic information is reported [Neale et al 2012, O'Roak et al 2012, Talkowski et al 2012, Bernier et al 2014, McCarthy et al 2014, Kimura et al 2016, Merner et al 2016, Stolerman et al 2016, Tatton-Brown et al 2017, Du et al 2018, Guo et al 2018, Wang et al 2018, Douzgou et al 2019, Ostrowski et al 2019, Alotaibi & Ramzan 2020, An et al 2020, Beighley et al 2020, Husson et al 2020, Tran et al 2020, Wu et al 2020, Coll-Tané et al 2021, Doummar et al 2021, Sadler et al 2021, Yamada et al 2021].

Of the 103 individuals for whom sex is known, 69 (67%) are male. This suggests a 2:1 male-to-female ratio, which is lower than the sex disparity previously reported [Douzgou et al 2019]. The reason for this sex difference is unknown, but it mirrors that of other neurodevelopmental disorders, indicating a possible ascertainment bias in who is referred for genetic testing.

The following description of the phenotypic features associated with CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is based on these reports.

Table 2.

Select Features of CHD8-Related Neurodevelopmental Disorder with Overgrowth

Feature% of Persons w/FeatureComment
Macrocephaly 80%
Tall stature 80%
ASD 75%-80%
DD/ID 75%-80%
  • Most, if not all, affected persons have some degree of DD.
  • Speech & motor delays are common.
  • ID is usually mild to moderate.
  • Possible developmental regression is observed in up to half of affected persons.
Sleep disturbances 67%
Gastrointestinal problems 63%Most frequently constipation
ADHD 50%
Anxiety 29%
Hypotonia 27%
Seizures 12%

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disorder

Neurodevelopmental/neuropsychiatric issues

  • Developmental delay (DD) in early childhood is common in individuals with CHD8-NDD. The majority are reported to have some degree of speech and/or motor delay, although the severity varies greatly. Developmental regression of social, speech, and/or motor skills in infancy and early childhood is reported in up to half of affected individuals [Bernier et al 2014, Merner et al 2016, Stolerman et al 2016, Wang et al 2018, An et al 2020, Wu et al 2020, Doummar et al 2021].
  • Speech/language delays. While most individuals gain verbal speech, there are several case reports of individuals who are nonverbal in later childhood [Douzgou et al 2019, An et al 2020].
  • Motor delays
    • When reported, delayed early motor milestones are present in 90% of affected individuals.
    • For those with delays, independent walking is usually achieved by age two years, although there is significant variability; one affected child was not yet walking at age nine years [Douzgou et al 2019].
    • Some affected individuals experience ongoing motor coordination difficulties, including poor fine motor skills [Stolerman et al 2016, Wang et al 2018, Douzgou et al 2019, Doummar et al 2021].
  • Intellectual disability (ID) is present in a majority of individuals with CHD8-NDD.
    • The severity ranges from mild to severe, although most individuals show cognitive impairment in the mild-to-moderate range.
    • Some individuals do not have ID but may have borderline intellectual functioning or learning disabilities [Bernier et al 2014].
  • Autism spectrum disorder (ASD) is diagnosed in most individuals with CHD8-NDD.
    • The average severity of autism symptoms is within the moderate range as measured by the Autism Diagnostic Observation Schedule (ADOS-2) [Bernier et al 2014].
    • A majority of affected individuals (approximately 80%) with CHD8-NDD who have ASD also have ID, ranging in severity from mild-to-severe cognitive impairment.
  • Other psychiatric conditions. Approximately 30% of individuals with CHD8-NDD have a psychiatric or behavioral diagnosis, with attention-deficit/hyperactivity disorder and anxiety disorders being the most commonly reported conditions.

Neurologic features

Macrocephaly and tall stature (typically defined as head circumference and height, respectively, that are more than 2 standard deviations above the mean for age and sex) are the most common findings among individuals with CHD8-NDD.

  • Macrocephaly is sometimes apparent at birth but often develops or is accentuated in infancy [Wang et al 2018].
  • Tall stature often becomes apparent in puberty [An et al 2020].
  • While some individuals are also reported to be overweight [Douzgou et al 2019], more often they present with a slender habitus [Bernier et al 2014], possibly because of impaired adipogenesis [Kita et al 2018]. One case study described an individual with features reminiscent of Marfan syndrome [Yamada et al 2021].

Sleep disturbance. About 70% of individuals with CHD8-NDD have disrupted sleep, including difficulty with both initiation (delayed sleep onset) and maintenance (frequent night awakenings) of sleep. While sleep problems are common among many children with neurodevelopmental disorders, there is evidence that those with CHD8-NDD experience greater difficulty falling asleep [Earl et al 2021] and higher rates of frequent or prolonged awakenings at night, possibly as a result of developmental hyperserotonemia [Coll-Tané et al 2021].

Gastrointestinal issues. Various gastrointestinal problems are common in CHD8-NDD, with the most prevalent being recurrent constipation with or without periods of diarrhea [Bernier et al 2014, Wang et al 2018, An et al 2020]. Other gastrointestinal problems in isolated case reports include the following [Kimura et al 2016, Stolerman et al 2016, Douzgou et al 2019]:

  • Inflammatory bowel disease
  • Gastropathy (without further definition of the specific issues in this particular affected individual [Bernier et al 2014])
  • Cyclical vomiting
  • Gastroesophageal reflux
  • Eosinophilic esophagitis

Facial features. Many individuals with CHD8-NDD share similar facial features, including a prominent supraorbital ridge, broad forehead with increased occipitofrontal circumference, widely spaced eyes, downslanted palpebral fissures, pointed chin, and large and/or posteriorly rotated ears [Talkowski et al 2012, Bernier et al 2014, Merner et al 2016, Alotaibi & Ramzan 2020, An et al 2020, Doummar et al 2021].

Other features reported (each in 1-2 affected individuals)

  • Respiratory abnormalities. "Respiratory problems" were reported in two affected individuals, but no details were given [Bernier et al 2014].
  • Feeding issues. Unspecified feeding problems were reported in two affected children [Guo et al 2018, Wu et al 2020].
  • Endocrine
  • Malignancy. There have been two people older than age 40 years who developed tumors [Bernier et al 2014]. However, there is no evidence that individuals with CHD8-NDD have an increased risk over the general populuation risk of developing a malignancy, and no tumor surveillance guidelines for this condition have been published.

Prognosis. There is no evidence that life span in individuals with CHD8-NDD is shortened, although limited information is available on affected adults. One reported individual is alive at age 53 years [Doummar et al 2021], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

Large population-based studies are lacking, making prevalence estimates difficult to calculate for the general population.

In one study, nine in 2,446 individuals with autism spectrum disorder and eight in 3,730 individuals with a variety of neurodevelopmental disorders were found to have a de novo loss-of-function pathogenic CHD8 variant [Bernier et al 2014]. Another study estimated the prevalence of de novo CHD8 pathogenic variants to be as high as one in 500 in a population of individuals with autism spectrum disorder [Wilkinson et al 2015]. Pathogenic CHD8 variants are particularly prevalent (12 in 710, 1.7%) among individuals with both overgrowth and intellectual disability [Tatton-Brown et al 2017].

Differential Diagnosis

Overgrowth conditions of interest in the differential diagnosis of CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) are summarized in Table 3.

Table 3.

Overgrowth Conditions to Consider in the Differential Diagnosis of CHD8-Related Neurodevelopmental Disorder with Overgrowth

Gene(s)/Genetic
Mechanism
Differential DisorderMOIClinical Features of Differential Disorder
Overlapping w/CHD8-NDDDistinguishing from CHD8-NDD
CDKN1C /
11p15 epigenetic & genomic alterations 1
Beckwith-Wiedemann syndrome Varies by genetic mechanismMacrosomiaNeonatal hypoglycemia, macroglossia, hemihyperplasia, omphalocele, embryonal tumors, visceromegaly, adrenocortical cytomegaly, renal abnormalities, ear creases/pits
DNMT3A Tatton-Brown-Rahman syndrome ADOvergrowth, DD/ID, ASD, behavior problems, hypotoniaKyphoscoliosis, cryptorchidism, hematologic malignancies, obesity
EED EED-related overgrowth (Cohen-Gibson syndrome)ADOvergrowth (tall stature, macrocephaly), mild-to-severe IDCharacteristic craniofacial features, facial hypotonia
EZH2 EZH2-related Weaver syndrome (See EZH2-Related Overgrowth.)ADTall stature, normal intellect to severe IDCharacteristic facial appearance, advanced bone age, poor coordination, soft doughy skin, camptodactyly of fingers/toes, umbilical hernia, abnormal tone, hoarse low cry in infancy
FMR1 Fragile X syndrome (See FMR1 Disorders.) XLDD/ID, ASD, anxiety & behavior problems, hypotonia, seizures, GI problems, sleep disordersCharacteristic craniofacial features, strabismus, joint laxity, flat feet, scoliosis, recurrent otitis media; adults may have mitral valve prolapse or aortic root dilatation.
GPC3
GPC4
Simpson-Golabi-Behmel syndrome type 1 XLPre- & postnatal macrosomia, mild-to-severe IDDistinctive craniofacial features, congenital anomalies, skeletal problems
NFIX Malan syndrome (OMIM 614753)ADOvergrowth, macrocephaly, DD, learning disability, ASD, hypotoniaDistinctive facial appearance, pectus excavatum, coxa valga, livedo reticularis, abnormalities on brain MRI
NSD1 Sotos syndrome ADLearning disability, mild-to-severe ID, ASD, overgrowth, seizuresDistinctive facial appearance, advanced bone age, cardiac anomalies, joint hyperlaxity, renal anomalies, scoliosis
PTCH1
SUFU
Nevoid basal cell carcinoma syndrome ADMacrocephaly, gross motor delaysJaw keratocytes, basal cell carcinomas, frontal bossing, coarse facial features, facial milia, skeletal anomalies, ectopic calcification of falx, cardiac & ovarian fibromas
PTEN PTEN hamartoma tumor syndrome ADMacrocephaly, DD, ASDBenign & malignant tumors of thyroid, breast, kidney, & endometrium, trichilemmomas, papillomatous papules
SUZ12 Imagawa-Matsumoto syndrome (OMIM 618786)ADOvergrowth, macrocephaly, hypotonia, DD, mild-to-severe IDCharacteristic facial features, advanced bone age, umbilical hernia, cryptorchidism

AD = autosomal dominant; ASD = autism spectrum disorder; CHD8-NDD = CHD8-related neurodevelopmental disorder with overgrowth; DD = developmental delay; ID = intellectual disability; GI = gastrointestinal; MOI = mode of inheritance; XL = X-linked

1.

Beckwith-Wiedemann syndrome is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5 (also known as the BWS critical region). Regulation may be disrupted by any one of numerous mechanisms (see Beckwith-Wiedemann Syndrome).

Developmental delay / intellectual disability. Because the clinical presentation of CHD8-NDD typically includes nonspecific developmental delays, all disorders associated with intellectual disability and/or developmental delay, with or without overgrowth, should be considered in the differential diagnosis. See OMIM Autosomal Dominant, Autosomal Recessive, Nonsyndromic X-Linked, and Syndromic X-Linked Intellectual Developmental Disorder Phenotypic Series.

Management

No clinical practice guidelines for CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CHD8-NDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with CHD8-Related Neurodevelopmental Disorder with Overgrowth

System/ConcernEvaluationComment
Constitutional Measurement of all growth parameters incl head circumferenceTo assess for signs of macrocephaly & generalized overgrowth
Development Developmental assessment
  • To incl eval of cognitive, speech/language, adaptive, social/emotional, & motor skills
  • Eval for early intervention / special education
  • Consider referral to developmental pediatrician, psychologist, &/or speech-language pathologist as warranted.
Psychiatric/
Behavioral
Behavioral history & exam
  • Incl screening for behavior concerns such as sleep disturbances, ADHD, anxiety, & traits suggestive of ASD
  • Consider referral to psychologist &/or psychiatrist as warranted.
Neurologic Neurologic history & exam 1
  • To incl brain MRI if HC ≥3 SDs above mean, person has rapidly ↑ HC, or signs/symptoms of CSF obstruction 2 or compression of brain stem, cerebellum, or cranial nerves. 3 Consider brain MRI if HC >2 SDs above mean, in absence of other symptoms.
  • To incl spinal cord MRI if signs/symptoms of spinal cord dysfunction 1
  • To incl EEG if history of signs/symptoms suggestive of seizures
  • Consider neurology consultation as clinically indicated.
Sleep
  • Assessment for signs/symptoms of sleep problems
  • Consider polysomnogram.
  • To incl assessment for difficulty falling asleep & frequent or prolonged awakenings at night
  • Consider referral to sleep medicine &/or psychologist, as warranted.
Gastrointestinal/
Feeding
GI- & feeding-directed history & exam
  • To incl eval for constipation & other GI problems
  • Consider referral to gastroenterologist, as warranted.
Genetic
counseling
By genetics professionals 4To inform affected persons & their families re nature, MOI, & implications of CHD8-NDD to facilitate medical & personal decision making
Family support
& resources
Assess need for:

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CSF = cerebrospinal fluid; EEG = electroencephalography; GI = gastrointestinal; HC = head circumference; MOI = mode of inheritance; MRI = magnetic resonance imaging; SD = standard deviation

1.

For example, for weakness, abnormal tone, abnormal deep tendon reflexes, loss of pain and temperature sensation, numbness/tingling of hands or feet

2.

For example, valsalva-induced occipital headache or cervical pain

3.

For example, dysphagia, central sleep apnea, hoarseness or dysarthria, dizziness, tinnitus, ataxia

4.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

There is no cure for CHD8-NDD.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Table 5.

Treatment of Manifestations in Individuals with CHD8-Related Neurodevelopmental Disorder with Overgrowth

Manifestation/ConcernTreatmentConsiderations/Other
Developmental delay /
Intellectual disability /
Behavioral issues
See Developmental Delay / Intellectual Disability Management Issues.
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for CHD8-NDD.
  • Education of parents/caregivers 1
Dystonia Standard treatment per neurologist2 affected persons w/childhood-onset progressive dystonia that was unresponsive to pharmacologic therapy experienced improvement w/deep brain stimulation. 2
Chiari I malformation Surgical treatment may incl bony decompression of foramen magnum & dorsal arch of C1.
Sleep disturbance
  • Behavioral interventions 3
  • Pharmacologic interventions may also be considered.
Bowel dysfunction Standard treatment of constipation & other GI problemsFluids, dietary fiber, bulk laxatives, osmotic agents, stimulant laxatives, or emollients as needed
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

ASM = anti-seizure medication; C1 = first cervical vertebra; GI = gastrointestinal

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

2.
3.

For example, cognitive behavioral therapy, including sleep restriction therapy

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility.
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA-based interventions, including naturalistic developmental behavioral interventions (NDBI), are targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed or supervised by a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, or other psychiatric or behavioral symptoms when necessary.

Concerns about aggressive or self-injurious behavior can be addressed by a pediatric psychiatrist or board-certified behavior analyst.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.

Table 6.

Recommended Surveillance for Individuals with CHD8-Related Neurodevelopmental Disorder with Overgrowth

System/ConcernEvaluationFrequency
Constitutional Measurement of growth parameters incl head circumferenceAt each visit 1
Development Monitor developmental progress & educational needs.
Psychiatric/
Behavioral
Monitor for signs/symptoms of anxiety, psychosis, ASD, ADHD, & aggressive or self-injurious behavior.
Neurologic Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures; changes in tone/movement disorders; & signs/symptoms of CSF obstruction, 2 compression of brain stem, cerebellum, or cranial nerves, 3 or spinal cord dysfunction. 4
Consider serial imaging for asymptomatic or minimally symptomatic Chiari I malformation detected previously. 5As clinically indicated
Sleep Screening for signs/symptoms of sleep disturbanceAt each visit
Gastrointestinal Monitor for signs/symptoms of constipation & feeding issues.
Family/
Community
Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination.

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder

1.

Head circumference should be measured until adulthood.

2.

For example, valsalva-induced occipital headache or cervical pain

3.

For example, dysphagia, central sleep apnea, hoarseness or dysarthria, dizziness, tinnitus, ataxia

4.

For example, weakness, abnormal tone, abnormal deep tendon reflexes, loss of pain and temperature sensation, numbness/tingling of hands or feet

5.

In some situations, an asymptomatic or minimally symptomatic Chiari I malformation that does not require immediate surgical intervention may be detected and may require clinical and MRI monitoring.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is an autosomal dominant disorder; the majority of affected individuals have a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

  • Most probands (85%-90%) reported to date with CHD8-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo CHD8 pathogenic variant.
  • An individual diagnosed with CHD8-NDD may have inherited a CHD8 pathogenic variant from a heterozygous parent. Details about heterozygous parents are scarce; one study reported three such parents with autistic features and nonverbal IQ scores in the borderline range [Guo et al 2018]. Another study described two parents who transmitted pathogenic CHD8 variants to their children, one from a father with autistic features, large head circumference, and recurrent sleep and gastrointestinal difficulties, and the other from a mother with mild autistic features, large head circumference, learning difficulties, and a history of childhood sleep problems [Bernier et al 2014]. There have been no published cases of parents who have the same pathogenic variant as their affected child but have no clinical features of the condition.
  • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with CHD8-NDD has a 50% chance of inheriting the CHD8 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CHD8 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the CHD8 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Unique: Understanding Rare Chromosome and Gene Disorders
    United Kingdom
    Phone: +44 (0) 1883 723356
    Email: info@rarechromo.org
  • Simons Searchlight Registry
    Simons Searchlight aims to further the understanding of rare genetic neurodevelopmental disorders.
    Phone: 855-329-5638
    Fax: 570-214-7327
    Email: coordinator@simonssearchlight.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CHD8-Related Neurodevelopmental Disorder with Overgrowth: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for CHD8-Related Neurodevelopmental Disorder with Overgrowth (View All in OMIM)

610528CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 8; CHD8
615032INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND MACROCEPHALY; IDDAM

Molecular Pathogenesis

CHD8 encodes chromodomain-helicase-DNA-binding protein 8 (CHD-8), a DNA helicase involved in several processes including transcriptional regulation, epigenetic remodeling, promotion of cell proliferation, and regulation of RNA synthesis. CHD-8 acts as a repressor by remodeling chromatin structure and recruiting histone H1 to target genes, an example being suppressing p53/TP53-mediated apoptosis. CHD-8 acts as a negative regulator of Wnt signaling by regulating beta-catenin (CTNNB1) activity. CHD-8 also acts as a transcription activator by participating in U6 RNA polymerase III transcription through interactions with zinc finger protein 143.

CHD8 is primarily expressed in both the adult and fetal brain [Weissberg & Elliott 2021]. Interestingly, increased head circumference is the most replicated finding across both human and animal studies of CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD), with mouse and zebra fish models demonstrating an increase in brain volume that is the result of overproliferation of progenitor cells in the frontal cortex during development [Sugathan et al 2014, Durak et al 2016, Katayama et al 2016, Suetterlin et al 2018].

Preliminary research in a zebra fish model suggests that gastrointestinal problems associated with CHD8 pathogenic variants may be caused by a reduced number of vagal neural crest cells, decreased intestinal mobility, and increased inflammation (see bioRxiv).

Somatic CHD8 variants may play a role in the cell cycle of gastric/colorectal cancers [Kim et al 2011]; however, there is no current evidence that individuals with CHD8-NDD are at increased risk for developing cancer. Additional research, including longitudinal studies, is needed to determine whether individuals with germline CHD8 pathogenic variants are at increased risk for specific cancer types.

Heterozygous pathogenic loss-of-function variants cause CHD8-NDD. The majority of pathogenic variants reported in association with CHD8-NDD have been deletions and truncating and splicing variants. The gene is highly intolerant to loss-of-function variants in the general population [Karczewski et al 2020]. Some de novo missense variants that potentially disrupt function have been identified [O'Roak et al 2012, Bernier et al 2014, McCarthy et al 2014, Wang et al 2018].

Mechanism of disease causation. Heterozygous loss of function

Chapter Notes

Acknowledgments

This work was supported by the National Institute of Mental Health of the National Institutes of Health, grant numbers U01MH119705 and R01MH074090. The authors would also like to thank all of the individuals and families with CHD8-related neurodevelopmental disorder with overgrowth for their participation in these research studies.

Revision History

  • 27 October 2022 (ma) Review posted live
  • 22 March 2022 (cm) Original submission

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