Bcl11a-Related Intellectual Disability
Summary
Clinical characteristics.
BCL11A-related intellectual disability (BCL11A-ID) is characterized by developmental delay / intellectual disability of variable degree, neonatal hypotonia, microcephaly, distinctive but variable facial characteristics, behavior problems, and asymptomatic persistence of fetal hemoglobin. Growth delay, seizures, and autism spectrum disorder have also been reported in some affected individuals.
Diagnosis/testing.
The diagnosis of BCL11A-ID is established in a proband with suggestive clinical and laboratory findings and a heterozygous pathogenic variant in BCL11A identified by molecular genetic testing.
Management.
Treatment of manifestations: Treatment is primarily supportive and dictated by symptoms. Standard antiepileptic medication for seizure disorder; standard treatment for abnormal vision and/or strabismus, sleep disturbance, scoliosis, joint laxity, gastroesophageal reflux disease (GERD), constipation, and developmental issues.
Surveillance: Assessment of growth parameters, feeding difficulties, GERD, constipation, scoliosis, developmental progress, and behavior at each visit. Monitor seizures as clinically indicated. Assessment of vision and eye alignment as needed.
Genetic counseling.
BCL11A-ID is inherited in an autosomal dominant manner; however, most affected individuals have the disorder as the result of a de novo BCL11A pathogenic variant. Once the BCL11A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
Diagnosis
Formal clinical diagnostic criteria for BCL11A-related intellectual disability (BCL11A-ID) have not been established.
Suggestive Findings
BCL11A-ID should be considered in individuals presenting with the following clinical, laboratory, and neuroimaging findings.
Clinical findings
- Mild-to-severe developmental delay or intellectual disability; AND
- Any of the following features presenting in infancy or childhood:
- Microcephaly
- Craniofacial features including flat midface, small nares, thin vermilion of the upper lip and everted vermilion of the lower lip [Dias et al 2016] (see Figure 1)
- External ear anomalies
- Strabismus
- Blue sclerae in infancy
- Generalized hypotonia of infancy
- Infant feeding difficulties
- Language delay and/or dyspraxia
- Joint laxity
- Behavioral concerns (repetitive behavior, autism spectrum disorder)
- Sleep disturbance
- Seizures
Laboratory findings. Persistence of fetal hemoglobin detected by standardized laboratory methods, such as hemoglobin HPLC (high-performance liquid chromatography) or hemoglobin electrophoresis
Nonspecific brain MRI findings. Hypoplasia of the corpus callosum, hypoplasia of the cerebellar vermis, or white matter abnormalities
Establishing the Diagnosis
The diagnosis of BCL11A-ID is established in a proband with suggestive findings by identification of a heterozygous pathogenic variant in BCL11A on molecular genetic testing (see Table 1).
Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing.
Note: Single-gene testing (sequence analysis of BCL11A, followed by gene-targeted deletion/duplication analysis) may be considered in individuals with nonfamilial persistence of fetal hemoglobin identified by hematologic assays.
CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including BCL11A) that cannot be detected by sequence analysis. See Genetically Related Disorders for discussion of individuals who have larger deletions or duplications of the 2p15-p16.1 region, which includes BCL11A and surrounding genes.
An intellectual disability (ID) multigene panel that includes BCL11A 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 at the most reasonable cost 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. Of note, given the rarity of BCL11A-ID, some panels for ID may not include this gene. (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.
Exome sequencing, which does not require the clinician to determine which gene is likely involved, yields results similar to an ID multigene panel but has the advantage that all rare genes recently identified as causing ID are represented, while some newly identified ID genes may not be included on a multigene panel.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in BCL11A-Related Intellectual Disability
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| BCL11A | Sequence analysis 3 | 21/27 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 | |
| CMA 7, 8 | 6/27 9 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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. 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.
Firth et al [2009], De Rubeis et al [2014], Iossifov et al [2014], Dias el al [2016], Cai et al [2017], Landrum et al [2018], Peron et al [2018], Soblet et al [2018], Yoshida et al [2018]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
- 7.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including BCL11A) 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 2p15-p16.1 region. CMA designs in current clinical use target the 2p15-p16.2 region.
- 8.
Includes partial or whole-gene deletions of BCL11A without disrupting other protein-coding genes (excludes contiguous gene deletion syndromes, namely 2p15-16.1 microdeletion syndrome).
- 9.
Firth et al [2009], Peter et al [2014], Balci et al [2015], Peron et al [2018]
Clinical Characteristics
Clinical Description
BCL11A-related intellectual disability (BCL11A-ID) is characterized by developmental delay / intellectual disability of variable degree (from mild to severe, but most frequently in the moderate range), neonatal hypotonia, microcephaly, distinctive but variable facial characteristics, behavior problems, and asymptomatic persistence of fetal hemoglobin (HbF). Growth delay, seizures, and autism spectrum disorder have also been reported in some affected individuals.
To date, 27 individuals have been reported with a pathogenic (or likely pathogenic) variant in BCL11A [Firth et al 2009, De Rubeis et al 2014, Iossifov et al 2014, Peter et al 2014, Balci et al 2015, Deciphering Developmental Disorders Study Group 2015, Dias et al 2016, Cai et al 2017, Landrum et al 2018, Peron et al 2018, Soblet et al 2018, Yoshida et al 2018]; the authors are aware of additional affected individuals. The following description of the phenotypic features associated with this condition is based on the reported cases and the authors' experience.
Developmental delay (DD) and intellectual disability (ID). All individuals with BCL11A-ID present with DD. Speech delay is always present, and gross and fine motor delays are usually seen as well. All affected individuals have ID, with variable levels ranging from mild to severe.
Other neurodevelopmental features:
- Neonatal hypotonia is seen in the majority of affected individuals, and may result in delayed acquisition of motor milestones (average age at walking: ~30 months). Hypotonia may resolve in childhood, though in some it persists into adolescence.
- Infant feeding difficulties are occasionally present and thought to be associated with central hypotonia as opposed to primary dysphagia.
- Ataxia and/or broad-based gait has been reported in three affected individuals.
Epilepsy has been reported in 5/25 affected individuals [Cai et al 2017, Peron et al 2018, Yoshida et al 2018].
- Various types of seizures have been described (including myoclonic, tonic, and atonic seizures; absence seizures; and spasms) without a common electroclinical pattern.
- Age at seizure onset among individuals reported in the literature varied from two months to three years.
- Seizures are usually controlled with single or combined (2) antiepileptic medication(s). Three reported individuals had seizures that were drug resistant [Peron et al 2018, Yoshida et al 2018] (see also Genetically Related Disorders).
Behavior problems. Most individuals reported have presented with behavior problems [Dias et al 2016].
- Autism spectrum disorder has been described in a subset of affected individuals [De Rubeis et al 2014, Iossifov et al 2014, Dias et al 2016, Cai et al 2017].
- Others exhibit autistic-like traits, such as repetitive behaviors.
- Other behavior problems:
- Attention deficit and self-injurious behaviors have been reported in one person each.
- Sleep disturbances have been reported in three people.
Hematologic. A key manifestation of BCL11A-ID is the persistence of fetal hemoglobin (HbF) in affected individuals. In individuals from the general population, HbF is high in the second and third trimester of gestation and in the neonatal period, physiologically decreasing after birth and within the first 12 months of life (with a transition to adult hemoglobin). Therefore, age-specific reference values for hemoglobin variants should be used up to age 24 months.
- Elevated HbF (% of total hemoglobin) has been identified in all affected individuals who have been tested [Dias et al 2016, Cai et al 2017, Peron et al 2018, Soblet et al 2018, Yoshida et al 2018].
- Persistence of HbF is not known to cause symptoms, and no affected individuals with hematologic problems have been reported thus far.
Growth. Intrauterine growth restriction (IUGR) and postnatal growth delay are occasionally present [Dias et al 2016, Cai et al 2017, Yoshida et al 2018], but more than half of the affected individuals have normal growth parameters.
Microcephaly (-2 to -3.5 SD) is seen in approximately half of affected individuals [Dias et al 2016, Cai et al 2017, Soblet et al 2018, Yoshida et al 2018].
Eyes. Strabismus has been reported in 10/21 affected individuals [Dias et al 2016, Cai et al 2017, Peron et al 2018] but no other vision or hearing impairments have been documented. Some affected children with pathogenic loss-of-function variants exhibit blue sclerae in infancy (see Genotype-Phenotype Correlations) [Dias et al 2016].
Neuroimaging. Brain MRI is normal in only a minority of affected individuals; however, most abnormal brain MRI findings are mild and/or nonspecific.
- Structural anomalies of the central nervous system can be present, including hypoplasia of the corpus callosum and/or cerebellar vermis [Dias et al 2016, Peron et al 2018].
- White matter abnormalities, including reduced white matter volume, have been reported [Dias et al 2016].
Other associated features
- Musculoskeletal features
- Joint hypermobility is a common finding (>80%) in individuals with BCL11A-ID.
- Scoliosis has occasionally been reported [Dias et al 2016, Cai et al 2017].
- Gastrointestinal problems. Infantile feeding problems with poor weight gain, gastroesophageal reflux disease (GERD), and constipation have occasionally been reported [Dias et al 2016].
- Craniofacial features. No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific.
- Affected individuals frequently have flat midface, full cheeks, small nares, thin vermilion of the upper lip, and full or everted vermilion of the lower lip [Dias et al 2016, Peron et al 2018].
- A subset of individuals have external ear anomalies, including overfolded helix, everted ears, and small earlobe [Liang et al 2009, Dias et al 2016, Soblet et al 2018].
Prognosis. BCL11A-ID is a congenital disorder without known regression of skills. Life span and typical cause of death are unknown due to the limited number of individuals reported to date and ascertainment bias toward diagnosis in childhood. However, the lack of life-limiting congenital anomalies in affected individuals suggests a favorable long-term prognosis with appropriate support. The authors are aware of two affected individuals who are alive and well at 19 and 23 years, respectively [Authors, personal observation], 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
With the limited number of affected individuals reported to date, no statistically significant genotype-phenotype correlations can be made. However, certain features described to date have been seen only in individuals with loss-of-function (nonsense and frameshift) variants [Dias et al 2016, Yoshida et al 2018]:
- Blue sclerae in infancy
- Epicanthal folds
- Micrognathia or retrognathia
- Short stature (mild)
Prevalence
The prevalence of BCL11A-ID is unknown. To date, 27 affected individuals have been reported in the literature.
Differential Diagnosis
Table 2 describes specific conditions that may have features that overlap with BCL11A-related intellectual disability (BCL11A-ID).
Note: The phenotypic features associated with BCL11A-ID are generally not sufficient to diagnose this condition. All disorders with intellectual disability (ID) without other distinctive findings should be considered in the differential diagnosis. To date more than 180 such disorders with ID have been identified. See OMIM Phenotypic Series: Autosomal dominant ID, Autosomal recessive ID, Nonsyndromic X-linked ID, and Syndromic X-linked ID.
Table 2.
Selected Disorders to Consider in the Differential Diagnosis of BCL11A-Related Intellectual Disability
| Disorder | Gene(s) | MOI | Key Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/BCL11A-ID | Distinguishing from BCL11A-ID | |||
| KANSL1-related intellectual disability syndrome | KANSL1 | AD | ID, infant hypotonia, joint hypermobility, everted lower lip, strabismus |
|
| Alpha-thalassemia X-linked intellectual disability syndrome (ATRX) | ATRX | XL |
|
|
AD = autosomal dominant; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
Peron et al [2018]
- 2.
Badens et al [2006]
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with BCL11A-ID, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with BCL11A-Related Intellectual Disability
| System/Concern | Evaluation | Comment |
|---|---|---|
| Neurologic | Assessment for hypotonia & signs/symptoms of seizures |
|
| Psychiatric/ Behavioral | Neuropsychiatric evaluation | For individuals age >18 mos: screen for behavior problems incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. |
| Constitutional | Weight, length/height, & head circumference | Assess for evidence of short stature, failure to thrive, microcephaly. |
| Eyes | Ophthalmologic evaluation | Assess for strabismus, visual acuity. |
| Musculoskeletal | Clinical evaluation for scoliosis | Consider radiographic scoliosis survey based on clinical suspicion & referral to orthopedic surgeon as appropriate. |
| Clinical evaluation for joint laxity | Consider referral to rehabilitation specialist & occupational therapist. | |
| Gastrointestinal/ Feeding | Assessment of feeding problems in infancy & for GERD at any age | Referral to feeding therapist if feeding problems identified |
| Hematologic | Hemoglobin HPLC or hemoglobin electrophoresis | Expect elevated HbF. |
| Miscellaneous/ Other | Developmental assessment |
|
| Consultation w/clinical geneticist &/or genetic counselor |
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disorder; HbF = fetal hemoglobin; HPLC = high-performance liquid chromatography; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with BCL11A-Related Intellectual Disability
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Seizures | Standardized treatment w/AEDs by experienced neurologist 1 | Many different AEDs may be effective, & no one AED has been demonstrated effective specifically for this disorder. |
| Sleep disturbances | Standard management. | Consider melatonin. |
| Abnormal vision &/or strabismus | Standard treatment(s) as recommended by ophthalmologist. | |
| Scoliosis | Standard management as recommended by orthopedist | |
| Joint laxity | PT &/or OT | |
| GERD &/or constipation | Referral to (pediatric) gastroenterologist | Symptomatic management to enhance nutritional intake & hydration |
AED = antiepileptic drug; GERD = gastroesophageal reflux disorder; OT = occupational therapy; PT = physical therapy
- 1.
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
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. In the US, early intervention is a federally funded program available in all states.
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.
Ages 5-21 years
- In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
- Discussion about transition plans including financial, vocation/employment, guardianship, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a 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 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.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one-on-one with a board-certified behavior analyst.
Consultation with a developmental pediatrician and/or a psychiatrist 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 (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Surveillance
Table 5.
Recommended Surveillance for Individuals with BCL11A-Related Intellectual Disability
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Neurologic | Monitor those w/seizures as clinically indicated. | As clinically indicated |
| Psychiatric | Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior | Monitor clinically at each visit; refer for evaluation as indicated. |
| Constitutional | Weight, length/height, & head circumference measurements plotted on standard growth chart | At each visit |
| Eyes | Ophthalmologic evaluation | As clinically indicated |
| Musculoskeletal | Monitor for scoliosis. Orthopedic evaluation as indicated. | Monitor clinically at each visit. |
| Gastrointestinal | Assessment of feeding difficulties, GERD, constipation | At each visit (particularly in infancy) |
| Miscellaneous/ Other | Monitor developmental progress & educational needs. | At each visit |
GERD = gastroesophageal reflux disorder
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.