Kleefstra Syndrome
Summary
Clinical characteristics.
Kleefstra syndrome is characterized by intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate-to-severe spectrum of intellectual disability although a few individuals have mild delay and total IQ within low-normal range. While most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed; these include heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy/febrile seizures, psychiatric disorders, and extreme apathy or catatonic-like features after puberty.
Diagnosis/testing.
The diagnosis of Kleefstra syndrome is established in a proband who has a heterozygous deletion at chromosome 9q34.3 that includes at least part of EHMT1 (~50%) or a heterozygous intragenic EHMT1 pathogenic variant (~50%).
Management.
Treatment of manifestations: Ongoing routine care by a multidisciplinary team specializing in the care of children or adults with intellectual disability. Referral to age-appropriate early-childhood intervention programs, special education programs, or vocational training; speech/language therapy, physical and occupational therapy, and sensory integration therapy; specialized care for those with extreme behavior problems, movement disorders, sleep disorders, and/or epilepsy; standard treatment for vision, hearing, cardiac, renal, urologic, and other medical issues.
Surveillance: Monitoring as needed of cardiac and renal/urologic abnormalities.
Genetic counseling.
Kleefstra syndrome, caused by a deletion at 9q34.3 or pathogenic variants in EHMT1, is inherited in an autosomal dominant manner. Almost all cases reported to date have been de novo; rarely, recurrence in a family has been reported when a parent has a balanced translocation involving the 9q34.3 region or somatic mosaicism for an interstitial 9q34.3 deletion. Except for individuals with somatic mosaicism for a 9q34.3 deletion, no individuals with Kleefstra syndrome have been known to reproduce. Prenatal testing may be offered to unaffected parents of a child with a 9q34.3 deletion or an EHMT1 pathogenic variant because of the increased risk of recurrence associated with the possibility of germline mosaicism, somatic mosaicism including the germline, or a balanced chromosome translocation.
Diagnosis
Kleefstra syndrome is characterized by intellectual disability, childhood hypotonia, and distinctive facial features. A complex pattern of other findings can also be observed [Dawson et al 2002, Cormier-Daire et al 2003, Stewart et al 2004, Kleefstra et al 2005, Yatsenko et al 2005, Kleefstra et al 2006a, Kleefstra et al 2006b, Stewart & Kleefstra 2007, Kleefstra et al 2009, Yatsenko et al 2009, Willemsen et al 2012].
Suggestive Findings
Kleefstra syndrome should be suspected in individuals with the following:
- Intellectual disability, usually moderate to severe and associated with severe speech delay
- Distinctive facial features (see Clinical Description)
- Childhood hypotonia
- Visual problems (hypermetropia)
- Hearing loss (sensorineural and/or conductive)
- Motor delay
- Heart defects
- Renal/urologic defects
- Genital defects (males)
- Severe infections (respiratory)
- Epilepsy/febrile seizures
- Autism spectrum disorder
- Psychiatric disorders (mood and psychotic disorders)
- Extreme apathy or catatonic(-like) features post puberty
- Nonspecific brain abnormalities: structural defects (corpus callosum hypoplasia), cortical hypoplasia, or white matter defects
Establishing the Diagnosis
The diagnosis of Kleefstra syndrome is established in a proband who has one of the following on molecular genetic testing (see Table 1):
- A heterozygous deletion of 9q34.3 (~50% of affected individuals) [Author, personal experience]. In 28 unrelated individuals with a 9q34.3 deletion, three distinct categories were identified [Yatsenko et al 2009]:
- 50% bona fide de novo terminal deletions
- 25% interstitial deletions
- 25% complex rearrangements or derivative chromosomes
- A heterozygous pathogenic variant involving EHMT1 (~50% of affected individuals)
When the phenotypic findings suggest the diagnosis of Kleefstra syndrome, molecular genetic testing approaches can include chromosomal microarray analysis (CMA), single-gene testing, use of a multigene panel, and, rarely, karyotype.
- Chromosomal microarray analysis (CMA) uses SNP and/or oligonucleotide arrays to detect genome-wide large deletions/duplications (including EHMT1) that cannot be detected by typical sequence analysis.
- Single-gene testing. Sequence analysis of EHMT1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.Approximately 5% of individuals with Kleefstra syndrome have an intragenic deletion detectable by an assay designed to detect single-exon deletions or duplications (e.g., multiplex ligation-dependent probe amplification [MLPA], qPCR, and gene-targeted CMA). Deletions that are not intragenic but too small to be detected by CMA (e.g., containing the last part of C90RF37 and the first exon of EHMT1) require such gene-targeted methods designed for this region for detection.Note: (1) FISH cannot reliably detect deletions <50-100 kb and cannot routinely size the deletion. (2) The 9q34.3 deletion cannot be identified by routine chromosome analysis.
- An intellectual disability multigene panel that includes EHMT1 and other genes of interest (see Differential Diagnosis) may also be considered. 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- Karyotype. In rare instances, Kleefstra syndrome can be caused by a balanced chromosome rearrangement that disrupts the expression of EHMT1. If this is suspected, karyotype and FISH analysis for the 9q34.3 region can be considered. However, the typical 9q34.3 deletion cannot be identified by routine chromosome analysis.
Table 1.
Molecular Genetic Testing Used in Kleefstra Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| EHMT1 | CMA 3 | ~50% 4 |
| Sequence analysis 5 | ~50% | |
| Gene-targeted deletion/duplication analysis 6 | See footnote 7 | |
| Karyotype | Rare; see footnote 8 |
- 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.
A chromosomal microarray (CMA) that includes probe coverage of EHMT1 can detect deletions of 9q34.3 (de novo terminal deletions, complex rearrangements or derivative chromosomes, interstitial deletion).
- 4.
CMA testing is appropriate to define breakpoints of large deletions; however, intragenic deletions in EHMT1 may not be detected by this method.
- 5.
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.
- 6.
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.
- 7.
Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. Gene-targeted deletion/duplication analysis of EHMT1 may detect an additional ~5% of affected individuals who have had a normal chromosomal microarray, but this is highly dependent on the resolution and probe coverage of the array platform that was used for analysis.
- 8.
Routine karyotype will not detect the 9q34.3 deletion. Karyotype may be considered in those with features of Kleefstra syndrome in whom a pathogenic variant (mutation or deletion) of EHMT1 has not been identified using other methods (e.g., CMA, sequence analysis). Karyotype can detect balanced chromosomal rearrangements that disrupt EHMT1.
Clinical Characteristics
Clinical Description
Kleefstra syndrome has a clinically recognizable phenotype that includes physical, developmental, and behavioral features. Males and females are affected equally [Stewart et al 2004, Yatsenko et al 2005, Kleefstra et al 2006b, Stewart & Kleefstra 2007, Kleefstra et al 2009, Willemsen et al 2012].
Birth weight is usually within the normal or above-normal range; weight increases in childhood, leading to obesity (50%) [Cormier-Daire et al 2003, Kleefstra et al 2009, Willemsen et al 2012]. The facial appearance is characterized by brachy(-micro)cephaly, broad forehead, unusual shape of eyebrows (arched or straight with synophrys), mildly upslanted palpebral fissures, midface retrusion, thickened ear helices, short nose with anteverted nares, fleshy everted vermilion of the lower lip and exaggerated cupid's bow or "tented" appearance of the vermilion of the upper lip, and protruding tongue and relative prognathism (Figure 1, Figure 2).
Figure 1.
Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of (more...)
Figure 2.
Photographs of affected individuals showing the characteristic facial profile comprising brachycephaly, widely spaced eyes, synophrys/arched eyebrows, midface retrusion, protruding tongue, eversion of the vermilion of the lower lip, and prognathism of (more...)
With age, the facial appearance becomes coarser, with persisting midface retrusion and prognathism. An increased frequency of dental anomalies, specifically neonatal teeth and retention of primary dentition, has been observed.
Cognitive development. Individuals with Kleefstra syndrome exhibit a range of cognitive and adaptive functioning [Vermeulen et al 2017a]. Most affected individuals function in the moderate-to-severe spectrum of intellectual disability, although a few individuals with only mild delay are known. Rarely, individuals with normal total IQ levels who have a diagnosis of an autism spectrum disorder have been described [Bock et al 2016; Author, personal observation]. Most affected individuals have severe expressive speech delay with hardly any speech development, whereas general language development is usually at a higher level; thus, sign language or use of pictograms is of value to many affected individuals.
Behavior. Besides issues with social behavior, the behavioral phenotype includes sleep disturbances, stereotypies, mild self-injurious behaviors, and autism spectrum disorder usually recognized in early childhood. A few reports of adolescents and adults revealed extreme, progressive apathy and catatonic(-like) behavior [Verhoeven et al 2010, Vermeulen et al 2017a, Vermeulen et al 2017b].
- Sleep disturbance is characterized by frequent nocturnal and early-morning awakenings as well as excessive daytime wakefulness – in contrast to the sleep disturbance observed in Smith-Magenis syndrome.
- Sleep disturbance in affected adolescents and young adults may be a precursor to severe regression, as well as the later development of psychoses, for which treatment is recommended.
Motor development is impaired by childhood hypotonia, but almost all individuals achieve independent walking after age two to three years.
Hearing and vision impairment. A substantial proportion of individuals have hypermetropia at a young age. Hearing impairment (both conductive and sensorineuronal) may also be present starting at a young age.
Congenital heart defects are observed in a significant number of individuals with Kleefstra syndrome. In 50% a (conotruncal) heart defect is present. Abnormalities that have been reported include ASD/VSD, tetralogy of Fallot, aortic coarctation, bicuspid aortic valve, and pulmonic stenosis. Atrial flutter has been reported in a number of individuals.
Genitourinary anomalies. Renal defects, seen in 10%-30% of affected individuals, comprise vesicoureteral reflux, hydronephrosis, renal cysts, and chronic renal insufficiency. Genital defects such as hypospadias, cryptorchidism, and small penis are reported in 30% of males.
Seizures, reported in 30%, can include tonic-clonic seizures, absence seizures, and complex partial epilepsy.
Other. Several affected individuals have had talipes equinovarus. Other abnormalities that have been observed are epigastric hernia, tracheo-/bronchomalacia with respiratory insufficiency, and gastroesophageal reflux.
Life expectancy. Longitudinal data are insufficient to determine life expectancy; however, it should be noted that death in infancy or childhood can occur from complications such as heart defects and recurrent aspiration and pulmonary infections [Stewart & Kleefstra 2007].
Genotype-Phenotype Correlations
EHMT1 loss of function accounts for the majority of features in Kleefstra syndrome. Current data indicate that individuals with an intragenic EHMT1 pathogenic variant (e.g., a missense, frameshift, or nonsense variant) and those with a small (<1-Mb) 9q34.3 deletion have similar clinical findings. Individuals with larger deletions (≥1 Mb), however, generally have more severe intellectual disability and more medical problems, such as congenital anomalies, feeding problems, and respiratory problems. Pulmonary infections and aspiration difficulties in particular appear to be more severe in individuals with larger 9q34 deletions than in those with smaller deletions or intragenic EHMT1 pathogenic variants.
Nomenclature
The disorder was first recognized following widespread subtelomeric FISH studies [Knight et al 1999, Dawson et al 2002]. After the identification of an individual with a similar phenotype and a de novo balanced translocation disrupting EHMT1, it was hypothesized that haploinsufficiency of this gene caused the phenotype present in individuals with a 9q34 deletion [Kleefstra et al 2005]. Subsequent identification of additional individuals with intragenic EHMT1 defects led OMIM to assign the name Kleefstra to the syndrome.
Prevalence
Reliable figures on penetrance are not yet available. Based on data from other rare disorders involving intellectual disability [McRae et al 2017], Kleefstra syndrome is estimated to affect at least 1:120,000 individuals who have a neurodevelopmental disorder [Author, personal observation]; as many individuals with this condition are not diagnosed, the true prevalence may be much higher.
The syndrome has been identified worldwide and in all ethnic groups.
Differential Diagnosis
Kleefstra syndrome should be distinguished from other syndromes that include developmental delay, infantile hypotonia, short stature, distinctive facies, and a behavioral phenotype. The most common of these include those in Table 2, which can be distinguished using cytogenetic (FISH) and/or molecular analysis.
Table 2.
Disorders to Consider in the Differential Diagnosis of Kleefstra Syndrome
| Disorder | Gene / Genetic Mechanism | MOI | Additional Overlapping Clinical Features |
|---|---|---|---|
| Down syndrome | Trisomy 21 | Virtually all de novo | Similar facial characteristics, incl:
|
| Smith-Magenis syndrome | Deletion or mutation of RAI1 on chromosome 17p11.2 1 | Virtually all de novo |
|
| Pitt-Hopkins syndrome | Haploinsufficiency of TCF4 | Most de novo |
|
| Angelman syndrome | Disruption of maternally imprinted UBE3A | See footnote 2 |
|
| KMT2C-associated syndrome 4 | KMT2C | AD |
|
| MBD5 haploinsufficiency | See footnote 5 | AD; typically de novo |
|
AD = autosomal dominant; ASD = autism spectrum disorder; ID = intellectual disability; MOI = mode of inheritance
- 1.
Approximately 95% of individuals with Smith-Magenis syndrome have the disorder as a result of an interstitial 17p11.2 deletion, which may have been previously excluded by chromosomal microarray testing.
- 2.
The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function.
- 3.
Facial features that differentiate Kleefstra syndrome from Angelman syndrome include synophrys and everted vermilion of the lower lip. Some mildly affected individuals with Kleefstra syndrome have a ≥100-word vocabulary & speak in sentences, which would be very unusual in an individual with Angelman syndrome.
- 4.
Koemans et al [2017]
- 5.
The diagnosis of MBD5 haploinsufficiency is established in a proband with one of the following: deletion of 2q23.1 that encompasses all or part of MBD5 (~90% of affected individuals); intragenic deletion involving one or more exons of MBD5 (~5%); a heterozygous pathogenic sequence variant in MBD5 (~5%); or, rarely, an apparently balanced complex chromosome rearrangement of the 2q23.1 region involving MBD5.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Kleefstra syndrome, 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 Kleefstra Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Constitutional | Weight, height, & body mass index (in those age >2 yrs) | Consider referral to nutritionist in those w/obesity. |
| Dental | Dental evaluation | To assess for dental issues, incl retention of primary dentition |
| Eyes | Ophthalmologic evaluation | To assess for refractive errors |
| Ears | Audiologic evaluation | To assess for hearing loss |
| Cardiovascular | Echocardiogram & electrocardiogram | To evaluate for structural heart defects & rhythm disturbance; consider referral to cardiologist. |
| Respiratory | Assess for history of sleep disturbance. | Consider referral to a sleep disorders clinic. |
| Gastrointestinal/ Feeding | Assess for signs & symptoms of gastroesophageal reflux disease. | |
| Genitourinary | Renal ultrasound | To evaluate for structural renal anomalies & hydronephrosis |
| Neurologic | Neurologic evaluation | Consider referral to neurologist. |
| EEG | If seizures are suspected | |
| Head MRI | If seizures &/or movement disorder, extreme apathy/catatonia, &/or regression in psychomotor development is present | |
| Psychiatric/ Behavioral | Neuropsychiatric evaluation | Screen individuals age >12 mos for behavior concerns incl sleep disturbances, mood problems, psychotic disorders, anxiety, &/or traits suggestive of ASD. |
| Miscellaneous/ Other | Developmental assessment | Evaluate motor, speech/language, general cognitive, & vocational skills. |
| Consultation w/clinical geneticist &/or genetic counselor |
ASD = autism spectrum disorder
Treatment of Manifestations
Treatment is primarily supportive. Ongoing routine pediatric care by a pediatrician or neurologist, psychiatrist, and/or (for adults) specialist in the care of adults with intellectual disability is recommended.
Table 4.
Treatment of Manifestations in Individuals with Kleefstra Syndrome
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Refractive error | Standard treatment | |
| Hearing loss | Auditory amplification as appropriate | See Hereditary Hearing Loss and Deafness Overview. |
| Congenital heart defects & rhythm disturbance | Standard treatment per cardiologist | |
| Sleep disturbance | Standard treatment | No well-controlled treatment trials have been reported. |
| Gastroesophageal reflux disease | Standard treatment | Consider referral to gastroenterologist for those w/severe issues. |
| Renal anomalies | Standard treatment | Consider referral to urologist &/or nephrologist. |
| Seizures | Standard treatment w/AEDs by experienced neurologist 1 | Many different AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder. |
AEDs = antiepileptic drugs
- 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, 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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
- Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
- For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox®, anti-parkinsonian medications, or orthopedic procedures.
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 may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.
Specialized neurologic and psychiatric care is advised for individuals with extreme behavior problems and/or movement disorder. Behavioral therapies include special education techniques that may help minimize behavioral outbursts in the school setting by emphasizing individualized instruction, structure, and a set daily routine.
Surveillance
Cardiac and renal/urologic abnormalities should be monitored as needed.
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.