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Kleefstra syndrome

Synonym(s) -
Prevalence <1 / 1 000 000
Inheritance Autosomal dominant
Age of onset Infancy
  • Q87.8
MeSH -
MedDRA -


Disease definition

Kleefstra syndrome (KS) is a genetic disorder characterized by intellectual disability, childhood hypotonia, severe expressive speech delay and a distinctive facial appearance with a spectrum of additional clinical features.


The prevalence is unknown. To date, 114 cases have been described.

Clinical description

Patients with KS have a distinctive facial appearance comprised of brachy-microcephaly, midface hypoplasia, unusual eyebrow shape, synophyrs, cupid bow upper lip, full everted lower lip, protruding tongue and prognathism. With age, facial features become coarser and dental anomalies, like retention of primary dentition, are seen. Birth weight is normal but half of children go on to suffer from obesity. Childhood hypotonia causes motor delay but most children walk independently by age 2 or 3. Most patients have moderate to severe intellectual disability with expressive speech delay and little speech development (nonverbal communication is possible). Additional features include congenital heart malformations (interauricular communication, ventricular septal defects, bicuspid aortic valve, pulmonary valve stenosis (see these terms)), genital defects in males (hypospadias, cryptorchidism, micropenis), renal defects (hydronephrosis, chronic renal insufficiency, renal cysts, vesico-ureteral reflux), epilepsy, recurrent infections, severe constipation and hearing problems. In adolescence/adulthood behavioral problems (aggressive/emotional outbursts, attention deficit problems, self-mutilation and severe sleep disturbances) can begin. Autistic-like behavior can be noted earlier in some children. Recurrent pulmonary infections, overweight and behavioral problems seem to be reported more often in those with KS due to a point mutation, whereas microcephaly, short stature, respiratory complications and tracheomalacia are more frequently seen in those with KS due to a 9q34 microdeletion.


KS is caused by either a point mutation in the euchromatic histone-lysine N-methyltransferase 1 (EHMT1) gene (rarely) or by a microdeletion in the chromosome region 9q34.3 (seen in >85% of cases), leading to the loss of the entire gene. This gene encodes an enzyme that modifies histone function and is essential for normal development. Larger deletions (>1mb) are associated with more severe symptoms.

Diagnostic methods

Diagnosis of KS is determined by the presence of the characteristic clinical features and molecular genetic testing. A microarray detects any duplications/deletions. Fluorescent in situ hybridization (FISH) or multiplex ligation-dependent probe amplification (MLPA) can then be used to detect the specific 9q34.3 deletion seen in KS. Sequencing of the entire coding region of the EHMT1 gene can detect sequence variants.

Differential diagnosis

Differential diagnoses include Down, Pitt-Hopkins, Smith-Magenis, Rett and 2q23.1 microdeletion syndromes (see these terms).

Antenatal diagnosis

Antenatal diagnosis is offered to unaffected parents of a child with KS as they have a higher risk of having another child with this disorder.

Genetic counseling

Most reported cases have been de novo but familial recurrence has been seen. KS has a theoretical autosomal dominant transmission, but the majority of patients do not reproduce.

Management and treatment

Treatment requires a multidisciplinary team, specializing in patients with intellectual deficiencies. Special education and vocational training along with speech therapy, physical and occupational therapy and sensory integration therapy are recommended from an early age. Standard treatment is necessary for those with renal, cardiac and urologic issues and for hearing loss. Psychiatric care along with behavioral intervention therapy may be needed. Cardiac screening (for the presence of arrhythmias) as well as intestinal and renal/urologic monitoring is recommended. Medical follow-up is life-long.


The prognosis of KS is variable but in most cases it is not a life-threatening disease.

Expert reviewer(s)

  • Dr T. [Tjitske] KLEEFSTRA

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