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The prevalence is unknown. However, based on genomic wide studies, it is estimated to be around 1 in 500 individuals with a neurodevelopmental disorder.

Patients with Kleefstra syndrome (KS) have a distinctive facial appearance comprised of brachy-microcephaly, midface hypoplasia, unusual eyebrow shape, synophrys, cupid bow upper lip, full-everted lower lip, protruding tongue and prognathism. With age, facial features become more coarse. Dental anomalies, like retention of primary dentition, are observed. 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 years. 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), 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 occur, these often coincide with regression. Autistic-like behavior can be noted earlier in some children.

The majority of the clinical features in KS can be attributed to loss of function of EHMT1, either due to a point mutation or a microdeletion in the chromosome region 9q34.3, leading to the loss of the entire gene. This gene encodes an enzyme that modifies histone function and is essential for normal development. Whilst there is not a clear gene-phenotype, correlation, individuals with an intragenic EHMT1 pathogenic variant or a small (<1Mb) 9q34.3 deletion have similar clinical findings whereas the phenotype of individuals with a relatively larger 9q34.3 deletion (i.e. ≥1Mb) appears to be more severe with a more pronounced intellectual disability and more comorbidities. Pulmonary infections and aspiration difficulties in particular appear to be more severe in individuals with a larger 9q34.3 defect. A similar phenotype is reported in patients with a loss of function mutation in the gene KMT2C (7q36.1).

Diagnosis of KS is determined by the presence of the characteristic clinical features and molecular genetic testing. Most cases will be identified by unbiased genetic testing, including chromosomal microarray, intellectual disability gene panels, whole exome or whole genome sequencing. Targeted genetic testing is possible.

Differential diagnoses include Down, Pitt-Hopkins, Smith-Magenis, Angelman, Rett and 2q23.1 microdeletion syndromes.

Antenatal diagnosis is offered to unaffected parents of a child with KS, especially in case of parental mosaicism of the pathogenic variant or in case of balanced chromosomal rearrangements in one of the parents.

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

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. Prognosis is mainly based on the incidence and severity of comorbidities that can occur with KS.