Kleefstra syndrome
Kleefstra syndrome is a complex disorder characterized by developmental delay, intellectual disability, and distinctive physical and facial features.
Overview
Kleefstra syndrome is a multisystem disorder. Affected individuals typically experience developmental delay, intellectual disability, severely limited or absent speech, and weak muscle tone (hypotonia). The condition is also associated with structural brain abnormalities, heart defects, and a tendency to develop severe respiratory infections.
Symptoms
- Physical Features: Unusually small head size (microcephaly), wide/short skull, eyebrows that grow together, widely spaced eyes, sunken midface, nostrils that open to the front, protruding jaw, everted lips, and a large tongue.
- Developmental/Behavioral: Developmental delay, intellectual disability, limited/absent speech, and potential features of autism. In adolescence, some individuals may develop apathy or catatonia.
- Other: Childhood obesity, high birth weight, seizures, and genitourinary abnormalities.
Causes
Kleefstra syndrome is caused by the loss of the EHMT1 gene or mutations that disable its function. This gene provides instructions for making the enzyme euchromatic histone methyltransferase 1, which modifies histones to regulate gene activity. Most cases involve a deletion of genetic material on chromosome 9 (specifically at 9q34.3). About 25 percent of cases are caused by mutations within the EHMT1 gene itself, resulting in an unstable or non-functional enzyme.
Inheritance
The inheritance is considered autosomal dominant, as a deletion or mutation in one copy of the EHMT1 gene is sufficient to cause the condition. Most cases are not inherited; they occur as random events during the formation of reproductive cells or in early fetal development. Rarely, an individual may inherit a chromosomal rearrangement from an unaffected parent who carries a balanced translocation or is mosaic for the deletion.