Kleefstra syndrome due to a point mutation

Kleefstra syndrome due to a point mutation (also known as Kleefstra syndrome 1, or EHMT1-related Kleefstra syndrome caused by intragenic mutation) is a rare genetic neurodevelopmental disorder caused by heterozygous loss-of-function point mutations in the EHMT1 gene (euchromatic histone methyltransferase 1) located on chromosome 9q34.3. While Kleefstra syndrome is more commonly caused by a microdeletion of the 9q34.3 region, a subset of patients carry intragenic point mutations in EHMT1 that produce a clinically similar phenotype. The EHMT1 gene encodes a histone methyltransferase involved in epigenetic regulation of gene expression, and its haploinsufficiency leads to widespread developmental consequences. The syndrome primarily affects the central nervous system, musculoskeletal system, and craniofacial structures. Core clinical features include moderate to severe intellectual disability, childhood hypotonia (low muscle tone), significant speech and language delay, and a characteristic facial appearance that may include microcephaly, midface hypoplasia, hypertelorism, synophrys, everted lower lip, and a protruding tongue. Behavioral features are common and may include autism spectrum disorder, apathy or periods of regression, sleep disturbances, and mood disorders, particularly in adolescence and adulthood. Congenital heart defects, renal and urological anomalies, epilepsy, and hearing impairment may also occur. Some patients experience a behavioral regression phenotype in adulthood characterized by extreme apathy, catatonia-like features, and loss of previously acquired skills. There is currently no cure or disease-specific treatment for Kleefstra syndrome. Management is supportive and multidisciplinary, involving early intervention programs, speech and occupational therapy, behavioral support, and monitoring for associated medical complications such as cardiac defects, seizures, and sleep apnea. Psychiatric symptoms and behavioral regression may require careful pharmacological management. Regular follow-up with neurology, cardiology, and developmental specialists is recommended.

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