Update on Kleefstra Syndrome

Abstract

Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.

Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome

“…25 Among patients with this microdeletion, 54% have behavioral and psychiatric problems, 58% demonstrate abnormalities on brain imaging, 36% have a concurrent diagnosis of epilepsy, and 20% are defined as obese.…”

“…25 Characterized by a phenotype of childhood hypotonia, intellectual disability, and distinctive facial features, this syndrome is often accompanied by myriad psychiatric and behavioral disorders. 12,22,25 While deep brain stimulation (DBS) has been used as a treatment for a number of neuropsychiatric conditions including obsessive-compulsive disorder (OCD), depression, and Tourette syndrome (TS), there is no literature on using DBS for the neuropsychiatric symptoms of a purely genetic disorder. In 1999, Nuttin and colleagues 18 were the first to describe the use of DBS for OCD, and their encouraging initial experience was confirmed with additional studies, 8,9,19 resulting in FDA approval of DBS for the treatment of OCD.…”

Promoting brown and beige adipocyte biogenesis through the PRDM16 pathway

“…29 Notably, it has been reported that 40-50% of the human patients with EHMT1 haploinsufficiency exhibit an obese phenotype. 34,35 We have shown that adipose-specific deletion of EHMT1 by an Adiponectin-Cre lowers whole-body energy expenditure and causes obesity, hepatic steatosis and insulin resistance under a high-fat diet. These results indicate that EHMT1 is a critical enzyme for whole-body energy homeostasis in rodents and in humans.…”

Azoospermia and ring chromosome 9—a case report

“…Microdeletions in the telomeric region of the long arm of chromosome 9 were found in patients with Kleefstra syndrome [6,7], whereas microdeletions of the telomeric end of the short arm may lead to 46,XY gonadal dysgenesis [2].…”

“…The literature regarding genital malformations in males with the presence of r(9) is very sparse; however the following malformations have previously been reported: cryptorchidism, hypospadias and micropenis [7]. Until now it is not clear whether the presence of r(9) affects spermatogenesis, as most cases have been described in young boys.…”