Kleefstra syndrome (KS), previously known as the 9q subtelomeric deletion syndrome (9qSTDS) is caused by haploinsufficiency of the EHMT1 gene. Both a single mutation and 9q34 microdeletions encompassing the entire gene can be responsible for this syndrome which is characterized by intellectual disability, hypotonia, and typical dysmorphisms, and may be associated with congenital heart and/or renal defects and epilepsy. Its behavioral phenotype has recently been described and comprises particular sleep disturbances and apathy. In this report, the evolution of the behavioral profile of KS is outlined by the description of three female patients aged 19, 33, and 43 years, respectively. In two patients, the syndrome was caused by an intragenic mutation and in the third by a 9q34 microdeletion encompassing the EHMT1 gene. MRI scanning of the brain in the two eldest patients demonstrated multifocal subcortical signal abnormalities. In general, the severity of the behavioral and motor deficiencies increased over time and became apparent after adolescence. It is concluded that the "regressive" phenotype of KS seems to be associated with the EHMT1 gene in particular. In addition, the utility of uncritical use of a classificatory diagnostic approach is discussed in the context of the motor and motivational disturbances that are prominent in this syndrome.
Detailed neurobehavioural profiles are of major value for specific clinical management, but have remained underexposed in the population with intellectual disabilities (ID). This was traditionally classified based on IQ level only. Rapid advances in genetics enable etiology based stratification in the majority of patients, which reduces clinical heterogeneity. This paper illustrates that specific profiles can be obtained for rare syndromes with ID. Our main aim was to study (mal)adaptive functioning in Kleefstra Syndrome (KS) by comparing and contrasting our findings to three other subgroups: Koolen-de Vries Syndrome, GATAD2B-related syndrome, and a mixed control group of individuals with ID. In total, we studied 58 individuals (28 males, 30 females) with ID; 24 were diagnosed with KS, 13 with Koolen-de Vries Syndrome, 6 with the GATAD2B-related syndrome, and 15 individuals with undefined neurodevelopmental disorders. All individuals were examined with a Vineland Adaptive Behavior Scale, mini PAS-ADD interview, and an Autism Diagnostic Observation Schedule to obtain measures of adaptive and maladaptive functioning. Each of the three distinctive genetic disorders showed its own specific profile of adaptive and maladaptive functioning, while being contrasted mutually. However, when data of the subgroups altogether are contrasted to the data of KS, such differences could not be demonstrated. Based on our findings, specific management recommendations were discussed for each of the three syndromes. It is strongly suggested to consider the genetic origin in individuals with congenital neurodevelopmental disorders for individual based psychiatric and behavioral management.
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