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Koolen syndrome is characterized by moderate to severe intellectual disability, hypotonia, amiable behavior, and highly distinctive facial features, including tall, broad forehead, long face, upslanting palpebral fissures, epicanthal folds, tubular nose with bulbous nasal tip, and large ears. Global psychomotor developmental delay is noted from an early age, but severity varies from mild to severe. More variable features include cardiac or genitourinary anomalies, joint hypermobility and/or hip dislocation/dysplasia, ectodermal anomalies of the hair, skin, and teeth, elbow dislocation, conductive hearing loss, hypertension due to renal scarring and seizures. Koolen syndrome can be caused by heterozygous mutation in the KANSL1 gene (which is located in 17q21.31) or by a larger deletion of several genes on chromosome 17q21.31 (usually spanning 500-650kb). It is proposed that the syndrome is currently underdiagnosed, with an estimated prevalence of 1:16,000, with no difference in males and females.
The syndrome was initially identified by Koolen et al (2006), who described a microdeletion of the chromosomal region 17q21.31 in patients with a characteristic phenotype. The detected deletions encompassed the MAPT and CRHR1 genes and were associated with a common 900kb inversion polymorphism (probably this inversion is necessary for the deletion to occur). In general, the deletion causing Koolen syndrome may encompass all the following genes: C17ORF69, CRHR1, IMP5, MAPT, STH and KANSL1 (previously known as KIAA1267). Later on Tan et al. (2009) reported additional patients with the 17q21.31 deletion syndrome and described additional features as being part of the syndrome. In 2012, Zollino et al. and Koolen et al reported patients showing Koolen syndrome without a deletion of the region 17q21.31, but with point mutations in a gene located in this region: KANSL1. The mutations described were de novo and truncating.
A website dedicated to the research on the microdeletion of 17q21.31 is available at http://www.17q21.com/en/.
References: see text.
