Clinical Description
Koolen-de Vries syndrome (KdVS) has a clinically recognizable phenotype that includes neonatal/childhood hypotonia, developmental delay / intellectual givdisability, dysmorphisms (see Figure 1), speech and language delays, congenital malformations, and behavioral features. To date, more than 200 individuals have been identified with KdVS [Koolen et al 2006, Sharp et al 2006, Koolen et al 2008, Grisart et al 2009, Tan et al 2009, Koolen et al 2012b, Zollino et al 2012, Zollino et al 2015, Koolen et al 2016, Morgan et al 2018a, Myers et al 2017, Amenta et al 2022, St John et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.
Dysmorphic craniofacial features that may suggest KdVS include:
The nose can have a high nasal bridge, a broad nasal root, long columella, and underdeveloped and/or thick alae nasi. The facial characteristics change with age. In infancy the facial gestalt is mostly characterized by hypotonia with an “open mouth” appearance. With increasing age there is usually elongation of the face and broadening of the chin, and the “tubular” or “pear” shape of the nose may become more apparent.
Developmental delay / intellectual disability. Psychomotor delay is noted in all affected individuals from an early age. The level of developmental delay varies significantly. The majority of individuals with KdVS function in the mild-to-moderate range of intellectual disability.
Hypotonia with poor sucking and slow feeding can be evident in the neonatal period and during childhood. Feeding difficulties may require hospitalization and/or nasogastric tube feeding in some neonates. Beyond infancy and into the preschool years, many children experience issues chewing difficult, lumpy, or solid textures [Morgan et al 2018a].
Epilepsy, including generalized seizures and unilateral clonic seizures, is noted in approximately 33% of affected individuals. The epilepsy phenotypic spectrum in KdVS is broad; however, most individuals have focal seizures, with some having a phenotype resembling the self-limited focal epilepsies of childhood [Myers et al 2017].
Neurobehavioral/psychiatric manifestations. In many affected individuals, behavior is described as friendly, amiable, and cooperative, with or without frequent laughing. However, behavioral findings including attention-deficit/hyperactivity disorder have been reported [Koolen et al 2008, Tan et al 2009, Koolen et al 2016]. A subset of affected individuals have autism and/or anxiety.
Growth. Short stature is not one of the most common clinical features of the syndrome. However, El Chehadeh-Djebbar et al [2011] reported a child with a 17q21.31 deletion, short stature (4 SD below the mean), complete growth hormone deficiency, and gonadotropic deficiency [El Chehadeh-Djebbar et al 2011]. Brain MRI showed partial pituitary stalk interruption, expanding the phenotypic spectrum of the syndrome.
Ophthalmologic involvement in individuals with this condition include hypermetropia, strabismus, congenital cataract, and optic atrophy.
Hearing impairment. A minority of affected individuals experience recurrent otitis media.
Neuroimaging/other neurodevelopmental features
Musculoskeletal. Joint hypermobility is common. Affected individuals may also experience joint dislocations. Other findings can include:
Congenital heart defects mainly include septal heart defects; however, cardiac valve disease, aortic root dilatation, and pulmonary stenosis have also been described.
Renal and urologic anomalies include vesicoureteral reflux, hydronephrosis, pyelectasis, and duplex renal system. Cryptorchidism has been reported in the majority of males. A minority of affected individuals experience recurrent urinary tract infection.
Respiratory. Some affected individuals experience recurrent respiratory infections. There is no known immune deficiency described in affected individuals that can explain this finding. Tracheo-/laryngomalacia has also been reported in a relatively small number of affected individuals.
Other associated features reported infrequently (fewer than 10% of known affected individuals)
Life span. Longitudinal data are insufficient to determine life expectancy, although survival into adulthood is typical. One reported individual is alive at age 63 years [Farnè et al 2022].
