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Koolen-De Vries syndrome
A rare multisystem disorder characterized by neonatal/childhood hypotonia, mild to moderate developmental delay or intellectual disability, epilepsy, dysmorphic facial features, hypermetropia, congenital heart anomalies, congenital renal/urologic anomalies, musculoskeletal problems, and a friendly/amiable disposition.
ORPHA:96169Classification level: Disorder
The prevalence of this disorder is unknown; however, the prevalence of the 17q21.31 deletion is approximately 1/55,000 individuals. The prevalence of single nucleotide variants (SNVs) in KANSL1 cannot be ascertained with precision owing to the limited number of cases identified thus far. Males and females are affected equally.
Hypotonia is most evident between the neonatal period and infancy with poor sucking and slow feeding, but may persist throughout life. Feeding difficulties may require hospitalization and/or nasogastric tube feeding in some neonates. Tracheo/Laryngomalacia is a common feature. Global psychomotor developmental delay is noted in all individuals from an early age, although the level of developmental delay varies significantly. The majority of individuals with Koolen-de Vries syndrome (KdVS) function in the mild to moderate range of intellectual disability. Oral hypotonia and apraxia in infancy and preschool, associated with severely delayed speech development is one of the hall marks of KdVS. A history of epilepsy is noted in ~30-50% of all cases and other neurological problems may also be present. The facial dysmorphism is characterized by upslanted palpebral fissures, blepharophimosis, epicanthal folds, ptosis, a pear-shaped nose with bulbous nasal tip, and large / protruding ears. Short stature, pectus excavatum, spine anomalies, dislocation of the hip(s), long slender fingers and slender lower limbs, and positional deformities of the hands/feet have been reported. Other features include heart defects (bicuspid aortic valve, atrial and ventricular septal defects), kidney and urologic anomalies, and cryptorchidism.
KdVS is typically a sporadic disorder caused either by a 17q21.31 deletion encompassing the KAT8 regulatory NSL complex subunit 1 (KANSL1) gene or a mutation of the KANSL1 gene.
Molecular genetic testing approaches can include a combination of chromosomal microarray (CMA), a multigene panel, and comprehensive genomic testing (exome sequencing, exome array, genome sequencing). In individuals with normal CMA results, targeted Sanger sequencing of the KANSL1-gene testing can be considered based on the clinical findings.
Differential diagnoses include Prader-Willi syndrome in the neonatal period and 22q11.2 deletion syndrome, fragile X syndrome, Angelman syndrome and blepharophimosis-intellectual disability syndrome, SBBYS type in older patients.
Almost all cases correspond to a single occurrence in a family, but prenatal testing can be offered for at risk pregnancies.
Genetic counseling should be proposed to parents of affected individuals. Whilst almost all affected individuals represent simplex cases (i.e., a single affected individuals in the family) with a very small risk of sibling recurrence, the pattern of inheritance is autosomal dominant and thus the risk to offspring of affected individuals inheriting KdVS is 50%
Management and treatment
Affected individuals should have routine examinations by the primary care physician and pediatrician. Cardiac investigations, and kidney and urologic evaluations are warranted. Speech production requires intensive motor speech treatment in preschool years and language development requires focused intervention and augmentative (sign language) or alternative (communication device) support until oral speech and language develops. Regular check up by a dermatologist can be considered in case of multiple nevi. Referral to other specialists is indicated if neurological or other systemic problems are suspected.
Longitudinal data are insufficient to determine life expectancy, although survival into adulthood is typical, autonomy is likely to be limited and affected individuals will probably require life-long support from caregivers.