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KANSL1

Clinical characteristics

The following description of the broad clinical spectrum is based on the Koolen et al., Eur J. Hum Genet 2016.

 

Growth parameters

Intrauterine growth retardation (IUGR) and postnatal growth retardation can be present, but the majority of children with KdVS have normal growth parameters. Short stature, if present, was proportionate. In some children, growth hormone deficiency, is reported.

 

Neurological features

Individuals with KdVS have developmental delay and ID. In general, the level of ID is within the mild to moderate range, but also low normal IQ has been described. However, in general the level of psychomotor delay is moderate and expressive language development seems to be particularly affected compared with receptive language or motor skills.

Neonatal hypotonia is a key feature of KdVS. It may result in severe feeding difficulties and hospitalisation and/or nasogastric tube feeding in the neonatal period. Hypotonia is present mainly during infancy but can continue into adulthood.

Also, feeding difficulties and oral motor dyspraxia, including drooling, gastro-oesophageal reflux, and aspiration pneumonia, can give rise to problems later in life.

Seizures are present in about 50% of all cases. Median age of seizure onset is ~3-4 years, and the majority of children have refractory epilepsy. Focal seizures with impaired awareness are the most frequent seizure type occurring usually with prominent autonomic features.

Structural anomalies of the central nervous system can be present, including corpus callosum dysgenesis, abnormal hippocampi and dilated ventricles, but also periventricular nodular heterotopia, dysembryoblastic neuroepithelial tumour, abnormal sulcation, brainstem and cerebellum abnormalities are observed.

Spinal cord anomalies, including tethered cord, hydromyelia of the thoracic cord, and painful disabling dural ectasia and Tarlov cysts have been described in some cases.

 

Neuropsychological disorders

In general, individuals with KdVS are sociable and have an amiable affect. However, behavioural problems are also present in the majority of individuals with KdVS, including autism/autistic traits, ADHD/attention deficit/hyperactivity, shyness, anxiety/phobias, impulsive-, stereotypic,- and compulsive behaviour, psychosis, and depression.

 

Facial dysmorphism

Individuals with KdVS have some characteristic facial features, mainly the long face, upslanting palpebral fissures, narrow/short palpebral fissures, ptosis, epicanthal folds, tubular- or pear-shaped nose with bulbous nasal tip, everted lower lip, and large prominent ears. With age, there is elongation and coarsening of the face. An abnormally shaped skull is reported in some cases, including brachycephaly, dolichocephaly, trigonocephaly, and turricephaly/scaphocephaly. Other nonfacial dysmorphic features that have been reported in the medical literature include fetal finger pads, slender lower limbs, and postaxial polydactyly of fingers and toes.

 

Musculoskeletal anomalies

Musculoskeletal anomalies are important in KdVS. Many children have tracheo/laryngomalacia, pectus excavatum or carinatum, scoliosis/kyphosis, hip dislocation/dysplasia, joint hypermobility, and positional deformities of the feet (mainly pes planus but also pes cavus). Tracheo/laryngomalacia can occasionally result in severe respiratory problems. Joint hypermobility mainly involved the fingers and hands. Less frequent features include cervical stenosis, spondylolisthesis, and spina bifida. Other musculoskeletal anomalies described in KdVS are fused vertebrae and compression of the spinal cervical cord, recurrent dislocation of the elbow, patellar dislocation, limited elbow extension and leg length discrepancy, and club feet. Finally, Dornelles-Wawruk et al described a case with chronic anaemia, mild cervical vertebral arthrosis, and multiple thoracic and lumbar vertebral fusions.

 

Visual and hearing impairments

Hypermetropia and strabismus are is common features in KdVS, though also other features involving the eye are observed such as optic nerve hypoplasia, coloboma, cerebral vision impairment and early cataract.

Hearing impairment is conductive in most cases and often the result of recurrent otitis media.

 

Cardiovascular defects

The congenital heart anomalies in our series mainly include atrial septal defect (ASD) or ventricular septal defect (VSD), but other cardiac anomalies have been reported, including patent ductus arteriosus, hypoplastic aortic valve, bicuspid aortic valve, common left pulmonary vein, dysplastic pulmonary valve, pulmonary stenosis, dilated left ventricle, anomalous right subclavian artery, doubly committed VSD, dilated aortic root, patent foramen ovale, and mitral insufficiency.

 

Renal and urogenital anomalies

Cryptorchidism is present in a significant proportion of males with KdVS. Other important anomalies of the renal and urogenital tract include vesiculoureteral reflux, hydronephrosis, pyelectasia, a duplex renal system, a pear-shaped bladder, and macroorchidism. Less common features include pyelectasia, reflux nephropathy associated hypertension, hypospadia, shawl scrotum, phimosis, and multicystic renal dysplasia.

 

Ectodermal abnormalities

Skin involvement in KdVS includes, among others, multiple nevi, depigmentosa, vitiligo, hyperkeratosis, eczema, keratosis pilaris, café-au-lait maculae, ichthyosis vulgaris, acne vulgaris, piezogenic papules, and hemangiomas.

Importantly, melanoma at young age has been reported. Therefore, for individuals with KdVS and a fair skin and multiple moles routine checkup by a dermatologist might be warranted.

Dental problems consist of enamel hypoplasia, caries, absence of secondary elements, and small, widely spaced, or conical teeth.

 

Miscellaneous

The clinical spectrum of KdVS is broad and some features that are not mentioned before include prenatal cerebral infarction, Addison’s disease, hypertension, neutropenia, and recurrent infections.