Gestation and growth parameters
Premature birth, fetal distress and intrauterine growth restriction (IUGR) are rather common in the subjects described by Tokita et al. (2016) and Kim et al. (2016). Growth failure during the neonatal period is rather prevalent as most subjects have a history of postnatal feeding difficulties, sometimes requiring placement of a gastrostomy feeding tube. Approximately half of the individuals with de novo loss-of-function variants in SON have short stature.
Developmental delay (DD) progressing into Intellectual Disability (ID) is shared by all individuals and often accompanied by additional neurological features. These include hyper- or hypotonia, epilepsy and electroencephalography (EEG) abnormalities. Seizures occurred in approximately 55% of affected individuals. Furthermore, regression of achieved skills has been reported.
Brain MRI revealed structural brain abnormalities in the majority of individuals carrying loss-of-function variants in SON. These include cortex malformations, ventriculomegaly, Arnold-Chiari malformations, arachnoid cysts, hypoplasia of the corpus callosum, hypoplasia of the cerebellar hemispheres and white matter abnormalities.
Mild hearing loss has been described in 2 individuals while deafness and hyperacusis have each been reported once by Kim et al. (2016).
Ophthalmological concerns are prevalent as a result of SON haploinsufficiency encompassing (suspicion of) cerebral visual impairment, hypermetropia, optic atrophy and strabismus (including among others exotropia and esotropia).
Facial dysmorphic features were present in the majority of individuals with SON loss-of-function variants. These include facial asymmetry, midface retraction, frontal bossing, bitemporal narrowing, low-set ears, downslanted palpebral fissures, epicanthal folds, deep-set eyes, horizontal eyebrows, nasal bridge abnormalities, a smooth or short philtrum, thin lips and a short mouth. Presence of these features can vary between individuals.
Skeletal abnormalities comprise hemivertebrae, cervical ribs, scoliosis or kyphosis, contractures, pedes plano valgus, joint hypermobility and joint laxity. Thumb agenesis has been reported in one individual.
A subset of individuals, approximately 25%, presented with heart-defects including atrial septal defect, ventricular septal defect, patent ductus arteriosus and abnormalities of the aorta (dysplastic aorta and bicuspid aorta).
Urogenital malformations, including horseshoe kidney and kidney cysts, were described in a number of individuals with haploinsufficiency of the SON gene.
Other reported congenital abnormalities include malrotation of the gut, cleft palate, bifid uvula and sacral dimple. Each of these features were observed only once in the cohort of 20 individuals described by Kim et al. (2016) while duodenal malformations were reported for two individuals.
Individuals may also present with craniosynostosis involving either the metopic or the sagittal sutures, mitochondrial dysfunction and/or O-glycosylation defects.