TELO2-related syndrome is a multisystemic disorder in which central nervous system involvement is predominant.
Its core features are global DD with poor motor and language acquisitions and later establishment of a severe ID, gait instability/ataxia, spasticity, short stature, microcephaly and facial anomalies. Approaching the broader phenotype requires caution, as the small number of patients described so far do not permit to confirm if the issue reported in addiction to the core phenotype can be ascribed to the genetic variants or if otherwise are are a casual association.
Furthermore, the clinical features can be variably expressed and may result in a slightly different phenotype also among members of the same family.
Prenatal and perinatal features
No anomaly has been described in ante-natal age by now.
At birth, children have not been reported to have remarkable problems.
Neurological features
All patients with TELO2-related syndrome show a delay in developmental milestones, affecting both motor functions and language and social abilities. Most patients are not able to walk independently and those who reach this skill present some degree of balance impairment, up to a clear ataxic gait. Expressive language is invariably absent or limited to few single words, while comprehension may be more developed. Only one patient has been reported to have reached autonomous walking around 4 years and later become wheelchair dependent ion late childhood; similarly, only one patient has been reported to have acquired a basic expressive language but experienced regression at a later stage.
Cognitive functions are strongly compromised and intellectual disability is invariably severe. Along with ID, the phenotype may be complicated by behavioral comorbidities, mainly anger outbursts and/or aggressiveness (both self than hetero directed) or features recalling Autism Spectrum Disorder. Also, sleep disturbance affects about 50% of the described patients.
Neurological examination is mostly characterized by an ataxic-spastic syndrome, with most patients showing gait unsteadiness and/or gait or truncal ataxia, tremor, dysarthria, oculomotor dysfunction (nystagmus, jerky eye pursuit); spasticity is reported to affect mainly distal lower limbs and may be associated with brisk tendon reflexes and Babinski sign.
Epilepsy may be present and some of the reported patients show epileptic activity at EEG registration but no epileptic manifestations; seizures can be early-onset or emerge in adolescence age.
Neurological signs don’t seem to have a radiological counterpart, as brain MRI showed no significant anomalies in must patients: literature only reports non-specific white matter abnormalities in one girl and small brain in agree with head reduction in another patient.
Growth parameters
Patients may show a stature shorter than that expected from their genetic target and, in some occasion, a definite short stature. Microcephaly is invariably present and may be extreme, reaching values around -7/8 SD.
Facial appearance
The majority of patients present a peculiar facial appearance, but no specific and recognizable phenotype has been found.
We only report the facial features reported in more than 3 patients, that include blue sclera, upslanting palpebral fissures, wide nasal bridge, short philtrum, downturned mouth corners, and micro-retrognathia.
Musculoskeletal anomalies
Minor hands and feet anomalies have been reported; these include, from the most to the least frequent, V finger clinodactyly, IV-V or II/III toe syndactyly, nails hypoplasia, small hands and feet, brachydactyly, tapering fingers. Additionally, two patients with progessive scoliosis and two with congenital talus feet have been described. Joint contractures may with spasticity progression.
Visual and ocular abnormalities
Ocular anomalies in the condition regards ocular movements and are a consequence of the cerebellar dysfunction.
Additionally, two children with cortical visual impairment and a few cases with congenital cataracts have also been reported.
Other medical issues
Cardiovascular defects (including double aortic arch, vascular ring, cleft mitral valve and aorta coarctation) interest a minority of patients and some other congenital defects have been anecdotally described (hypogenitalism, hypospadias, double outlet kidney, annular pancreas, and cleft palate). Some patients may experience hearing loss.