hypotonia

Patients have multiple severe systemic abnormalities.  There is generalized developmental delay along with mild microcephaly and hypotonia.   The forehead is often broad while the face appears flattened with anteverted nares, a flat nasal bridge, a short philtrum, low-set and crumpled ears.  Infants may have an inadequate upper respiratory apparatus with atrophic vocal cords and some die of laryngeal obstruction in the first days of life.  Sialorrhea and difficulty swallowing have been noted.  Mild to moderate neurosensory hearing loss is often present but there may also be a conduction component to this. 

Brain imaging has revealed large ventricles, with subcortical hypomyelination, a thin corpus callosum, and prominent cortical sulci.  The vertebrae may have coronal clefts and scoliosis often develops. Generalized metaphyseal dysplasia and delayed bone age are usually present.  The anus may be imperforate and a rectovaginal fistula and cryptorchidism have been reported.  Long bones may be malformed as well and most patients are short in stature. Delayed dentition, enamel dysplasia, and abnormal cusp morphology are often present.  Cardiac septal defects may be seen.

Infants are born with low birth weight due to intrauterine growth retardation and there is often a history of oligohydramnios.  Newborns are often floppy and hypotonic although spasticity may develop later.  A small midface and microcephaly (80%) with a sloping forehead and a flat occiput are frequently evident.  The ears are large, floppy, and low-set while the hard palate is highly arched and the degree of micrognathia can be severe.  The fists are often clenched and the digits can appear narrow and arachnodactylous.  Hiatal hernias may be present.

Many patients develop features of the nephrotic syndrome in the first year of life with proteinuria and hypoalbuminemia due to glomerular kidney disease and renal system malformations.  Renal biopsies show focal segmental glomerulosclerosis in the majority of glomeruli.

Evidence of abnormal neuronal migration with brain deformities such as cystic changes, porencephaly, encephalomalacia, and spinal canal anomalies have been reported.  MRI imaging shows diffuse cortical and cerebellar atrophy atrophic optic nerves, and thinning of the corpus callosum.  The normal striated layers of the lateral geniculate nuclei are obliterated.  The cerebellum shows severe cellular disorganization with profound depletion of granule cells and excessive Bergmann gliosis.  The vermis is shortened. 

Multifocal seizures are sometimes (40%) seen in infancy and early childhood and the EEG generally shows slowed and disorganized backgound and sometimes a high-voltage hypsarrhythmia.  The degree of psychomotor delay and intellectual disability is often severe.   Most patients are unable to sit independently (90%), ambulate (90%), or make purposeful hand movements (77%).  The majority (87%) of children have extrapyramidal movements and a combination of axial dystonia and limb chorea.  Mean age of death is about 11 years (2.7 to 28 years in one series) and most die from renal failure.

Onset of neurological symptoms usually occurs in childhood during or following an acute febrile illness which may be recurrent.  This may consist of cerebellar ataxia, hypotonia, drowsiness, dysarthria, and lethargy.  There may be partial or full recovery following the febrile illness initially but some signs remain after subsequent episodes.  Areflexia and sensorineural deafness can be additional signs and pes cavus eventually appears.

The acute febrile episodes tend to decrease in time along with the progression of neurological signs.  Plantar responses remain normal while peripheral neuropathy and seizures are not consistent features.  MRI imaging of the brain is normal.  Cognitive function usually remains normal but some children have autism features and social adjustment problems have been noted.

Polydactyly of the hands is a common feature.  The central metacarpal is often Y-shaped leading to ‘central polydactyly’.  The large toes may be bifid.  Cognitive deficits are common and some patients have been considered mentally retarded.  The ears are low-set and rotated posteriorly.  Some patients have a conductive hearing loss.  Oral anomalies may include a lobed tongue, lingual and sublingual hemartomas, micrognathia, clefting, and multiple buccoalveolar frenula.  Congenital heart anomalies, micropenis, and cryptorchidism have been reported.  Tachypnea and tachycardia have been noted.  Some patients have some degree of skeletal dysplasia and many individuals are short in stature.

The presence of cerebellar abnormalities such as hypoplasia (including absence) of the vermis may help to distinguish type VI from other forms of OFDS.  Hypothalamic dysfunction may be responsible for poor temperature regulation (hyperthermia). The ‘molar tooth sign’ seen on brain MRIs in Joubert syndrome (213300) is also present in OFDS VI.