joubert syndrome ( js ) was initially described in 1968 in 4 siblings with agenesis of the cerebellar vermis presented with episodic hyperpnea , abnormal eye movements , ataxia , and intellectual disability1 ) .
several years later , a pathognomonic midbrain - hindbrain malformation  the  molar tooth sign  ( mts)was detected first in js2 ) , and then in several other conditions previously considered as distinct entities .
this neuroradiological sign is now represented as a mandatory criterion for the diagnose of js .
js can be assumed in all infants presented with hypotonia , altered respiratory pattern , abnormal eye movement , and developmental delay3 ) . in the newborn period , episodic hyperpnea , a subtle facial appearance , and abnormal eye movements
nystagmus , colobomas , strabismus , ptosis , and retinal pigmentation are associated with eye abnormalities in neonates3 ) .
concomitant symptoms of ptosis , anisocoria with unilateral miosis , and unilateral enophthalmos , which are compatible with horner syndrome ( hs ) , have not been documented in the children of js children thus far .
we now describe a neonate of js presented with hypotonia and unique eye abnormalities of nystagmus , ptosis , anisocoria , and unilateral enophthalmos . to the best of our knowledge ,
a 2-month - old boy was referred to the pediatric neurology clinic due to bilateral nystagmus , bilateral ptosis with left - dominant , left - sided enophthalmos , and anisocoria since the second week after birth .
the patient was the first baby of a healthy 28-year - old mother and a healthy 32-year - old father .
the baby was a 3,050 g ( 10th25th percentile ) infant born at gestational age of 38 weeks by normal vaginal delivery after an uneventful pregnancy .
his height was 48.5 cm ( 25th50th percentile ) , with a head circumference of 33 cm ( 10th25th percentile ) .
after birth , the baby had laryngomalacia , hypotonia , and a systolic murmur best heard at the upper left sternal border .
an electrocardiogram and echocardiogram revealed normal sinus rhythm , and a small sized secundum atrial septal defect .
on physical examination , both pupils promptly reacted to light , but unilateral miosis and enophthalmos of the left eye and left - dominant bilateral ptosis were observed , which could be indicative of hs ( fig .
other physical examination findings were unremarkable . in order to evaluate the symptoms of hs and horizontal nystagmus , magnetic resonance imaging ( mri ) of the orbit ,
orbit and brain mri showed hypoplastic cerebellar vermis and a narrowed anteroposterior diameter of the midbrain with a characteristic of  molar tooth appearance ( fig .
2 ) , which were compatible with typical findings of js . neck mri showed no definite lesion or mass around the cervical sympathetic nerve chain , thymus , and mediastinum as the underlying cause of hs .
laboratory examinations including renal and hepatic function tests and an abdominal ultrasonography showed normal findings .
left - sided visual loss was found in ophthalmological examinations , and neither coloboma nor pigmentary retinal changes were observed .
no abnormality was noted in an audiological test and follow - up electrocardiogram and echocardiogram . molecular genetic test was not performed .
clinical development at the age of 10 months was global delayed , as explained by the following : he could not babble , follow with or turn his eyes on objects , control his head , sit independently , or hold his bottle .
he underwent ophthalmologic surgery ( bilateral frontalis operation ) due to persistent visual disturbance by bilateral ptosis , and had distinct improvement of ptosis ; however , unilateral enophthalmos , and anisocoria remained ( fig .
he is currently actively undergoing rehabilitation therapy , and will be regularly monitored through comprehensive developmental examination and follow - up imaging tests , including hepatorenal , cardiac , and ophthalmologic test .
the gross photos of the figure were permitted by his parents through the informed consent .
js is a rare autosomal - recessive disorder , which is characterized by midbrain - hindbrain malformation mainly in the form of agenesis or dysgenesis of cerebellar vermis3 ) .
the incidence rate is 1 out of 800,000 to 100,000 per a year in the newborn5 ) .
describe several diagnostic criteria ; ( 1 ) cranial mri findings demonstrating the mts on axial imaging with these three components : midline cerebellar vermis hypoplasia , deepened interpeduncular fossa , and thick , elongated superior cerebellar peduncles , ( 2 ) hypotonia in infancy , ( 3 ) global developmental delay / mental retardation , and ( 4 ) one or both of the following ( not absolutely required but supportive of the diagnosis ) : ( i ) irregular breathing pattern in infancy ( episodic tachypnea and/or apnea ) , and ( ii ) abnormal eye movement ( nystagmus , jerky eye movements , and difficulty with smooth visual pursuits ) .
pathological findings of mts correspond to an image of severe hypo - dysplasia of the cerebellar vermis with midline clefting , fragmentation of cerebellar nuclei and heterotopias of purkinje - like neurons , along with dysplasia of the pontine and medullary structures such as the basis pontis , reticular formation , inferior olivary , dorsal column , and solitary tract nuclei .
moreover , typical findings are expressed by the lack of decussation both of the superior cerebellar peduncles and of the corticospinal tracts at the medullary pyramids6 ) .
a diagnosis of js should be assumed in all infants presented with hypotonia , abnormal eye movement and developmental delay .
especially , a neonate of js shows the characteristic physical signs and symptoms ( table 1)3 ) . the infant may lie in a froglike position , and moderate to severe hypotonia can be observed3 ) .
the most common presented feature in the newborn period is an abnormal breathing pattern , characterized by episodic hyperpnea23 ) .
the distinctive short alternate episodes of apnea and hyperpnea or episodic hyperpnea lone , sometimes described as  panting like a dog, may intensify with stress and progressively improve with age , usually disappearing around sixth months23 ) .
the 7 children were diagnosed with js at younger than 1 year old of age78910 ) , and the case of neonatal onset was only one7 ) .
the cardinal symptoms of them were unexplainable episodic tachypnea alternating with apnea during neonatal period , abnormal ocular movement , hypotonia , ataxia , and developmental delay . in rare cases
most of the patients showed nystagmus , saccadic palsy , or congenital ocular motor apraxia as the abnormal ocular movement , however , one 7-month - old boy had a severe vision loss as leber 's congenital amaurosis8 ) .
ocular and oculomotor involvement is common in js2411 ) , however , it has variable phenotypes among patients with js .
colobomas , nystagmus , strabismus , ptosis , and abnormal retinal pigmentation are noted in neonates3 ) .
genetype - phenytype correlations have stressed the predictive value for specific mutations of retinal involvement .
retinal involvement is present in about 80% of patients with ahi1 and cep290 mutations12 ) .
ocular misalignment is common in js411 ) , because the lesions of cerebellum lead to dysmetric and slow saccades .
this patient showed unique eye abnormalities with transient nystagmus , anisocoria and enophthalmos , and eyelid ptosis .
when both anisocoria and ptosis are coexistent , one must consider 2 main possible causes : a third nerve palsy ( parasympathetic pathway ) or a hs ( sympathetic pathway)13 ) .
in most cases , a third nerve palsy can usually have disconjugate gaze with limitations of eye movements .
hs is a problem of the disturbance of the oculosympathetic pathway13 ) , which is bilaterally originating in the hypothalamus , descending ipsilaterally in the reticular formation of the brainstem , eventually synapsing with the second - order neuron in the lower cervical or upper thoracic spinal cord .
the second - order neuron enters the sympathetic chain , which then ascends within the soft tissues of the neck , outside of the spinal cord , where it is vulnerable to disruption at various locations .
it finally synapses within the superior cervical ganglion to form the third - order neuron .
this third - order neuron forms a plexus surrounding the carotid artery and into the cavernous sinus , finally innervating the dilator muscle of the iris and the mller muscle in the upper and lower eyelids .
hs is characterized by a combination of ptosis due to superior tarsal muscle palsy , enophthalmos due to mller muscle palsy , rising of inferior eyelid due to inferior tarsal muscle palsy , miosis , and anhidrosis of the involved face when there is a defect of the sympathetic nerve route from hypothalamus to the orbit14 ) .
typical causes include birth trauma , neuroblastoma , vascular anomalies of the large arteries , and chest surgery .
if there is no history of birth trauma , an acquired hs in children should prompt evaluation for a tumor , particularly paraspinal neuroblastoma .
imaging studies , such as mri of the head , neck , chest , and abdomen , as well as the measurement of urine catecholamines should be evaluated .
these variable ocular phenotypes might be supported by a third nerve palsy and multiplex neuropathological findings of the cerebellar vermis and of several pontine and medullary structures .
it may arise from the genetic heterogeneity of js and related disorders15 ) . in conclusion
, we describe an infant of js with unique eye abnormalities , likely as symptoms of hs .
it may suggest that a neonate or young infant with diverse eye abnormalities should be considered for early neuroimaging to evaluate the underlying etiology , although there may be no focal neurologic deficit or significant developmental delay .
furthermore , once a diagnosis of js has been made , a further evaluation to assess the possibility of multiorgan involvement should be considered in children .
 joubert syndrome ( js ) is characterized by the  molar tooth sign  
 ( mts ) with cerebellar vermis agenesis , episodic hyperpnea , abnormal eye movements , and hypotonia . 
 ocular and oculomotor abnormalities have been observed ; however , horner syndrome ( hs ) has not been documented in children with js . 
 we present the case of a 2-month - old boy having ocular abnormalities with bilateral nystagmus , left - dominant bilateral ptosis , and unilateral miosis and enophthalmos of the left eye , which were compatible with hs . 
 brain magnetic resonance imaging ( mri ) revealed the presence of the mts . 
 neck mri showed no definite lesion or mass around the cervical sympathetic chain . 
 his global development was delayed . 
 he underwent ophthalmologic surgery , and showed some improvement in his ptosis . 
 to the best of our knowledge , the association of hs with js has not yet been described . 
 we suggest that early neuroimaging should be considered for neonates or young infants with diverse eye abnormalities to evaluate the underlying etiology . 