Joubourt Syndrome: Description, Causes and Risk Factors:
Joubert syndrome is a rare genetically heterogeneous inherited disorder with an estimated prevalence in the world 1 in 100,000. Joubert syndrome is characterized by congenital ataxia, hypotonia, developmental delay, and at least one of the following features: neonatal respiratory disturbances and abnormal eye movements, including nystagmus and oculomotor apraxia. In some cases, Leber congenital amaurosis, pigmentary retinopathy, renal and hepatic abnormalities can also be found. The presence of a characteristic neuroimaging finding, known as molar tooth sign, is highly suggestive of Joubourt Syndrome diagnosis.
The incidence of Joubourt Syndrome has been estimated to be between 1/80,000 and 1/100,000 live births. Joubert syndrome and related disorders are genetically heterogenous with mutations in 13 genes known to cause Joubert syndrome to date (OMIM). Most demonstrate autosomal recessive inheritance, although cases of X-linked inheritance (CXORF5) and autosomal dominant inheritance (TTC21B) have been described.
Joubourt Syndrome is also genetically heterogeneous, with two known loci, on 9q34 (JBTS1) and 11p11-q12 (CORS2), representing only a fraction of cases. In addition, candidate gene approaches have failed so far to detect mutations in the WNT1, EN1, EN2, and FGF8 genes of patients with Joubourt Syndrome. Homozygosity mapping can be used as an alternative method to bypass the problem of genetic heterogeneity by studying large consanguineous families with autosomal recessive disorder. Using this strategy, identified a Joubourt Syndrome locus on chromosome 9q34.3 (JBTS1) in two families of Omani origin. However most of the families studied by and by researchers (unpublished results) are excluded for linkage to this locus. Recently, valente and Keeler identified a second Joubert syndrome locus associated with nephronophthisis on chromosome 11p11-q12 (cerebello-oculorenal syndrome 2, CORS2). We report here the identification of a third locus on 6q23 (JBTS3) from the study of two consanguineous families, including the second reported Joubourt Syndrome family. On the other hand, linkage to 6q23 was excluded for nine out of 15 additional families diagnosed with Joubert syndrome, the remaining families being too small to allow conclusions to be drawn.
The age at last examination of patients without renal problems was not indicated. The 11p11-q12 locus was named CORS2 for cerebello-oculorenal syndrome, with JBTS1 corresponding to CORS1. CORS2 patients contrast with the six patients of families 1 and 2, who have not developed renal failure past the age of 17. Moreover, reduced vision with retinal dystrophy was found in both families, while retinal presentation of CORS2 patients was more heterogeneous. The 6q23 locus was therefore named JBTS3, which may correspond to CORS3 if future linked families reveal renal heterogeneity. The knowledge of three Joubourt Syndrome loci opens up the possibility of investigating genotype/phenotype correlations that should help clarify nosologic delineation among CORS and facilitate the search for defective genes from homogeneous patient groups.
Presently, three genes for this disorder have been identified, NPHP1, AHI1, and CEP290. These genes are associated with the complications of retinal dystrophy and/or nephronophthisis in the majority of individuals with causative mutations. However, these genes are not the cause in many individuals with Joubert syndrome, and the genetics of these disorders remain complex. It is likely that alterations in other genes cause this condition. Research is currently underway to assist medical professionals in developing a greater understanding about this disorder.
The prognosis in Joubert Syndrome is poor. The 5 year survival rate is 50%. There is severe mental and motor retardation. Death is usually due to feeding difficulties and respiratory infections. The recurrence risk for the syndrome is 25%. There is an indication for careful ultrasonography in subsequent pregnancies.
The clinicalsymptoms in Joubert syndrome are variable, andit is unknown whether it represents a clinicallyuniform disease entity. Irregular breathing inthe neonatal period, developmental delay,mental retardation
, hypotonia, ocular motorabnormalities, and, occasionally, retinaldystrophy and cystic kidneys are the mainfeatures of this syndrome and are associatedwith cerebellar malformation.Vermishypoplasia or agenesis and abnormalities at thepontomesencephalic junction
are the hallmarksof the diagnosis, yet the relationship betweenradiologic and clinical findings has beentargeted in only a few studies.
Facial features may be abnormal in appearance (eyes far set from each other, small ear lobes, broadforehead, arched eyebrows, broad mouth).
- Oculomotor apraxia (OMA), which is a specific eye movement abnormality in which it is difficult forchildren to track objects smoothly. Eyes may appear to jump, with jerky eye movements.
- Abnormal breathing pattern with episodes of rapid breathing or panting (hyperpnea), which may befollowed by pauses in breathing (apnea).
- Abnormal collections of cerebrospinal fluid in the posterior fossa that may resemble Dandy-Walkermalformation.
- Difficulty processing and reacting to information received through their five senses.
- Jerking eye movements, called nystagmus.
- Episodes of rapid abnormal breathing, called episodic hyperpnea.
- Mental retardation.
- Drooping eyelids, called ptosis.
- Low-set ears.
- Difficult in coordinating voluntary muscle movements.
- Mouth opened with protruding tongue.
The diagnosis of Joubert syndrome is confirmed with MRI, which shows classic neuroradiologic finding of a complex midbrain-hindbrain malformation known as the MTS (molar tooth sign), originating from the association of cerebellar vermis hypoplasia, horizontally-oriented and thickened superior cerebellar peduncles and a deepened interpeduncular fossa.
- Detection of the MTS should be followed by a diagnostic protocol to assess multiorgan involvement.
- MRI findings also include dilated Cisterna magna, occipital meningoencephalocele, Dandy-Walker malformation, hypoplasia of the corpus callosum, retrobulbar cystic mass.
- Abdominal ultrasound may show cystic kidneys.Genetic testing is not currently available but the physical abnormalities may be detected at antenatal ultrasound. A fetal MRI scan at between 20 and 22 weeks of gestation has been shown to be an effective method of antenatal diagnosis.
Joubert syndrome cannot be cured, but treatment is very important to help with symptoms such as breathing problems and to support the child's development. This may include physical therapies, infant stimulation, speech therapy and special schooling.
NOTE 1: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.