Cerebelloparenchymal disorder IV, Classic Joubert syndrome, CPD IV, Joubert syndrome type A, Joubert-Boltshauser syndrome, Pure Joubert syndrome
Joubert syndrome (JS) is characterized by congenital malformation of the brainstem and agenesis or hypoplasia of the cerebellar vermis leading to an abnormal respiratory pattern, nystagmus, hypotonia, ataxia, and delay in achieving motor milestones. Prevalence is estimated at approximately 1/100,000. In the neonatal period, the disease often manifests by an irregular breathing pattern (episodic tachypnea and/or apnea), and nystagmus. During infancy, hypotonia may appear. Cerebellar ataxia (staggering gait and imbalance) may develop later. Delayed acquisition of motor milestones is common. Cognitive abilities are variable, ranging from severe intellectual deficit to normal intelligence. Neuro-ophthalmologic examination may show oculomotor apraxia. In some cases, seizures occur. Careful examination of the face shows a characteristic appearance: large head, prominent forehead, high rounded eyebrows, epicanthal folds, ptosis (occasionally), an upturned nose with prominent nostrils, an open mouth (which tends to have an oval shape early on, a 'rhomboid' appearance later, and finally can appear triangular with downturned angles), tongue protrusion and rhythmic tongue motions, and occasionally low-set and tilted ears. Other features sometimes present in Joubert syndrome include retinal dystrophy, nephronophthisis, and polydactyly. The syndrome is genetically heterogeneous. Seven genes, AHI1 (6q23), NPHP1 (2q13), CEP290 (12q21), TMEM67 (8q22), RPGRIP1L (16q12), ARL13B (3p12.3-q12.3) and CC2D2A (4p15), and two loci on chromosomes 9q34 (JBTS1) and 11p12-q13 (CORS2/JBTS2) have been associated with the disease so far. Transmission is autosomal recessive. Diagnosis is based on the main clinical features (hypotonia, ataxia, development delay and oculomotor apraxia), which must be accompanied by the presence of a neuroradiological hallmark, designated as the ``molar tooth sign'' (MTS) on magnetic resonance imaging (MRI). MTS results from hypoplasia of the cerebellar vermis and midbrain-hindbrain malformations. Differential diagnoses include Joubert syndrome-related disorders (JSRD), cerebellar vermis malformations without the MTS (which include Dandy-Walker malformation), X-linked cerebellar hypoplasia, ataxia with oculomotor apraxia types 1 and 2 (AOA1, AOA2), congenital disorders of glycosylation (CDG), 3-C syndrome, pontocerebellar hypoplasias/atrophies, orofaciodigital syndromes II and III, and Meckel-Gruber syndrome (see these terms). Antenatal diagnosis is feasible through molecular and imaging studies (fetal ultrasonography and MRI). Prenatal testing may be available for families in which both disease-causing mutations have been previously identified in an affected family member. Genetic counseling is an important clinical tool for preventing new cases, especially for couples with an affected first child. The risk of having an affected child in further pregnancies is 25%. Management is symptomatic and should be multidisciplinary. Education programs, physical, occupational, and speech therapy may improve the hypotonia and reduce the delay in achieving motor milestones. Prognosis is favorable for moderate forms of the disease. Management of patients with more severe forms should be carried out at a specialized reference centre.