Joubert syndrome (JS) is an autosomal recessive developmental brain condition characterized by hypoplasia/dysplasia of the cerebellar vermis and by ataxia, hypotonia, oculomotor apraxia, and neonatal breathing dysregulation.
The association of retinal dystrophy and renal anomalies defines JS type B. JS is a genetically heterogeneous condition with mutations in several genes: AHI1 at 6q23 (MIM.608894), CEP290 at 12q21 (MIM.610412) and TMEM67 at 8q21 (MKS3) (MIM.609884).
Synopsis
craniofacial anomalies
- macrocephaly
- prominent forehead
- high, rounded eyebrows
- hemifacial spasms
- low-set ears
- ’tilted’ ears
- upturned nose
- anteverted nostrils
- triangular-shaped open mouth
- protruding tongue
- rhythmic tongue movements
- soft tissue tumors of the tongue (less common)
ocular anomalies
- abnormal, jerky eye movements
- impaired smooth pursuit
- impaired saccades
- oculomotor apraxia
- bilateral colobomata (11186426)
- coloboma of optic nerve
- chorioretinal coloboma
- retinal dysplasia (less common) (JS type B)
- retinal dystrophy (less common) (JS type B)
- Leber congenital amaurosis (8456821, 3508675)
- epicanthal folds
- ptosis
respiratory anomalies
- neonatal breathing dysregulation
- hyperpnea, episodic
- tachypnea, episodic
- central apnea
+/- ductal plate malformation with hepatic fibrosis (congenital hepatic fibrosis) (7538263)
Hirschsprung disease (17516083)
+/- renal anomalies (JS type B)
- renal cysts
- multicystic kidneys (8456821, 9438658)
- congenital medullary cystic disease of the kidneys (7538263)
limb anomalies
- postaxial polydactyly (less common) (17160906)
- mussing digital phalanges (less common)
neurological anomalies
- delayed psychomotor development
- mental retardation
- ataxia
- hypotonia
- cortical polymicrogyria (JBTS3 with AHI1 mutations)
- occipital meningocele (less common)
- occipital myelomeningocele (less common)
- Dandy-Walker malformation (1887836)
- corpus callosum hypoplasia (1887836)
- occipital meningo-encephalocele (1887836)
- bilateral coloboma of the optic nerve with retrobulbar cystic mass (1887836)
- midline defects (1887836)
- hypoplasia of the brainstem
- occipital encephalocele (17160906)
- malformation of brainstem structures
- ’molar tooth sign’ on MRI
- cerebellar vermis hypoplasia
- dysgenesis or agenesis of the cerebellar vermis
- deep posterior interpeduncular fossa
- thick and elongated superior cerebellar peduncles
- hyperactivity
- aggressiveness
- self-mutilation
Variants
Joubert syndrome type B: association of JS with retinal dysplasia and nephronophthisis (cerebello-oculo-renal syndrome or CORS)
- germline mutations in RPGRIP1L
JBTS3: JS with cortical polymicrogyria (AHI1 mutations)
Etiology
The association of retinal dystrophy and renal anomalies defines JS type B. JS is a genetically heterogeneous condition with mutations in several genes: AHI1 at 6q23 (MIM.608894), CEP290 at 12q21 (MIM.610412) and TMEM67 at 8q21 (MKS3) (MIM.609884).
Joubert syndrome type 1 (JBTS1 or CORS1 at 9q34.3) (MIM.213300)
- gene unknown
Joubert syndrome type 2 (JBTS2 or CORS2 at 11p12-q13.3) (MIM.608091)(12908130)
- gene unknown
Joubert syndrome type 3 (JBTS3 or CORS3)
- Joubert syndrome with cortical polymicrogyria (JBTS3 or CORS3 at 6q23.3)
- recessive mutations in the gene AHI1 (Abelson helper integration site 1) (MIM.608894)
- the gene product, jouberin, contains a coiled-coil, an SH3 (src-homology domain 3) and six WD40 domains
Joubert syndrome type 4 (JBTS4 or CORS4 at 17p11.2) (MIM.609583)
- Smith-Magenis locus
Joubert syndrome type 5 (JBTS5 or CORS5 at 12q21.32) (MIM.610188)
- germline mutation in the CEP290 gene
- allelic to NPHP6 (MIM.610142) on 12q21.32
Joubert syndrome type 6 (JBTS6 or CORS6 at 8q21-q22) (MIM.610188)
- TMEM67 germline mutations at 8q21-q22 (MKS3 locus) (17160906)
- allelic to Meckel syndrome (MKS3 locus)
Joubert syndrome type B (cerebello-oculo-renal syndrome or CORS syndrome at 16q12.2)
- germline mutations of RPGRIP1L
NPHP1 Gene Deletion at 2q13 (15138899)
- allelic to juvenile nephronophtisis (NPHP1)
Associations
occipital encephalocele (17160906)
polydactyly (17160906)
Hirschsprung disease (17516083)
See also
Joubert-related cerebello-oculo-renal syndromes
References
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Tory K, Lacoste T, Burglen L, Moriniere V, Boddaert N, Macher MA, Llanas B, Nivet H, Bensman A, Niaudet P, Antignac C, Salomon R, Saunier S. High NPHP1 and NPHP6 Mutation Rate in Patients with Joubert Syndrome and Nephronophthisis: Potential Epistatic Effect of NPHP6 and AHI1 Mutations in Patients with NPHP1 Mutations. J Am Soc Nephrol. 2007 May;18(5):1566-1575. PMID: 17409309
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Chance PF, Cavalier L, Satran D, Pellegrino JE, Koenig M, Dobyns WB. Clinical nosologic and genetic aspects of Joubert and related syndromes. J Child Neurol. 1999 Oct;14(10):660-6; discussion 669-72. PMID: 10511339
Witzleben CL, Sharp AR. "Nephronophthisis-congenital hepatic fibrosis": an additional hepatorenal disorder. Hum Pathol. 1982 Aug;13(8):728-33. PMID: 7106736