Clinical characteristics.

Classic Joubert syndrome (JS) is characterized by three primary findings:

• A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS)
• Hypotonia
• Developmental delays

Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.

Diagnosis/testing.

The clinical diagnosis of JS is based on the presence of characteristic clinical features and MRI findings. To date pathogenic variants in 34 genes are known to cause JS; 33 of these are autosomal recessive and one is X-linked. A molecular diagnosis of JS can be established in about 62%-94% of individuals with a clinical diagnosis of JS by identification of biallelic pathogenic variants in one of the 33 autosomal recessive JS-related genes or a heterozygous pathogenic variant in the one X-linked JS-related gene.

Management.

Treatment of manifestations: Infants and children with abnormal breathing may require stimulatory medications (e.g., caffeine); supplemental oxygen; mechanical support; or tracheostomy in rare cases. Other interventions may include speech therapy for oromotor dysfunction; occupational and physical therapy; educational support, including special programs for the visually impaired; and feedings by gastrostomy tube. Surgery may be required for polydactyly and symptomatic ptosis and/or strabismus. Nephronophthisis, end-stage kidney disease, liver failure and/or fibrosis are treated with standard approaches.

Surveillance: Annual evaluations of growth, vision, and liver and kidney function; periodic neuropsychologic and developmental testing.

Agents/circumstances to avoid: Nephrotoxic medications such as nonsteroidal anti-inflammatory drugs in those with renal impairment; hepatotoxic drugs in those with liver impairment.

Genetic counseling.

JS is predominantly inherited in an autosomal recessive manner. JS caused by pathogenic variants in OFD1 is inherited in an X-linked manner. Digenic inheritance has been reported.

For autosomal recessive inheritance: at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible. For pregnancies known to be at increased risk for JS, prenatal diagnosis by ultrasound examination with or without fetal MRI has been successful.

Establishing the Diagnosis

The clinical diagnosis of JS is based on the presence of characteristic clinical features and MRI findings. To date pathogenic variants in 34 genes are known to cause JS; 33 of these are autosomal and one is X-linked. A molecular diagnosis of JS can be established in about 62%-94% of individuals with a clinical diagnosis of JS by identification of biallelic pathogenic (or likely pathogenic) variants in one of the 33 autosomal recessive JS-related genes or a heterozygous pathogenic (or likely pathogenic) variant in the one X-linked JS-related gene [Bachmann-Gagescu et al 2015a] (see Tables 1a and 1b).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (a multigene panel) and genomic testing (comprehensive genomic sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because of the extensive clinical and genetic heterogeneity in JS, Vilboux et al [2017] have suggested starting with a multigene panel, followed by exome sequencing if a molecular diagnosis has not been established.

• A multigene panel that includes some or all of the 34 JS-genes and other genes of interest (see Genetically Related Disorders). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder testing that includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing (when clinically available) includes exome sequencing and genome sequencing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: While single-gene testing or serial single-gene testing is rarely useful and typically NOT recommended because of the vast clinical and genetic heterogeneity of JS, targeted analysis for pathogenic variants in a specific gene can be performed first in individuals of the following ethnicity/ancestry if appropriate:

• Ashkenazi Jewish: p.Arg73Leu in TMEM216 [Edvardson et al 2010]
• Dutch: p.Arg2904Ter in CPLANE1 [Kroes et al 2016]
• French Canadian: several variants in CPLANE1, CC2D2A, NPHP1, and TMEM231 [Srour et al 2015]
• Hutterite: p.Arg18Ter in TMEM237 [Huang et al 2011], c.363_364delTA in CSPP1 [Shaheen et al 2014]
• Japanese: c.6012-12T>A in CEP290 [Suzuki et al 2016]

See Table 1a for the most common genetic causes of JS (i.e., pathogenic variants of any one of the genes included in this table account for >1% of JS) and Table 1b for less common genetic causes of JS (pathogenic variants of any one of the genes included in this table are reported in only a few families).

Clinical Description

Classic Joubert syndrome (JS) is characterized by the three primary findings of: a distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS), hypotonia, and developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Table 2 associates phenotypic features with genes; Table 3 associates genes with phenotypic features. Both intra- and interfamilial phenotypic variation are seen in JS.

Many of the clinical features of JS are evident in infancy [Joubert et al 1969, Boltshauser & Isler 1977]. The findings of nystagmus, oculomotor apraxia, and abnormal breathing patterns can be observed in all clinical subtypes. Most children with JS develop truncal ataxia and, in combination with hypotonia, exhibit delayed acquisition of gross motor milestones.

Nystagmus. Many children with Joubert syndrome demonstrate horizontal nystagmus at birth that improves with age. Torsional and pendular rotatory nystagmus have also been observed.

Oculomotor apraxia is often identified in childhood rather than in infancy, perhaps because of under-recognition of the finding [Steinlin et al 1997]. Many children with oculomotor apraxia demonstrate head thrusting as a compensatory mechanism for their inability to initiate saccades [Hodgkins et al 2004, Khan et al 2008, Weiss et al 2009]. Horizontal head titubation (i.e., a "no-no" head tremor) has been described in infants and young children younger than age two years [Poretti et al 2014]. Visual acuity and functional vision may improve with age as a result of visual maturation, in spite of significantly aberrant eye movements at birth [M Parisi and A Weiss, personal observation].

Respiratory findings. Many children with JS exhibit apnea, tachypnea, or both, sometimes alternating, particularly in the neonatal period [Saraiva & Baraitser 1992, Steinlin et al 1997, Maria et al 1999a, Valente et al 2008]. Although some infants have died of apnea, episodic apnea generally improves with age and may completely disappear [Maria et al 1999b]. Children with JS are at increased risk for sleep apnea, including central (particularly in infancy and childhood) and obstructive (particularly in later childhood/adolescence related to tongue hypertrophy, hypotonia, and obesity) [Parisi 2009]. A survey of self-reported sleep behaviors in individuals with JS using a validated sleep questionnaire suggested sleep-related breathing disorders in six of the 14 individuals surveyed [Kamdar et al 2011]. Some individuals with Leber congenital amaurosis resulting from biallelic pathogenic variants in CEP290 have also been found to have abnormalities in motile respiratory cilia that may predispose to respiratory symptoms including chronic rhinitis, recurrent sinusitis, and bronchitis [Papon et al 2010].

Central nervous system findings

• Cognitive abilities are variable, ranging from severe intellectual disability to normal cognitive function [Poretti et al 2009]; a few individuals have attended college. When present, intellectual disability is typically in the moderate range [Steinlin et al 1997, Hodgkins et al 2004, Bulgheroni et al 2016, Summers et al 2017]. A correlation between severity of cerebellar vermis hypoplasia and cognitive impairment was identified in a study of 110 persons with JS [Poretti et al 2017].
• Speech apraxia, a common finding, may account for the observed discrepancy between speech comprehension and verbal abilities [Hodgkins et al 2004, Braddock et al 2006].
• Abnormal EEG and/or seizures are present in some affected individuals; the exact incidence is unknown [Saraiva & Baraitser 1992]. One study identified greater cognitive impairment in individuals with JS and an abnormal EEG [Summers et al 2017].
• Autism has been reported in some children with JS [Holroyd et al 1991, Ozonoff et al 1999]; however, more recent surveys suggest that many of these behavioral disturbances do not represent classic autism spectrum disorder [Takahashi et al 2005].
• Behavioral findings including inattention, hyperactivity, and atypical behaviors such as temper tantrums are present in some children and adolescents [Deonna & Ziegler 1993, Hodgkins et al 2004, Farmer et al 2006]. Emotional and behavior issues were reported in almost 40% in one survey of 54 individuals with JS [Bulgheroni et al 2016]. In another survey of 76 individuals, behavior issues were more likely to manifest as internalizing (anxiety, depression) than externalizing (aggression, oppositional defiance) [Summers et al 2017].

JS Clinical Subtypes

See Table 2 and Table 3.

Table 2.

Joubert Syndrome: Clinical Subtypes

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Name of Clinical Subtype	Mandatory Features in Addition to Primary Criteria 1	Strongly Associated Features 2	Other Names	Genes (bold = major gene)
Classic or pure Joubert syndrome			JS; JS type A	Many genes
Joubert syndrome w/retinal disease (JS-Ret)	Retinal dystrophy (including LCA)		JS type B	AHI1 CEP290 CEP41 INPP5E MKS1 TMEM107 TMEM138 TMEM216
Joubert syndrome w/renal disease (JS-Ren)	NPHP (includes cystic kidney disease)			AHI1 CC2D2A CEP290 NPHP1 OFD1 RPGRIP1L TMEM138 TMEM216 TMEM237 ZNF423
Joubert syndrome w/oculorenal disease (JS-OR)	Retinal dystrophy (incl LCA); NPHP	CHF (occasional)	JS type B; CORS; Senior-Løken syndrome; Dekaban-Arima syndrome	AHI1 CC2D2A CEP290 NPHP1 POC1B RPGRIP1L TMEM216 TMEM231 TMEM237
Joubert syndrome w/hepatic disease (JS-H)	CHF	Colobomas; NPHP	COACH syndrome; Gentile syndrome	CC2D2A CEP290 INPP5E RPGRIP1L TMEM67
Joubert syndrome w/oral-facial-digital features (JS-OFD)	Tongue hamartomas; oral frenulae; polydactyly 3	Cleft lip/palate	Varadi-Papp syndrome; OFD VI; OFD IV; Mohr-Majewski syndrome	B9D2 C2CD3 CPLANE1 CEP120 KIF7 OFD1 TCTN2 TCTN3 TMEM107 TMEM216
Joubert syndrome w/acro-callosal features (JS-AC)	Agenesis of corpus callosum; polydacyly 3	Hydrocephalus	Acrocallosal syndrome	KIF7
Joubert syndrome w/Jeune asphyxiating thoracic dystrophy features (JS-JATD)	Skeletal dysplasia (short ribs, small thorax, short limbs, renal cystic disease)	Polydactyly 3; cone-shaped epiphyses; CHF	Jeune asphyxiating thoracic dystrophy; Mainzer-Saldino syndrome	CEP120 CSPP1 IFT172 KIAA0586

Adapted from Brancati et al [2010]. This classification scheme should not be interpreted as definitive, given the extreme clinical heterogeneity of the manifestations and the variable age of onset of many of these features.

AC = acro-callosal; CHF = congenital hepatic fibrosis ; COACH = cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis; CORS = cerebello-oculo-renal syndromes; H = hepatic; JATD = Jeune asphyxiating thoracic dystrophy; LCA = Leber congenital amaurosis; NPHP = nephronophthisis; OFD = oral-facial-digital syndrome; OR = oculorenal; Ren = renal; Ret = retinal

1.

Primary criteria = molar tooth sign (MTS), hypotonia, developmental delay (DD)

2.

Other features including encephalocele, postaxial polydactyly, other structural brain malformations (including polymicrogyria), congenital heart defects, Hirschsprung disease, and situs defects can be seen in these subtypes but are not major features.

3.

Polydactyly is often postaxial, especially of hands, and preaxial, especially of feet. Distinctive for OFD VI syndrome: mesaxial or central polydactyly with a Y-shaped metacarpal.

Joubert syndrome with retinal disease (JS-Ret) is characterized by a pigmentary retinopathy that may be indistinguishable from classic retinitis pigmentosa; it can occasionally be severe with neonatal onset of congenital blindness and an attenuated or extinguished electroretinogram that resembles Leber congenital amaurosis (LCA) [Tusa & Hove 1999]. However, the retinal disease may not be progressive and is not always present in infancy or early childhood [Steinlin et al 1997]. One survey of 235 families with JSRD identified retinal dystrophy in 30% [Doherty 2009].

• Ocular colobomas are most often described as chorioretinal [Saraiva & Baraitser 1992, Parisi 2009] and may be associated with hepatic fibrosis, as in the COACH syndrome variant [Doherty et al 2010]. One survey described colobomas in 19% of families with JSRD [Doherty 2009]. A retinal change described as the "morning glory disc anomaly" has been described in an extended Austrian family from the Tyrolean region with biallelic TMEM237 pathogenic variants [Janecke et al 2004, Huang et al 2011].
• Other. Variably present:
  • Ptosis, strabismus, and/or amblyopia
  • Third nerve palsy [Hodgkins et al 2004]

Joubert syndrome with renal disease (JS-Ren) has been described traditionally in two forms (nephronophthisis and cystic dysplasia); however, these now appear to be part of a continuum with the specific renal manifestation varying by stage of renal disease. Juvenile nephronophthisis, a form of chronic tubulointerstitial nephropathy, often presents in the first or second decade of life with polydipsia, polyuria, urine-concentrating defects, growth restriction, and/or anemia. Progression to end-stage kidney disease occurs on average by age 13 years [Hildebrandt et al 1998]. Renal changes visible on ultrasound examination occur late in the course and consist of small, scarred kidneys with increased echogenicity and occasional cysts at the corticomedullary junction, findings consistent with cystic dysplasia (i.e., multiple variably sized cysts in immature kidneys with fetal lobulations) [Saraiva & Baraitser 1992, Steinlin et al 1997, Satran et al 1999].

In addition to the nephronophthisis and cystic dysplasia spectrum, a second type of renal disease that resembles autosomal recessive polycystic kidney disease (ARPKD) has been reported.

• Three individuals with JS caused by biallelic TMEM67 pathogenic variants were reported to have renal disease more typical of ARPKD, with enlarged, diffusely microcystic kidneys and early-onset severe hypertension as well as congenital hepatic fibrosis; in addition, they exhibited chronic anemia characteristic of nephronophthisis [Gunay-Aygun et al 2009].
• In the Hutterite population, approximately 70% of probands with JS caused by biallelic TMEM237 pathogenic variants have cystic renal disease and abnormal renal function, with hypertension reported in some [Boycott et al 2007, Huang et al 2011].

Renal disease has been reported in 23% [Doherty 2009] and 30% [Saraiva & Baraitser 1992] of persons with JS. These prevalence values may increase as a cohort ages, as renal disease can develop during childhood and adolescence [Steinlin et al 1997].

Joubert syndrome with oculorenal disease (JS-OR). Retinal disease and renal impairment often occur together in the same individual, and many of JS-related genes are associated with both renal cystic disease and retinal dystrophy, a combination sometimes known as Senior-Løken syndrome [Parisi 2009, Brancati et al 2010] (Table 2). In the past JS-OR was also known as Dekaban Arima syndrome (retinopathy, cystic dysplastic kidneys), which can be evident prenatally or at birth.

Joubert syndrome with hepatic disease (JS-H). Hepatic fibrosis is usually progressive but rarely symptomatic at birth. Congenital hepatic fibrosis is a developmental disorder of the portobiliary system characterized histologically by defective remodeling of the ductal plate (ductal plate malformation), abnormal branching of the intrahepatic portal veins, and progressive fibrosis of the portal tracts. Clinical findings include enlarged, abnormally shaped liver, relatively well-preserved hepatocellular function, and portal hypertension resulting in splenomegaly, hypersplenism, and gastroesophageal varices.

Hepatic fibrosis was observed in 18% of individuals with JS in one cohort [Doherty 2009].

When present in JS, hepatic fibrosis is often associated with chorioretinal colobomas and sometimes with renal disease. The combination of colobomas, cognitive impairment ("oligophrenia"), ataxia, cerebellar vermis hypoplasia, and hepatic fibrosis has been termed COACH syndrome [Satran et al 1999, Gleeson et al 2004, Doherty et al 2010].

Joubert syndrome with oral-facial-digital features (JS-OFD). Oral findings can include midline upper-lip cleft, midline groove of tongue, hamatomas of the alveolar ridge (Figure 2B), cleft palate, oral frenulae, and tongue lobulations or hamartomas. Craniofacial features often include wide-spaced eyes or telecanthus, hypoplastic alae nasi, and micrognathia.

Figure 2.

Clinical features in JSRD A. Facial features in a girl with JS/COACH syndrome at age 27 months showing broad forehead, arched eyebrows, strabismus, eyelid ptosis (on right eye), and open mouth configuration indicating reduced facial tone

Polydactyly is described in 8%-19% of probands [Doherty 2009, Brancati et al 2010]. Polydactyly can be unilateral or bilateral and is often postaxial (Figure 2C), although preaxial polydactyly of the toes is also frequently reported (Figure 2D) [Saraiva & Baraitser 1992].

Mesaxial polydactyly, in which the extra digit occurs between the central digits and is often accompanied by a Y-shaped metacarpal, has been described in some individuals with JS, many of whom have other features of oral-facial-digital syndrome type VI/Varadi-Papp syndrome [Gleeson et al 2004]. OFD VI has now been defined as a form of JS, requiring the MTS as well as one or more of the following features: tongue hamartoma/oral frenula/upper-lip notch, mesaxial polydactyly, and hypothalamic hamartoma [Poretti et al 2012].

Joubert syndrome with acrocallosal features (JS-AC). Agenesis of the corpus callosum is common in JS [Valente et al 2005]. In one survey of 20 individuals with JS, 80% had some degree of callosal dysgenesis [Senocak et al 2010]. Callosal abnormalities are relatively frequent in those with biallelic KIF7 pathogenic variants [Bachmann-Gagescu et al 2015a], suggesting overlap with acrocallosal syndrome (see Genetically Related Disorders) in which polydactyly and hydrocephalus are also seen [Putoux et al 2011].

Joubert syndrome with Jeune asphyxiating thoracic dystrophy (JS-JATD). Features of JATD (see Genetically Related Disorders) and the related short-rib thoracic dysplasia condition, Mainzer-Saldino syndrome, have been reported in several children with a JS, reflecting the shared ciliary origin of these conditions [Lehman et al 2010, Halbritter et al 2013, Shaheen et al 2015b].

Phenotype Correlations by Gene

Table 3 includes preliminary information on genotype-phenotype correlations.

Nomenclature

The term "Joubert syndrome and related disorders" (JSRD) has been used in the past to describe conditions that share the molar tooth sign and the clinical features of classic Joubert syndrome and also have other organ system involvement. In an evolving nomenclature designed to reduce reliance on confusing and inconsistently used eponyms, at least eight clinical subtypes of JS that share the three primary findings have been proposed (Table 2) [Brancati et al 2010]. More recently, "Joubert syndrome" has become the accepted term to describe all forms of JS.

In the past, some of the following disorders were described as distinct syndromes, but more recent studies indicate that many individuals with these disorders demonstrate the molar tooth sign [Satran et al 1999, Gleeson et al 2004]. Examples of such autosomal recessive disorders include the following:

• Dekaban-Arima syndrome (retinopathy, cystic dysplastic kidneys) [Dekaban 1969]
• Senior-Løken syndrome (SLS; retinopathy and juvenile-onset nephronophthisis) [Løken et al 1961, Senior et al 1961]
• COACH syndrome (cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis) [Verloes & Lambotte 1989, Gentile et al 1996]
• Varadi-Papp syndrome (oral-facial-digital syndrome VI [OFD VI]) includes cerebellar vermis hypoplasia, oral frenulae, tongue hamartomas, and midline cleft lip as well as the distinctive feature of central polydactyly with a Y-shaped metacarpal [Münke et al 1990]. Renal and cardiac involvement have been described.

Prevalence

The prevalence of Joubert syndrome (JS) has not been determined. Many authors use a range between 1:80,000 and 1:100,000, but this may represent an underestimate [Kroes et al 2007, Parisi et al 2007, Brancati et al 2010].

There is a relatively high prevalence of JS in the French Canadian population, with several founder variants noted. The family first described by Joubert et al [1969] has been traced to a founder who immigrated to Quebec from France in the 1600s [Badhwar et al 2000]. However, in this family and others, it appears that there are multiple CPLANE1 pathogenic variant-containing haplotypes in the French Canadian population. In fact, in 35 French Canadian families, pathogenic variants were identified in 33 (94%) in the following genes (number of affected families given in parentheses): CPLANE1 (14), CC2D2A (9), NPHP1 (3), TMEM231 (2); and CEP290, TMEM67, TCTN1, OFD1, B9D1, C2CD3, and CEP104 (1 family each). Many French Canadian individuals are compound heterozygous for different pathogenic variants in either CPLANE1, CC2D2A, TMEM231, or NPHP1 [Srour et al 2012a, Srour et al 2012b, Srour et al 2015].

A different founder variant in CPLANE1, p.Arg2904Ter, occurs in the Dutch population [Kroes et al 2016].

A TMEM216 founder variant, p.Arg73Leu, has a carrier rate of 1:92-1:100 in the Ashkenazi Jewish population [Edvardson et al 2010, Valente et al 2010].

In a Canadian Hutterite population, ten related individuals with a MKS-like phenotype including encephaloceles and cystic kidneys were homozygous for a nonsense pathogenic variant (c.52C>T; p.Arg18Ter) in TMEM237, reflecting a carrier frequency of 6% in this population [Huang et al 2011]. Two different Schmiedeleut Hutterite families had the same homozygous pathogenic frameshift variant, c.363_364delTA, in CSPP1 [Shaheen et al 2014], representing a separate founder variant.

In a survey of Japanese families with JS, 6/27 had pathogenic variants in CEP290, with c.6012-12T>A found on nine out of 12 disease alleles; 7/27 families had pathogenic variants in TMEM67 but no founder alleles were identified [Suzuki et al 2016].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Joubert syndrome (JS), the following baseline evaluations to identify the extent of disease in affected infants/children are recommended [Parisi et al 2007] (full text). Recommendations were developed by a consensus panel and are outlined on the Joubert Syndrome and Related Disorders Foundation website.

• Examination of high-quality MRI scan to assess for cerebral malformations, neuronal migration disorders, or cephaloceles that could portend a poorer prognosis or seizures, if not done at the time of diagnosis
• A baseline neurologic evaluation with particular attention to tone, respiratory pattern (tachypnea and apnea), eye movements, development, and cerebellar function
• Sleep history with polysomnogram as baseline evaluation and particularly if symptomatic apnea is present
• Assessment of oromotor function by a speech therapist and/or by fluoroscopic swallowing studies
• Developmental assessment with age-appropriate tools
• Evaluation by a pediatric ophthalmologist via dilated eye examination for colobomas and retinal changes, as well as strabismus and ptosis, with consideration of specialized testing such as visual-evoked potentials, electroretinogram, and ocular motility testing
• Abdominal ultrasound examination to evaluate for hepatic fibrosis or renal cysts and/or findings consistent with nephronophthisis (e.g., loss of corticomedullary differentiation)
• Tests of renal function, including blood pressure, blood urea nitrogen (BUN), serum creatinine concentration, complete blood count (CBC), and urinalysis from first-morning void for specific gravity to test concentrating ability (if feasible)
• Liver function tests including serum concentrations of transaminases, albumin, bilirubin, and prothrombin time
• For males with micropenis or any child with signs of growth hormone deficiency, endocrine evaluation for other pituitary abnormalities
• Skeletal survey and/or limb radiographs if there is suspicion of a skeletal dysplasia such as short-rib polydactyly or JATD
• Consultation with a clinical geneticist to document family history, to evaluate growth and head size, and to evaluate for other anomalies including polydactyly, dysmorphic facial features, tongue tumors/lobulations, and micropenis

Treatment of Manifestations

Respiratory

• Infants and children with abnormal breathing patterns should be considered for apnea monitoring if the abnormality is severe. Supportive therapy may include stimulatory medications such as caffeine or supplementary oxygen, particularly in the newborn period.
• Anesthetic management during surgical procedures for infants with significant respiratory disturbance may be accomplished in some cases by the use of:
  • Regional anesthesia without opioids to avoid exacerbation of apneic episodes [Vodopich & Gordon 2004];
  • Alpha-2 agonists such as clonidine or dexmedetomidine to avoid respiratory depression and other complications of opioids while achieving motion-free images [Sriganesh et al 2014].
• In rare cases, mechanical support and/or tracheostomy may be considered in a child with severe respiratory dysfunction.
• Aggressive treatment of middle ear infections is indicated to avoid conductive hearing loss.

Hypotonia and therapeutic interventions

• Appropriate management and therapy of oromotor dysfunction by a speech therapist
• Nasogastric feeding tubes or gastrostomy tube placement for feeding in children with severe dysphagia
• Occupational, physical, and speech therapy through early intervention programs
• Individualized educational assessment and support for school-aged children to maximize school performance
• Periodic neuropsychologic and developmental testing at appropriate ages

Other CNS malformations

• Neurosurgical consultation is indicated for those with evidence of hydrocephalus (rapidly increasing head circumference and/or bulging fontanelle). Note: When hydrocephalus occurs in JS, it rarely requires shunting.
• Posterior fossa cysts and fluid collections rarely require intervention.
• Encephalocele may require primary surgical closure.
• Seizures should be evaluated and treated by a neurologist using standard anti-seizure medication.
• A variety of psychotropic medications have been used to treat the behavioral complications in Joubert syndrome; no single medication has been uniformly effective for all children.

Ophthalmologic

• Surgery as needed for symptomatic ptosis, strabismus, or amblyopia
• Corrective lenses for refractive errors
• Possible vision therapies for oculomotor apraxia, although specific studies are lacking in this disorder
• Interventions for the visually impaired when congenital blindness or progressive retinal dystrophy are present

Renal disease

• Consultation with a nephrologist is indicated.
• End-stage kidney disease (ESKD) resulting from nephronophthisis frequently requires dialysis and/or kidney transplantation during the teenage years or later.
• Hypertension, anemia, and other complications of ESKD require specific treatment.

Hepatic fibrosis

• Consultation with a gastroenterologist is indicated.
• Liver failure and/or fibrosis should be managed by a gastroenterologist with arrangements for surgical intervention such as portal shunting for esophageal varices and portal hypertension, as appropriate.
• Some individuals have needed orthotopic liver transplantation.

Skeletal

• Surgical treatment for polydactyly
• Appropriate medical management by an orthopedic specialist for scoliosis

Other

• Orofacial clefting is treated by standard surgical interventions.
• Tongue tumors that impair normal swallowing or cause respiratory obstruction may require surgical resection.
• Symptoms of obstructive sleep apnea and/or tongue hypertrophy in older individuals may require evaluation with a polysomnogram and/or by an otolaryngologist for consideration of adenoidectomy, tonsillectomy, or surgical tongue reduction. Some children have used BiPAP or C-PAP at night.
• Consultation with an endocrinologist for menstrual irregularities and for pituitary hormone deficiency (with hormone replacement as indicated) is appropriate.
• Obesity should be managed with appropriate measures, including diet, exercise, and behavioral therapies
• Congenital heart defects and situs abnormalities should be treated by conventional therapies.
• Surgical correction of Hirschsprung disease (if present) is indicated.

Prevention of Secondary Complications

Antibiotic prophylaxis for surgical and dental procedures is indicated for individuals with structural cardiac anomalies.

Surveillance

Because no uniformly reliable distinguishing characteristics allow prediction of the complications that may develop in an infant or young child with Joubert syndrome, a number of annual evaluations are recommended (see also Joubert Syndrome and Related Disorders Foundation website):

• Pediatric and neurologic evaluation and monitoring of growth, sexual maturation, breathing (including apnea symptoms), and motor function
• Neuropsychological and developmental evaluation and testing, as appropriate
• Ophthalmologic evaluation for visual acuity, tracking ability, and development of retinal dystrophy
• Abdominal ultrasound examination for evaluation of possible liver and kidney abnormalities
• Liver function tests
• Evaluation of renal function: measurement of blood pressure, serum concentrations of BUN and creatinine, CBC, and assessment of first-morning void urinalysis

Agents/Circumstances to Avoid

Individuals with renal impairment should avoid nephrotoxic medications such as nonsteroidal anti-inflammatory drugs.

Individuals with liver impairment should avoid hepatotoxic medications.

Evaluation of Relatives at Risk

Sibs or relatives who have clinical features similar to those of an individual with JS warrant genetic consultation. If the pathogenic variant(s) have been identified in a proband, testing symptomatic relatives for these pathogenic variants is appropriate.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Joubert syndrome (JS) is inherited predominantly in an autosomal recessive manner.

OFD1-related JS is inherited in an X-linked manner (click here (pdf) for discussion of X-linked inheritance).

Risk to Family Members (Autosomal Recessive Inheritance)

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant in a JS-related gene).
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• The offspring of a proband are obligate heterozygotes (carriers) for a pathogenic variant in a JS-related gene.
• Although no individuals with JS are reported to have reproduced, the broad spectrum of cognitive impairment now known in this condition may increase the likelihood that reports of individuals who have had offspring will be forthcoming.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant in a JS-related gene.

For information about risk to family members ‒ X-linked inheritance (OFD1-related) click here (pdf).

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the JS-related pathogenic variant(s) in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirned (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the JS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for JS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Prenatal imaging. First-trimester diagnosis of JS for pregnancies at 25% risk has been reported using ultrasound examination to identify structural brain abnormalities such as encephalocele [van Zalen-Sprock et al 1996, Wang et al 1999]. More typically, prenatal diagnosis in at-risk fetuses has been accomplished by prenatal ultrasound examination of the posterior fossa and/or kidneys (for cysts and enlarged and/or hyperechoic kidneys) and digits (for polydactyly) as early as the second trimester [Ní Scanaill et al 1999, Aslan et al 2002, Doherty et al 2005]. In reality, prenatal sonographic findings in fetuses with JS are relatively nonspecific and include increased nuchal translucency, enlarged cisterna magna, cerebellar vermis aplasia/hypoplasia, occipital encephalocele, and ventriculomegaly, making definitive diagnosis of JS difficult in the absence of a family history. Moreover, the cerebellar vermis is a relatively late-developing structure, and may not cover the fourth ventricle until 18 weeks' gestation, making visualization of the molar tooth sign (MTS) difficult earlier in gestation [Bromley et al 1994]. The use of 2D ultrasound and 3D sonographic reconstruction with surface rendering has allowed visualization of the MTS as early as 22 weeks in several fetuses without a prior family history of JS [Quarello et al 2014].

Accurate prenatal diagnosis of JS in an at-risk fetus has been achieved by serial prenatal ultrasound imaging starting at 11 to 12 weeks' gestation, with detailed evaluation of cerebellar and other fetal anatomy through 20 weeks' gestation, followed by fetal MRI imaging at 20 to 22 weeks' gestation [Doherty et al 2005]. In a series of 12 pregnancies at 25% risk of having a fetus with JS, one center was able to correctly diagnose JS in the three affected fetuses based on fetal MRI findings at the pontomesencephalic junction (including the MTS) as early as 22 weeks' gestation [Saleem & Zaki 2010]. In the earliest reported diagnoses to date, MTS was identified in two separate at-risk pregnancies at 17 to 18 weeks' gestation via fetal MRI [Saleem et al 2011]. Although prenatal imaging, including fetal MRI, is useful in the diagnosis of posterior fossa anomalies, its sensitivity and specificity for the diagnosis of JS is unknown, and its use has not been systematically evaluated.

For a couple who has already had a child with JS, the presence of findings that suggest a prenatal diagnosis of Joubert syndrome and related disorders (e.g., encephalocele, renal cystic changes, polydactyly, or posterior fossa anomalies on fetal imaging) is highly significant; however, the absence of these signs does not preclude a diagnosis of Joubert syndrome and related disorders because of the unknown sensitivity of imaging and because of intrafamilial variability.

Molecular Pathogenesis

All of the genes in which pathogenic variants are known to cause Joubert syndrome (JS) localize to the primary cilium and/or basal body and centrosome where they may play a role in the formation, morphology, and/or function of these organelles. The cilia are membrane-found, hair-like projections that are anchored by the basal body.

Motile cilia have a 9+2 microtubule axonemal structure that allows for movement and flow of fluids; they are found on specialized cell types such as respiratory epithelia and spermatozoa. Primary cilia have a 9+0 microtubule structure and are usually non-motile. Primary cilia are found on most cell types and appear to play a role in cellular chemo- and mechanosensation and cell signaling, including the WNT, sonic hedgehog (SHH), and PDGF signaling pathways involved in differentiation, cell division, and planar cell polarity.

Ciliopathies, conditions caused by defects in one or more of the many proteins important in ciliary function, share many features including renal disease, retinal dystrophy, and polydactyly [reviewed in Badano et al 2006]. The association of ciliary defects with specific phenotypes has not been completely elucidated, but in the case of the hindbrain malformation seen in Joubert syndrome, it is known that SHH signaling is critical for both dorsal-ventral patterning of the neural tube and cerebellar granule cell proliferation [Doherty 2009].

Note: Detailed information about JS-related genes in which pathogenic variants account for more than 1% of JS (see Table 1a) appears in this section. Detailed information about JS-related genes in which pathogenic variants account for less than 1% of JS (see Table 1b) appears here (pdf).

Author Notes

University of Washington Joubert Center

Revision History

• 29 June 2017 (bp) Comprehensive update posted live
• 11 April 2013 (cd/mp) Revision: mutations in TMEM231 and TCTN3 identified to cause JSRD; clarification of the uncertainty of a role for mutation in TTC21B; sequence analysis and deletion/duplication analysis available clinically for mutations in C5orf42 and CEP41; edits to Figure 2
• 13 September 2012 (cd) Revision: sequence analysis available clinically for TCTN1, TCTN2, TTC21B, and TMEM13; deletion/duplication analysis available for TMEM138
• 14 June 2012 (cd/mp) Revision: targeted mutation analysis for the TMEM216 founder mutation c.218G>T available clinically
• 24 May 2012 (cd/mp) Revision: Joubert syndrome 11, 15, 16, and 17 result from mutations in TTC21B, CEP41, TMEM138, and C5orf52 respectively
• 29 March 2012 (me) Comprehensive update posted live
• 8 March 2007 (cd) Revision: mutations in TMEM67 (MKS3) identified in 3/22 individuals with JS who did not have NPHP1 deletions; MKS3 is sixth JS locus.
• 4 August 2006 (cd) Revision: clinical testing and prenatal diagnosis available for CEP290 mutations
• 25 July 2006 (cd) Revision: AHI1 sequence analysis clinically available; prenatal diagnosis for AHI1 and NPHP1 clinically available
• 30 June 2006 (ca) Revision: mutations in CEP290 (NPHP6) identified in individuals with JTS
• 24 February 2006 (me) Comprehensive update posted live
• 9 July 2003 (me) Review posted live
• 27 January 2003 (mp) Original submission

Published Guidelines / Consensus Statements

• Parisi MA, Doherty D, Chance PF, Glass IA. Joubert syndrome (and related disorders) (OMIM 213300). Available online. 2007. Accessed 12-12-22.

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