Joubert syndrome …

David J Harris MD

Developmental Malformations

Updated 01.19.2024
Released 05.14.1999
Expires For CME 01.19.2027

Joubert syndrome

Author: David J Harris MD

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Editor: Ganeshwaran H Mochida MD

Joubert syndrome

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Introduction

Overview

Joubert syndrome is a malformation syndrome affecting brainstem and cerebellum, resulting in early hypotonia, subsequent truncal ataxia, delayed milestones, and, finally, cognitive impairment of varying degrees. Although a rare condition, its pathogenetic understanding is likely to contribute significantly to the organization and function of the hindbrain. Molar tooth sign is the diagnostic neuroimaging finding on axial cuts through the midbrain/hindbrain region. Experience has shown that some mutations (in particular NPHP1, C5orf42, autosomal recessive SUFU variants) tend to be associated with a mild molar tooth, which may be easily overlooked. It is worth considering heterozygous dominant (familial or de novo) SUFU variants associated with congenital ocular motor apraxia if a mild molar tooth is found. In this article, the author gives an update of the diagnostic workup, quotes newly provided healthcare recommendations for this potential multisystem disorder, refers to other cerebello-oculo-renal syndromes, and summarizes the actual knowledge about molecular genetics. The genetic situation is complex in view of marked genetic heterogeneity and modifier genes. More than 40 different associated genes have been reported; however, in about 30% of affected individuals, a pathogenic mutation is still unknown; increasing use of whole-exome sequencing will lower this percentage. All genes are related to the primary (nonmotile) ciliary-basal body apparatus. Joubert syndrome can be grouped among the ciliopathies. Joubert syndrome is now the best-studied hindbrain malformation.

Historical note and terminology

In 1969, Marie Joubert and colleagues reported a previously undescribed syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation associated with agenesis of the cerebellar vermis (33). They observed this condition in four siblings of a family; there was remote consanguinity of the parents. Boltshauser and Isler added three cases and suggested the designation “Joubert syndrome” (08). Friede and Boltshauser published the first detailed postmortem report in 1978 (25). Maria and colleagues drew attention to characteristic MRI findings (molar tooth appearance of midbrain) and gave detailed neuro-ophthalmologic findings (41). So far, larger series reported are from Maria and colleagues and Boltshauser and colleagues (41; 65; 26). Studies of larger American patient series were particularly supported by a patient organization called the Joubert Syndrome Foundation, later named Joubert Syndrome and Related Disorders Foundation. Diagnostic criteria were discussed on October 16, 1998, in Montreal at a satellite symposium of the Child Neurology Society Meeting; this symposium was devoted to Joubert syndrome.

The publication by Gleeson and colleagues reporting a Molar Tooth Sign in apparently different syndromes was responsible for the change in terminology to “Joubert Syndrome and Related Disorders.” However, this change also created confusion among parents and professionals. It is preferable to stick to “Joubert Syndrome,” realizing that this is an umbrella term encompassing a genetically heterogeneous group of ciliopathies sharing the neuroimaging hallmark of a molar tooth (27).

Clinical manifestations

Presentation and course

Many patients first come to medical attention as neonates because of respiratory abnormalities (eg, tachypnea-apnea), but these abnormalities are seen in only 50% to 75% of cases. The remainder will be assessed for hypotonia, developmental delay, or eventually, ataxia and ocular motor apraxia. Horizontal head titubation has been added as a benign self-limiting presentation in 13 infants (49).

Diagnostic criteria suggested by Maria and coworkers are still useful (40):

Table 1. Diagnostic Criteria for Joubert Syndrome

Constant findings
	• Hypotonia • Delayed motor milestones followed by ataxia • Cognitive developmental delay or impairment • Characteristic neuroimaging pattern
		- Vermis hypoplasia or dysplasia (“Vermis clefting”) - Elongated, thickened superior cerebellar peduncles with horizontal orientation - Deeper than normal interpeduncular fossa. This results in the axial plane in a molar tooth sign. - MRI in sagittal plan shows an abnormally shaped and rostrally displaced fastigium of fourth ventricle. Note that the molar tooth sign is not always straightforward. Mild molar tooth sign can be seen in particular in mutations of NPHP1, C5orf42, and hypomorphic recessive SUFU variants (21).
Common abnormalities
	• Breathing abnormalities
		- Episodic tachypnea-apnea - Pronounced in neonatal period and infancy
	• Ocular motor apraxia with vestibulo-ocular cancellation and pursuit defects • Facial phenotype
		- Large head - Prominent forehead - High-arched eyebrows - Broad nasal bridge - Mild epicanthus - Anteverted nostrils - Open mouth with irregular tongue protrusion - Tented upper lip, which is less pronounced with increasing age
	• Behavioral phenotype
		- Most patients are placid - Rarely autistic traits - Rarely aggressive behavior - Insensitivity to noise
	• Kidneys: chronic renal disease affects about 30% of patients • Retina: retinal dystrophy is observed in at least 30% of patients
Occasional findings
	• Liver (hepatic fibrosis, portal hypertension as probable complication) • CNS: Occipital meningocele • Face: Ptosis • Limbs: Postaxial polydactyly • Various: Short stature, hoarse voice; cataract and scoliosis (personal observations)

In our experience, hydrocephalus and seizures are only exceptionally seen in Joubert syndrome patients.

Even among affected siblings, there may be marked variability in motor and cognitive performance. Many patients have acquired the ability to sit by around 18 months and walk independently between two and 10 years, with a median age around five years. Cognitive delay is an almost constant feature. Developmental testing revealed developmental quotients of 0,6 to 0,85 in part of our cohort and values around 0,3 in the other part (65). Differences may be found in subtest results. Detailed testing seems mandatory to provide appropriate supportive measures. Normal cognitive functions have been demonstrated in exceptional patients (50).

Many children with Joubert syndrome have a similar behavioral phenotype: they are reported to be pleasant, friendly, and socially well integrated (20; 65). Self-injury is an unusual feature, but mild aggressive manners may be provoked if too much is demanded. Parents have commonly observed hypersensitivity to noise.

Initially the nature and prognosis of retinal and renal involvement were not clear. Mild retinal dystrophy, apparently congenital and nonprogressive, was seen in nearly half of the patients reported by Steinlin and colleagues (65), congenital retinal amaurosis may occur in rare instances (37). Increasing experience has shown that retinal dystrophy and renal involvement are usually progressive (see Prognosis and complications).

Prognosis and complications

A number of infants with Joubert syndrome have died unexpectedly in the first three years of life. It is not known whether their deaths were related to respiratory abnormalities or apneic episodes. Prognosis for early demise seems to be worse in infants who have highly pronounced respiratory abnormalities and who do not achieve typical developmental milestones. Prognosis for cognitive development is guarded. All patients studied by Steinlin and colleagues and Gitten and colleagues had cognitive impairment (65; 26). In an Italian cohort of 54 patients about 40% had emotional and behavioral problems and six had a full IQ in the normal range (12). An evaluation of neuroimaging findings in 110 patients with Joubert syndrome suggested that worse developmental outcome was associated with more severe degree of vermis hypoplasia (52).

A prospective evaluation of kidney involvement in 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center revealed renal disease in 30% of patients, most commonly in association with CEP290, TMEM67, and AHI1. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease were found to be part of the Joubert syndrome kidney phenotype (24). Early-onset hypertension occurred in 24% of patients with kidney disease. A selection bias in this cohort towards more affected patients is possible. Therefore, blood pressure and kidney function need to be monitored. Evolving renal failure leads to kidney transplantation in a growing number of patients.

A comprehensive ophthalmic assessment performed prospectively at the National Institutes of Health Clinical Center on 99 patients yielded the following main results: ocular motor apraxia in 78%, strabismus in 72%, nystagmus in 67%, ptosis in29%, colobomas in 30%, definite retinal degeneration in 24%, and optic atrophy not due to end-stage retinal dystrophy in 8% of affected individuals (11). Most patients with coloboma did not have retinal dystrophy, and vice versa. A bias toward a higher prevalence of patients with kidney and liver disease in this cohort is possible. A macular staphyloma was documented as a new finding by spectral domain optical coherence tomography in six patients (68).

Characteristics of liver disease in 100 individuals with Joubert syndrome prospectively evaluated are now available (66). Patients were classified as having liver disease if they had elevation of liver enzymes or abnormal liver parenchyma on ultrasonography. Forty-three patients (43%) had liver involvement but only four individuals were symptomatic. Liver synthetic function was not affected, and splenomegaly was not a feature. Patients with probable portal hypertension had an increased prevalence of mutations in TMEM67, and colobomas were significantly more common. Individuals with liver disease were relatively older underscoring the progressive nature of hepatic fibrosis; hence, regular monitoring is required.

Clinical vignette

A girl, the third child of healthy, unrelated parents, was seen for retarded development and hypotonia at 18 months. She was unable to sit or crawl. Her facial appearance, with intermittent mild tongue protrusion and the hint of a short episode of tachypnea, raised the possibility of Joubert syndrome. Neuroimaging confirmed this assumption, showing cerebellar vermis split and a molar tooth aspect of the midbrain. Renal ultrasound was normal. At that time, ocular motor apraxia was not yet evident, but this was obvious at later reevaluation. Further developmental milestones were delayed despite intensive supportive measures; she was walking with assistance at 2.5 years and took her first unaided steps (free walking) at 3.5 years. Marked delay of expressive speech was, in part, explained by tongue apraxia—a common finding in Joubert syndrome. Gesture and signs predominantly supported communication. At four years of age, she had achieved the ability to say “yes” and “no”; by 6.5 years of age, she had a vocabulary of about 10 words. Testing of cognitive function gave a developmental quotient of about 0,65. She attended a special class for handicapped children. At 6.5 years of age, she was able to climb stairs unaided, could ride a bike with lateral support, and was almost able to dress and eat without assistance. Working with a “speaking computer” had not yet been successful. When last seen at 15 years of age, she was almost independent in activities of daily living and was able to communicate about practical needs. She was still attending a special class.

Joubert syndrome (facial phenotype)

Note the frontal bossing, high-arched eyebrows, low nasal bridge, epicanthic folds, anteverted nostrils, open mouth, and tented upper lip, respectively. (A) 7-month-old patient, (B) 18-month-old infant, (C) 4-year-old girl (same p...
Joubert syndrome (MRI)

(A) Coronal and (B) axial section revealing vermian cleft, (C) axial cut through midbrain showing deep interpeduncular fossa and elongated and thickened superior cerebellar peduncles giving rise to “molar tooth” aspect, (D) sagitt...
Joubert syndrome (CT)

(A) Axial section showing midline vermian cleft and umbrella shaped forth ventricle, (B) higher axial cut revealing “molar tooth” aspect of midbrain and superior cerebellar peduncles. (Contributed by Dr. Eugen Boltshauser.)

Biological basis

Etiology and pathogenesis

Joubert syndrome was considered an autosomal recessive disorder as judged from the observation of several families with two or more affected children. Progress in mutation analyses has subsequently confirmed this assumption. So far, the reported number of male patients exceeds females (about 2:1); this observation is not explained. It is not yet clear whether a separate X-linked form with retinal colobomas exists. See below for an X-linked form without colobomata.

Initially, no mutations were found in the nephronophthisis type 1 gene (31). Later, Parisi and colleagues identified NPHP1 gene deletions in two families with mildly affected subjects (48).

In a consanguineous Arab family, linkage to a locus on chromosome 9q34.3 was found (57).

A second locus on chromosome 11p11-q12 was independently identified in a Sicilian family and in three Arab families (34; 72). The four affected Sicilian patients had renal involvement but no retinal abnormalities. A third locus on chromosome 6q23 was confirmed by Lagier-Tourenne and colleagues (35). It appears not to be associated with renal dysfunction but rather retinal dystrophy. This locus was subsequently confirmed, and mutations were identified in the AHI1 gene (18; 23). Valente and colleagues gave a detailed analysis of AHI1 mutations in 10 families without liver and renal involvement (71).

Mutations in the CEP290 gene on chromosome 12q21, encoding a centrosomal protein, were identified in a few families with variable neurologic, retinal, and renal manifestations (73).

MKS3 gene (Meckel-Gruber syndrome) was identified as the sixth Joubert syndrome locus in four patients (04).

A further gene has been identified as causative of Joubert syndrome type 7 (03). The RPGRIP1L gene encodes for a protein localized to basal bodies and centrosomes interacting with other ciliary proteins.

The Joubert-related Hutterite patients were excluded from the known Joubert syndrome/Meckel syndrome loci (09). The gene was later identified (32).

In 2008, two additional genes (ARL13B and CC2D2A) related to ciliary function were found mutated in single families with Joubert syndrome (14; 28).

In 2009, the genes INPP5E for Joubert syndrome 1 (07) and TMEM216 for Joubert syndrome 2 (19) were found, and a first X-linked gene, OFD1, was identified in a multi-generation Malaysian family (16).

An additional six recessive genes were published in 2011 and early 2012, contributing to very marked genetic heterogeneity (32; 38; 39). In subsequent months, five genes were identified (C5ORF42, TCTN3, ZNF423, TMEM231, TCTN2; for the latter an OMIM number was assigned only in 2015) (60; 64).

Reports about novel genes have broadened the potential clinical phenotypes. Homozygous PDE6D mutations were recognized in three affected siblings of a consanguineous Pakistani family (67). The clinical phenotype was not reported in detail; however, it appears that microphthalmia was a feature, not known so far from other associated mutations. Mutations in the intraflagellar transport subcomplex B component IFT172 were found in some patients with the rare co-occurrence of Jeune asphyxiating thoracic dystrophy (30). CSPP1 was identified as a novel gene for Joubert syndrome, as well as Joubert-Jeune phenotype (01; 69).

In 2014, additional genes were associated with Joubert syndrome: MKS1, B9D1, POC1B, CEP120 (Beck et al 2014; 55).

In 2015 the following genes were published: B9D2, CEP104, CEP90 (PIBF1), KIAA0586, KIAA0556, TMEM107 (06; 56; 63; 77; 36).

In 2016 HYLS1 and KIAA0753 (observed in single families) were added, and MKS1 was confirmed (15; 46).

In 2017 ARMC9 and hypomorphic recessive SUFU variants were added to the increasingly long list of associated genes, rising the number to 38 genes (OMIM JBTS 1-34, plus C2CD3, HYLS1, KIAA0753, and POC1B) (17; 75).

In 2018 nonsense mutations in ARL3 (disrupting ciliary protein composition) were found in four patients from two consanguineous families (from Saudi Arabia and Pakistan respectively). The affected children had retinal involvement (02).

The list of candidate genes was subsequently expanded. Accepting that a molar tooth sign is the key diagnostic imaging finding, mutations in two genes required for normal ciliary biology were reported. IFT80, so far only associated with Jeune syndrome, was associated in a girl of East Indian descent with an oro-facial-digital type VI phenotype (43). Shaheen and colleagues found mutations in FAM149B1 in children of three related Arab families and one Turkish family with a phenotype along the Joubert syndrome spectrum (62).

Variants in CBY1 are the most recent genes associated with a Joubert phenotype and a molar tooth sign on imaging (22).

All genes actually known to be associated with Joubert syndrome are responsible for a fraction (estimated 60% to 70% and likely to improve with increasing use of whole-exome sequencing) of patients. This has been confirmed. In a large study using whole-exome sequencing in 287 probands with Joubert syndrome, a causative mutation could not be identified in more than half of affected individuals (01). Actually, in a large cohort of 440 affected individuals from 375 families, the most prevalent genes are C5ORF42, CC2D2A, CEP290, AHI1, TMEM67, and CSPP1 (06).

The pathogenetic mechanism leading to Joubert syndrome is not yet clear. Remarkably, Ferland and colleagues demonstrated that the (first) discovered AHI1 gene is highly expressed in neurons that give rise to the crossing axons of the corticospinal tract and superior cerebellar peduncles (23). This is a confirmation of earlier postmortem and imaging studies pointing to a failure of such decussations in Joubert syndrome (47). MR tractography has confirmed a failure of pyramidal tract and superior cerebellar peduncle fibers decussation, a finding known from previous postmortem studies (78).

All gene products of Joubert syndrome are related to the function of proteins expressed in the primary cilia or its apparatus (basal body and centrosome), confirming the overlap of Joubert syndrome with other “ciliopathies” (eg, Meckel-Gruber, nephronophthisis, Senior-Loken; Joubert syndrome is allelic to these syndromes at multiple gene loci). Mitchison and Valente provide an informative update on the spectrum and overlaps of nonmotile ciliopathies (42). For genotype-phenotype correlation, see the publication by Valente and colleagues (70; 10). Because most patients with isolated vermis agenesis (as seen in Cogan syndrome) have normal cognitive function, we assume that brainstem abnormalities are responsible, in great part, for developmental delay and respiratory patterns. Because of overlapping clinical features and shared genetic variation, a clinical spectrum of Joubert-Meckel-nephronophthisis has been proposed (74). This paper also includes biochemical and cellular features as well as the continued expansion of genetic variants (12 candidate genes). Because retinal disease may be present, progress in the therapy of that group of disorders may be applied to this group as well (58).

Oral-facial-digital syndrome type VI falls under the umbrella of Joubert syndrome in view of the shared molar tooth sign. Based on a literature review and a cohort of 16 patients, diagnostic criteria were suggested for oral-facial-digital syndrome type VI (53). The oral-facial-digital syndrome type VI phenotype has now been associated with OFD1, TMEM210, TMEM216, C5orf42, HYLS1, KIAA0753, INTU, and TCTN1.

Diagnostic workup

The diagnosis of Joubert syndrome relies on recognition of the clinical features listed in Table 1 and requires detailed neuroimaging, preferably with MRI. The diagnosis depends on typical midbrain or cerebellar abnormalities. Great caution in interpretation of MRI is needed as a “mild” molar tooth (repeatedly seen in particular in mutations of NPHP1, C5orf42, and hypomorphic recessive SUFU variants) can be easily overlooked. Note that the dominant SUFU variants will likely be missed in a Joubert gene panel (61). A wide spectrum of infra- and supratentorial imaging findings in a cohort of 75 patients was presented by Poretti and colleagues, pointing to a high proportion of brainstem as well as supratentorial anomalies (51). If renal and retinal involvements are suspected, renal ultrasound should be performed and electroretinography has to be considered, if appropriate. Repeated evaluation of kidney function is recommended. In a large Italian cohort (93 patients) Nuovo and coworkers confirmed that the frequency of chronic kidney disease increases with age and suggested that urine osmolality (impaired urinary concentration) represents an early sensitive biomarker of the risk of kidney disease progression (45).

Molecular genetic testing should be considered. Genotype-phenotype correlations are emerging, eg, pure Joubert syndrome is mostly due to AHI1 mutation, and a majority of patients with liver fibrosis carry TMEM67 mutations, whereas nephronophthisis in Joubert syndrome is preferentially associated with NPHP1, RPGRIP1L, and CEP290 mutations. These correlations are helpful in prioritizing genes to be tested in an individual patient, and to anticipate long-term complications (such as nephronophthisis, liver fibrosis with portal hypertension).

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References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

David J Harris MD

Dr. Harris of Yale University has no relevant financial relationships to disclose.
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Editor

Ganeshwaran H Mochida MD

Dr. Mochida of Boston Children's Hospital and Harvard Medical School has no relevant financial relationships to disclose.
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Former Authors

Joseph R Siebert PhD
Eugen J Boltshauser MD
Harvey B Sarnat MS MD FRCPC

Patient Profile

Age range of presentation: 0 month to 5 years
Sex preponderance: male>female, >1:1
Heredity: Heredity may be a factor

Autosomal recessive

X-linked recessive (OFD1 only)
Population groups selectively affected: Increased prevalence in French-Canadian population assumed (JBTS17, JBTS20, CEP104)

Increased prevalence in Hutterite community (JBTS14, CEP90, CSPP1)

Increased prevalence in Ashkenazi Jews (JBTS2)
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Joubert syndrome: 742.2
ICD-10: Joubert syndrome: Q04.3
OMIM: Joubert syndrome 1: #213300

Joubert syndrome 2: #608091

Joubert syndrome 3: #608629

Joubert syndrome 4: #609583

Joubert syndrome 5: #610188

Joubert syndrome 6: #610688

Joubert syndrome 7: # 611560

Joubert syndrome 8: #612291

Joubert syndrome 9: #612285

Joubert syndrome 10: #300804

Joubert syndrome 11: #613820

Joubert syndrome 12: #200990

Joubert syndrome 13: #614173

Joubert syndrome 14: #614424

Joubert syndrome 15: #614464

Joubert syndrome 16: #614465

Joubert syndrome 17: #614615

Joubert syndrome 18: #614815

Joubert syndrome 19: #614844

Joubert syndrome 20: #614970

Joubert syndrome 21: #615636

Joubert syndrome 22: #615665

Joubert syndrome 23: #616490

Joubert syndrome 24: #616654

Joubert syndrome 25: #616781

Joubert syndrome 26: #616784

Joubert syndrome 27: #617120

Joubert syndrome 28: #617121

Joubert syndrome 29: #617562

Joubert syndrome 30: #617622

Joubert syndrome 31: #617761

Joubert syndrome 32: #617757

Joubert syndrome 33: #617767

Joubert syndrome 34: #614175

Joubert syndrome 35: #618161

Joubert syndrome 36: #618763

Joubert syndrome with bilateral chorioretinal coloboma: %243910

(Note: OMIM has not assigned a number to all known genes)

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Joubert syndrome

Associated Disorders

Cerebellar hypoplasias
Congenital ocular motor apraxia
Hepatic fibrosis
Jeune asphyxiating thoracic dystropy
Medullary cystic kidney disease
- Mental retardation
- Nephronophthisis
- Occipital meningocele
- Polydactyly
- Retinal dystrophy

Differential Diagnosis

Rett syndrome
Mohr syndrome
Dandy-Walker syndrome
Pitt-Hopkins syndrome

Also Relevant

Autism spectrum disorder
Cerebellar hypoplasia, dysplasia, and enlargement
Dandy-Walker syndrome
Oral-facial-digital syndromes

Clinical Categories

Developmental Malformations

Patient Handouts

Joubert syndrome

Web References

Testing

Joubert syndrome …

Joubert syndrome

Introduction

Overview

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Diagnostic Criteria for Joubert Syndrome

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

X-linked hydrocephalus (L1 syndrome)

Cerebro-oculo-facio-skeletal syndrome

Schizencephaly

Fetal anticonvulsant syndrome

Rhombencephalosynapsis

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

Joubert syndrome

Introduction

Overview

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Diagnostic Criteria for Joubert Syndrome

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

X-linked hydrocephalus (L1 syndrome)

Cerebro-oculo-facio-skeletal syndrome

Schizencephaly

Fetal anticonvulsant syndrome

Rhombencephalosynapsis

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

This is an article preview.
Start a Free Account
to access the full version.