Hemimegalencephaly is a rare central nervous system disorder of neuronal cell lineage, proliferation, maturation, and migration characterized by in utero
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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. Recent 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.
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; 64; 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).
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):
- Vermis hypoplasia or dysplasia (“Vermis clefting”)
• Breathing abnormalities
- Episodic tachypnea-apnea
• Ocular motor apraxia with vestibulo-ocular cancellation and pursuit defects
- Large head
• Behavioral phenotype
- Most patients are placid
• Kidneys: chronic renal disease affects about 30% of patients
• Liver (hepatic fibrosis, portal hypertension as probable complication)
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 (64). 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; 64). 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 (64), 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).
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 (64; 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 (67).
Characteristics of liver disease in 100 individuals with Joubert syndrome prospectively evaluated are now available (65). 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.
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 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; 71). 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 (70).
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 (72).
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, 2 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, 5 new genes were identified (C5ORF42, TCTN3, ZNF423, TMEM231, TCTN2; for the latter an OMIM number was assigned only in 2015) (59; 63).
Reports about novel genes have broadened the potential clinical phenotypes. Homozygous PDE6D mutations were recognized in three affected siblings of a consanguineous Pakistani family (66). 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; 68).
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; 62; 75; 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; 73).
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 2 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 3 related Arab families and 1 Turkish family with a phenotype along the Joubert syndrome spectrum (61).
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 (76).
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). (Note: OMIM has not assigned a number for all known genes, actually JBTS 1–36). For genotype-phenotype correlation, see the publication by Valente and colleagues (69; 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.
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.
The prevalence is not known. An approximate estimate is 1 out of 80,000 based on known patients in the United States and birth rates.
Nuovo and coworkers reported age and sex prevalence estimates of Joubert syndrome in Italy based on a cohort of 284 patients (44). The overall female- and male-specific population-based prevalence rates in the age range of 0 to 19 years were 1.7, 1.62, and 1.80 per 100,000 population.
Autosomal recessive inheritance for all JBTS forms (except JBTS10 with x-linked inheritance) implies a recurrence risk of 25% for subsequent affected siblings. Prenatal diagnosis is possible if a mutation in an older sibling is known. Experience with prenatal ultrasound diagnosis is limited. It has been accomplished and found feasible in instances accompanied by a Dandy-Walker-like aspect of the posterior fossa or occipital meningocele (74). Fetal MRI has confirmed prenatal diagnosis of Joubert syndrome in at-risk pregnancies. On theoretical grounds, it is doubtful whether a reliable prenatal diagnosis is possible with neuroimaging before the 18th week of gestation because fusion of midline cerebellar structures is not completed before 18 weeks’ gestation. Saleem and Zaki confirmed a molar tooth sign on fetal MRI at 22 weeks (58). Pugash and colleagues reported sonographic diagnosis of molar tooth sign in gestational week 21 (54).
For the majority of Joubert syndrome patients, the diagnosis is not problematic if neuroimaging features (molar tooth sign in particular), neurodevelopmental aspects, and facial phenotype are respected. Isolated vermian agenesis is not sufficient for diagnosing Joubert syndrome.
Abnormal respiratory pattern (tachypnea-apnea) may occur in other syndromes such as Rett, Mohr, Dandy-Walker, and Pitt-Hopkins. Clinical and neuroimaging findings will distinguish these syndromes from Joubert syndrome.
Schröder and colleagues reported a cohort of 15 individuals from 6 unrelated families with heterozygous truncating variants (familial or de novo) of SUFU presenting as congenital ocular motor apraxia (60). They had a mild molar tooth on neuroimaging. These individuals had no other organ involvement, and cognitive development was largely within normal limits. These variants would likely be missed in a Joubert gene panel as they need to be specifically searched for in the appropriate context.
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 (60). 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).
Published healthcare recommendations for Joubert syndrome highlight diagnostic criteria, molecular genetic investigations, differential diagnosis, potential medical complications of this multisystem disorder, history and physical examination checklists, suggestions for laboratory and imaging testing, and baseline and follow-up evaluation (05).
No specific therapy is available. Supportive measures have to be tailored to patients’ needs and require appropriate neurodevelopmental testing. In cases that include gross motor delay, fine motor delay, language delay, and cognitive impairment, support will include physiotherapy, speech therapy, appropriate schooling, etc.
Kidney transplantation has been successfully performed in patients with end stage renal failure.
Families should be informed about patients’ organizations (eg, The Joubert Syndrome Foundation & Related Cerebellar Disorders).
Habre and colleagues suggest controlled ventilation, avoidance of opioids, and close perianesthetic monitoring (29) in regards to anesthesia. Buntenbroich and Dullenkopf reported total intravenous anesthesia (13). Several uneventful anesthetic procedures were done at our hospital for squint surgery, spinal surgery, renal transplantation, etc.
Eugen J Boltshauser MD
Dr. Boltshauser of the University of Zurich has no relevant financial relationships to disclose.See Profile
Harvey B Sarnat MD FRCPC MS
Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.See Profile
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