Joubert Syndrome
Summary
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 renal 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.
Diagnosis
Diagnostic criteria for Joubert syndrome (JS) continue to evolve but most authors concur that the neuroradiologic finding of the molar tooth sign is obligatory [Valente et al 2008, Parisi 2009, Brancati et al 2010].
The diagnosis of Joubert syndrome is based on the presence of the following three primary criteria:
- The molar tooth sign. The MRI appearance of hypoplasia of the cerebellar vermis and accompanying brain stem abnormalities in an axial plane through the junction of the midbrain and pons (isthmus region) [Maria et al 1997, Maria et al 1999b, Quisling et al 1999]. The molar tooth sign comprises an abnormally deep interpeduncular fossa; prominent, straight, and thickened superior cerebellar peduncles; and hypoplasia of the vermis, the midline portion of the cerebellum (Figures 1A, 1B) [Maria et al 1999b]. A high-quality MRI with thin (3-mm thickness) axial cuts through the posterior fossa from the midbrain to the pons as well as standard axial, coronal, and sagittal cuts is recommended.
- Hypotonia in infancy with later development of ataxia
- Developmental delays / intellectual disability
Figure 1.
Molar tooth sign in Joubert syndrome A. Axial MRI image through the cerebellum and brain stem of a normal individual showing intact cerebellar vermis (outlined by white arrows)
Additional features often identified in individuals with JS:
- Abnormal breathing pattern (alternating tachypnea and/or apnea)
- Abnormal eye movements, typically oculomotor apraxia or difficulty in smooth visual pursuit and jerkiness in gaze and tracking [Saraiva & Baraitser 1992, Steinlin et al 1997, Maria et al 1999b, Tusa & Hove 1999]
Other findings that may occur in fewer than half of individuals with JS include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and other abnormalities. The term "classic" or "pure" JS has been used to refer to JS without any of these other findings. In reality, however, a significant proportion of individuals diagnosed with classic JS in infancy or early childhood may manifest one or more of these findings over time.
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 variants in one of the 33 autosomal recessive JS-related genes or a heterozygous pathogenic variant in the one X-linked JS-related gene [Bachmann-Gagescu et al 2015a] (see Tables 1a and 1b).
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 at the most reasonable cost 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).
Table 1a.
Molecular Genetics of Joubert Syndrome: Most Common Genetic Causes
| Gene 1, 2 | % of JS Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detected by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| AHI1 | ~7%-10% 6, 7, 8 | >95% | See footnote 9 |
| CPLANE1 | 8%-14% 7, 8, 10 | 100% | None reported |
| CC2D2A | ~8%-11% 7, 8, 11 | Close to 100% | See footnote 12 |
| CEP290 | 7%-10% 7, 8, 13, 14 | ~99% | See footnote 15 |
| CSPP1 | 2%-4% 7, 8, 16 | 100% | None reported |
| INPP5E | 2%-4% 7, 8 | 100% | None reported |
| KIAA0586 | ~2%-7% 8, 17 | Two reported, one recurrent multiexon deletion 18 | |
| MKS1 | ~2%-6% 7, 8, 19 | ~95% | See footnote 20 |
| NPHP1 | ~1%-2% 7, 8, 21, 22 | See footnote 22 | 20%-25% 22 |
| RPGRIP1L | 1%-4% 7, 8, 23 | 100% | None reported |
| TCTN2 | ~1% 7 | 13/13 24 | None reported |
| TMEM67 | ~6%-20% 7, 8, 9, 12, 25 | ~99% | See footnote 26 |
| TMEM216 | ~2%-3% 7, 8, 27 | 8/8 26 | None reported |
Pathogenic variants of any one of the genes included in this table account for >1% of JS.
- 1.
Genes are listed alphabetically.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on pathogenic variants detected.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Parisi et al [2006], Valente et al [2006a]
- 7.
Bachmann-Gagescu et al [2015a] tested 440 individuals from 375 families for pathogenic variants in 27 JS-related genes.
- 8.
Vilboux et al [2017] identified pathogenic variants in 81 (94%) of 86 families tested (100 individuals total) using a combination of 27-gene multigene panel and exome sequencing.
- 9.
Three reported [Utsch et al 2006, Bachmann-Gagescu et al 2015a, Watson et al 2016]
- 10.
Kroes et al [2016] evaluated 22 JS-related genes and 599 additional ciliary genes in a cohort of 51 northern Europeans with JS. Unlike other cohorts, this group identified CPLANE1 pathogenic variants in 12% of their cohort.
- 11.
Gorden et al [2008], Doherty et al [2010]. The prevalence of CC2D2A pathogenic variants in one large cohort was 16/209 (7.7%) [Bachmann-Gagescu et al 2012].
- 12.
Two reported [Mougou-Zerelli et al 2009, Su et al 2015]
- 13.
Data from Sayer et al [2006], Valente et al [2006b], Valente et al [2008], Travaglini et al [2009] and Bachmann-Gagescu et al [2015a] support 7%-10%. In contrast, only one of 51 cases (2%) in a northern European cohort was positive [Kroes et al 2016].
- 14.
Suzuki et al [2016] reported 83% yield of variant analysis in a cohort of 30 families (all but 3 were Japanese), with pathogenic variants identified in TMEM67 (26% of cohort), CEP290 (22% of cohort) and OFD1, INPP5E, AHI1, and CPLANE1 (each in 7.4% of the cohort).
- 15.
One reported [Travaglini et al 2009]
- 16.
Tuz et al [2014], Akizu et al [2014]
- 17.
Pathogenic variants in KIAA0586 accounted for nine (2.5%) of 366 families with JS in one cohort [Bachmann-Gagescu et al 2015b] but may be more prevalent than previously realized due to the high frequency of a single-base deletion (c.428delG) in the general population [Roosing et al 2015] and a broad range of clinical phenotypes [Alby et al 2015, Malicdan et al 2015].
- 18.
In three of six individuals with compound heterozygous pathogenic variants in KIAA0586, one pathogenic variant was an 800-bp deletion of exons 8-10 [Malicdan et al 2015].
- 19.
MKS1 pathogenic changes were identified in two separate series: in 2/260 individuals with JS [Romani et al 2014] and in 9/371 families with JS [Slaats et al 2016].
- 20.
Four reported [Kyttälä et al 2006, Frank et al 2007, Abu-Safieh et al 2012, Szymanska et al 2012]
- 21.
May be higher in individuals with nephronophthisis
- 22.
Homozygous deletions have been associated with rare cases of JS. Deletion/duplication analysis alone will detect a heterozygous deletion but not a single-nucleotide variant in NPHP1; this genotype is expected to be rare. The common ~290 kb deletion is the most frequently detected.
- 23.
Arts et al [2007], Delous et al [2007], Parisi [2009]
- 24.
Juric-Sekhar et al [2012], Bachmann-Gagescu et al [2015a]
- 25.
Baala et al [2007], Brancati et al [2009], Doherty et al [2010]
- 26.
One reported [Khaddour et al 2007]
- 27.
Fourteen (~3%) of 462 families with JS had pathogenic variants in TMEM216 [Valente et al 2010].
- 28.
- 28">
Valente et al [2010], Lee et al [2012b]
Table 1b.
Molecular Genetics Joubert Syndrome: Less Common Genetic Causes
| Gene 1, 2, 3 | Comment |
|---|---|
| ARL13B | 2 families; phenotype ranged from classic JS to JS w/occipital encephalocele & pigmentary retinopathy [Cantagrel et al 2008]; no deletions/duplications reported. |
| B9D1 | 2 families, both w/"pure" form of JS; pathogenic variants in this gene also cause MKS. No deletions/duplications reported [Romani et al 2014]. |
| B9D2 | 2 families, both w/polydactyly & 1 w/encephalocele, cleft palate, & tongue hamartomas; pathogenic variants in this gene also cause MKS. No deletions/duplications reported [Bachmann-Gagescu et al 2015a]. |
| C2CD3 | 2 families identified in 1 series, both w/cleft palate and/or oral frenulae suggestive of features of OFD. No deletions/duplications reported [Bachmann-Gagescu et al 2015a]. |
| CEP41 | 3 families w/8 individuals w/JS described w/pathogenic variants in CEP41, based on screening at least 725 individuals w/JS, many of whom had been excluded for pathogenic variants in known JS-related genes. Slightly more than 50% of affected persons have demonstrated unilateral or bilateral postaxial polydactyly. Only 2 individuals have evidence of retinal disease, 1 of whom had unilateral coloboma, unilateral kidney disease, & ambiguous genitalia & died at age 7 days. Within 1 family, all 5 affected males had micropenis & 2 had growth hormone deficiency. Only splice site variants have been identified; no deletions/duplications reported [Lee et al 2012a]. |
| CEP104 | 3 families, all w/"pure" form of JS; no deletions/duplications reported [Srour et al 2015]. |
| CEP120 | 4/491 individuals w/JS had missense, frameshift, nonsense, or splice variants in this gene; phenotypes ranged from "pure" JS to MKS, OFD, and JS-JATD; no large deletions/duplications reported [Shaheen et al 2015b, Roosing et al 2016a]. |
| IFT172 | 1/440 individuals with JS had missense pathogenic variants in this gene [Bachmann-Gagescu et al 2015a]. 2/12 families w/missense and/or truncating pathogenic variants had overlapping features of JS & JS-JATD (one w/Mainzer-Saldino syndrome features as well) including retinal dystrophy, hepatic fibrosis, NPHP, & cerebellar vermis hypoplasia. No deletions/duplications reported [Halbritter et al 2013]. |
| KATNIP (KIAA0556) | Homozygous truncating pathogenic variants in this gene identified in 3 sibs of a consanguineous family; 2/3 had panhypopituitarism (the male had micropenis & the female had a hypoplastic pituitary on MRI) [Sanders et al 2015]. In another consanguineous family, 2 sibs w/classic JS features had homozygous truncating pathogenic variants; no deletions/duplications reported [Roosing et al 2016b]. |
| KIF7 | 3/440 families had pathogenic variants in this gene [Bachmann-Gagescu et al 2015a]. Individuals often have OFD features, w/ or w/out other CNS findings such as agenesis/hypoplasia of the corpus callosum, hydrocephalus, & macrocephaly [Dafinger et al 2011, Putoux et al 2011]. The combination of polydactyly & these CNS findings suggests acrocallosal and/or hydrolethalus syndromes [Putoux et al 2011]. Nonsense & frameshift pathogenic variants predominate; no deletions/duplications reported. |
| OFD1 | X-linked; no deletions/duplications reported. Pathogenic variants in this gene identified in 4/440 families [Bachmann-Gagescu et al 2015a] & in 2/250 families (2/84 w/only males affected) [Coene et al 2009]. Features include encephalocele, hydrocephalus, macrocephaly, polymicrogyria, polydactyly, & retinal disease. 1 family also had renal cystic disease, hydrocephalus, macrocephaly, & polymicrogyria [Field et al 2012]. |
| PDE6D | In 1 consanguineous family w/3 sibs (w/a homozygous splice site variant), phenotype included renal hypoplasia, retinal dystrophy, microphthalmia, ocular coloboma, & postaxial polydactyly [Thomas et al 2014]. |
| POC1B | A homozygous pathogenic missense variant in this gene was identified in an extended Iraqi family with LCA, enlarged, polycystic kidneys (resembling ADPKD rather than NPHP), & classic features of JS w/out liver fibrosis. Of note, the same homozygous pathogenic variant was identified in a family w/severe & slowly progressive cone-rod dystrophy w/out features of JS [Beck et al 2014]. No deletions/duplications reported. |
| TCTN1 | 1/440 families had pathogenic variants in this gene [Bachmann-Gagescu et al 2015a]. Two sibs w/homozygous splice site variants had fronto-temporal pachygyria but no retinal or renal findings [Garcia-Gonzalo et al 2011]. No deletions/duplications reported. |
| TCTN3 | 1/440 families had pathogenic variants in this gene [Bachmann-Gagescu et al 2015a]. 1/58 families (for whom known JS-genes were excluded) had biallelic pathogenic variants [Thomas et al 2012]. Homozygous truncating variants were identified in 5 pedigrees w/a severe prenatal lethal form of OFD type IV (Mohr-Majewski syndrome); however, since the phenotype also included postaxial polydactyly, cystic renal disease, bile duct proliferation, & occipital encephalocele, it is debatable whether this represents a type of OFD or MKS. 2 probands from a Turkish family w/JS, who had a homozygous missense variant, had scoliosis w/variable polydactyly, oral findings, horseshoe kidney, & ventricular septal defect [Thomas et al 2012]. No deletions/duplications reported. |
| TMEM107 | Of 238 individuals w/JS or "OFD VI," 1 set of consanguineous twins who were homozygous for a missense variant in this gene had retinopathy & features of OFD including postaxial polydactyly; another male w/classic JS & retinopathy had compound heterozygous pathogenic variants [Lambacher et al 2016]. No deletions/duplications reported. |
| TMEM138 | 1/440 families had pathogenic variants in this gene [Bachmann-Gagescu et al 2015a]. 11 individuals from 8 consanguineous Arab families had coloboma (6), retinal dystrophy (3), cystic kidney, or NPHP (3). Polydactyly has been observed; 1 fetus w/MKS had an encephalocele [Lee et al 2012b]. No deletions/duplications reported |
| TMEM231 | Pathogenic variants in this gene account for some individuals w/JS of French-Canadian descent. 3 persons in 2 families had a severe phenotype (lack of ambulation, aggressive behaviors, lack of independent living skills). 2 have macroscopic renal cysts & retinal disease; 1 has postaxial polysyndactyly [Srour et al 2012a]. A pathogenic gene conversion event between this gene & its pseudogene has been described [Maglic et al 2016]. |
| TMEM237 | 1/440 families had pathogenic variants in this gene [Bachmann-Gagescu et al 2015a]. Only 2/201 individuals w/JS & 90 individuals w/MKS/JS had pathogenic variants in this gene [Huang et al 2011]. This form of JS was originally described as MKS in the Hutterite population [Boycott et al 2007], in which the carrier rate is estimated at 6% [Huang et al 2011]. Encephalocele, hydrocephalus, & cystic kidney disease are common. The "morning glory disc anomaly" has also been described in an extended family from Austria w/biallelic pathogenic variants [Janecke et al 2004, Huang et al 2011]. A 24-kb deletion including TMEM237 exon 1 & 1a extending into the adjacent gene has been identified [Watson et al 2016]. |
| TTC21B | To date, no individuals w/JS & biallelic pathogenic variants in this gene have been reported. The functional significance of a single (heterozygous) pathogenic variant is unknown. No clinical information was provided on 3 persons with a heterozygous change. See TTC21B, Pathogenic variants (pdf). In a clinically diverse cohort of 753 individuals w/a ciliopathy, 5% had pathogenic variants in this gene; however, only 33% had a 2nd pathogenic variant in a different ciliopathy gene [Davis et al 2011]. |
| ZNF423 | 1 consanguineous family w/infantile-onset NPHP, cerebellar vermis hypoplasia, & situs inversus had homozygous pathogenic missense variants in this gene; 2/96 other individuals w/JS had heterozygous changes in the gene in specific interaction domains, leading to proposed (but not proven) loss of function via a dominant-negative mechanism [Chaki et al 2012]. No deletions/duplications reported. |
Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., account for <1% of JS).
ADPKD = autosomal dominant polycystic kidney disease; JS-JATD = Jeune asphyxiating thoracic dystrophy; LCA = Leber congenital amaurosis; MKS = Meckel syndrome; NPHP = nephronophthisis; OFD = oral-facial-digital syndrome
- 1.
Genes are listed alphabetically.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
Genes are not described in detail in Molecular Genetics, but may be included here (pdf).
Clinical Characteristics
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 problems 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 problems were reported in almost 40% in one survey of 54 individuals with JS [Bulgheroni et al 2016]. In another survey of 76 individuals, behavior problems 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
| Name of Clinical Subtype | Mandatory Features in Addition to Primary Criteria 1 | Strongly Associated Features 2 | Other Names |
|---|