Joubert syndrome (JS) is a congenital disorder first reported by Marie Joubert in 1969 3). It is classified as a ciliopathy resulting from structural and functional abnormalities of primary cilia.
The three main features are as follows:
The prevalence is estimated at 1 in 80,000 to 100,000 people 1). Ethnic clustering has been reported in Ashkenazi Jewish, French-Canadian, Hutterite, and Japanese populations. Inheritance is primarily autosomal recessive, except for the OFD1 gene which shows X-linked inheritance 1). More than 34 causative genes have been identified, and in 10–40% of cases the genetic cause remains unknown.
JS is classified into 6 types based on the pattern of associated organ involvement (JSRD classification) 5). The median age at diagnosis is 33 months 3), and the recurrence risk for siblings is 25% 2).
| Classification | Main complications |
|---|---|
| Pure JS | No ocular or renal involvement |
| JS + retinal dystrophy | Rod-cone dystrophy |
| JS + kidney disease | Nephronophthisis |
| JS + oculorenal type | Retina + kidney |
| JS + liver disease | Congenital hepatic fibrosis |
| JS + orofaciodigital syndrome | Polydactyly and oral anomalies |
The prevalence is estimated to be 1 in 80,000 to 100,000 people1). It is primarily autosomal recessive, and if both parents are carriers, the recurrence risk for siblings is 25%2).
Symptoms of JS become apparent from the neonatal period to infancy.
Various ophthalmic abnormalities are a major feature of JS.
Ocular Motor Abnormalities
Ocular motor apraxia: Present in about 80% of cases. Horizontal saccades are selectively impaired, and head thrusts (compensatory head movements) accompany gaze shifts. It is often noticed around 4–6 months of age.
Strabismus: About 74%. Intermittent exotropia and convergence strabismus have been reported1)7).
Retinal and Optic Nerve Abnormalities
Retinal dystrophy: Complicated in about 38% of cases. Rod-cone dystrophy is common and detected by electroretinogram abnormalities. There is also a late-onset case diagnosed at age 32 with visual acuity reduced to 6/604).
Coloboma: Approximately 30%. Presents with retinal coloboma3).
Optic atrophy: Observed in about 22%.
Ptosis: Observed in about 44%.
Visual development is delayed but may mature by 4–6 years of age. May be accompanied by head tremor at 3 Hz, 5–10 degrees. Chorioretinitis and retinal vasculopathy have been reported1).
Characteristic facial features are present3)5).
Ocular motor apraxia is the most frequent finding, occurring in about 80% of cases, followed by strabismus (74%) and nystagmus (72%). Selective impairment of horizontal saccades is characteristic, and it is often noticed through compensatory head movements called head thrusts.
JS is caused by mutations in genes involved in the structure and function of primary cilia. The inheritance pattern is mainly autosomal recessive, with only OFD1 showing X-linked inheritance1).
Currently, more than 40 causative genes have been identified8). Major genes and their frequencies are shown below.
| Gene | Frequency/Features |
|---|---|
| CEP290 | Approximately 50%. Also associated with LCA |
| AHI1 | Approximately 7%. Oculorenal type 4) |
| TMEM67 | JS type 6, COACH syndrome 1)7) |
| KATNIP | JS type 26 8) |
| Major 5 genes | 6–9% each1) |
Primary cilia are organelles essential for signal transduction, and in the eye, they are present in the cornea, lens, trabecular meshwork, photoreceptors, and retinal pigment epithelium. Abnormalities in cilia cause symptoms affecting multiple organs.
The recurrence risk for siblings is 25%2), and genetic counseling is recommended.
If not detected by panel testing, proceed to whole exome sequencing (WES) or genome analysis. Intronic mutations in known genes may be missed by standard analysis, so RNA analysis can be useful in some cases8).
Head MRI is central to diagnosis, and the following characteristic findings are confirmed2)5).
However, in KATNIP-related JS, the molar tooth sign was absent in 4 out of 11 reported cases8). It is important to note that the absence of the molar tooth sign does not rule out JS.
Definitive diagnosis is made by gene panel testing or whole exome sequencing (WES)1)7).
Ultrasound can be performed from 11–12 weeks of gestation, and fetal MRI from 20–22 weeks2)6). Prenatal WES has also been reported7).
There is no curative treatment for JS. Symptomatic treatment and comprehensive management through multidisciplinary collaboration are fundamental2).
Ophthalmologic Management
Refractive correction: Prescription of appropriate corrective lenses.
Amblyopia monitoring: Early detection of amblyopia associated with strabismus or refractive errors.
Strabismus and ptosis surgery: Surgical treatment considered as needed.
Visual rehabilitation: Support for delayed visual development.
Systemic Management
Respiratory management: NIV (non-invasive ventilation) is used for apnea attacks in the neonatal period5)3).
Nutritional management: Assessed by videofluoroscopic swallow study, and if necessary, gastrostomy (G-tube) or Nissen fundoplication is performed3).
Renal function management: Lifelong monitoring is required. Dialysis or kidney transplantation may become necessary4)2).
Rehabilitation: Physical therapy, occupational therapy, and speech therapy2).
For dental management, fluoride application and oral hygiene guidance are important for enamel hypoplasia6).
Because of abnormalities in the respiratory center, opioids and nitrous oxide should be avoided. Sevoflurane is recommended 5)6). Before surgery, inform the anesthesiologist of the JS diagnosis, and ensure adequate postoperative respiratory monitoring.
Lifelong regular renal function evaluation is necessary. A late-onset case has been reported where renal function decline began at age 51 and led to dialysis at age 58 4), so vigilance is required even after adulthood.
The core pathology of JS is structural and functional impairment of primary cilia. Primary cilia are microtubule-based organelles protruding from the cell membrane, essential for signaling pathways such as Wnt, Hedgehog, and Notch.
The outer segment of photoreceptors is a modified primary cilium, and protein transport via the connecting cilium is essential for photoreceptor survival. Impaired ciliary function leads to photoreceptor degeneration and retinal dystrophy.
Cerebellar vermis hypoplasia causes truncal ataxia, and brainstem abnormalities underlie respiratory dysregulation. Abnormalities of primary cilia in renal collecting duct epithelium lead to nephronophthisis.
With the widespread use of WES, the genetic diagnostic rate for previously undiagnosed JS cases has improved 4).
Collard et al. (2021) reported a case of AHI1-related JS in a 61-year-old woman 4). She was diagnosed with rod-cone dystrophy at age 32, with visual acuity declining to 6/60; renal function decline (eGFR 57 mL/min) began at age 51, leading to dialysis initiation at age 58. This case of late-onset in adulthood highlights the importance of lifelong monitoring.
Kozina et al. (2023) reported a 5-year-old girl with JS type 6 due to a novel compound heterozygous mutation in TMEM67 1). She presented with intermittent exotropia, chorioretinitis, and retinal vasculopathy.
Tedesco et al. (2025) studied 11 individuals from 7 families with KATNIP-related JS (JS type 26) 8). The molar tooth sign was absent in 4 of 11 cases, pituitary abnormalities were found in 4 cases, and growth hormone deficiency in 3 cases. These findings suggest the presence of endocrine complications beyond the classic JS phenotype.
Intron mutations are difficult to detect with standard WES pipelines, and the combined use of RNA analysis is expected 8). The possibility of early diagnosis by prenatal WES is also being investigated 7).
