Joubert syndrome

Joubert syndrome, also called familial aplasia of the vermis, molar tooth midbrain-hindbrain malformation, agenesis of cerebellar vermis or cerebello-oculo-renal syndrome, is a rare autosomal recessive genetic neurodevelopmental disorder that affects the brain’s cerebellum and brainstem, leading to issues with balance and coordination such as ataxia (loss of muscle control), as well as other neurological problems such as low muscle tone (hypotonia), developmental delays and intellectual disability, abnormal eye movements (nystagmus), abnormal breathing patterns ¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸. The key feature of Joubert syndrome is a specific brain malformation called the “molar tooth sign” on brain scans such as magnetic resonance imaging (MRI), indicating a malformed cerebellum and brainstem – consisting of cerebellar hypoplasia with vermian dysplasia, thick and horizontally oriented superior cerebellar peduncles, and an abnormally deep interpeduncular fossa (see Figure 3 below) ³, ⁹. The “molar tooth sign” results from the abnormal development of structures near the back of the brain, including the cerebellar vermis and the brainstem ⁹. The “molar tooth sign” got its name because the characteristic brain abnormalities resemble the cross-section of a molar tooth when seen on an MRI ⁶.

Joubert syndrome is a multisystem neurodevelopmental disorder that affects many parts of the body. The signs and symptoms of Joubert syndrome vary among affected individuals, even among members of the same family. Most infants with Joubert syndrome have low muscle tone (hypotonia) in infancy, which contributes to difficulty coordinating movements (ataxia) in early childhood. Other characteristic features of Joubert syndrome include episodes of unusually fast (hyperpnea) or slow (apnea) breathing in infancy, and abnormal eye movements (ocular motor apraxia) ⁹. Most affected individuals have delayed development and intellectual disability, which can range from mild to severe ⁹. Distinctive facial features can also occur in Joubert syndrome; these include a broad forehead, arched eyebrows, droopy eyelids (ptosis), widely spaced eyes (hypertelorism), low-set ears, and a triangle-shaped mouth ⁹.

Joubert syndrome can include a broad range of additional signs and symptoms. Joubert syndrome is sometimes associated with other eye abnormalities such as retinal dystrophy, which can cause vision loss, and coloboma, which is a gap or split in a structure of the eye, kidney disease including polycystic kidney disease and nephronophthisis, liver disease, skeletal abnormalities such as the presence of extra fingers and toes, or hormone (endocrine) problems ⁹. A combination of the characteristic features of Joubert syndrome and one or more of these additional signs and symptoms were previously referred to as Joubert syndrome and related disorders (JSRD). Now, however, any instances that involve the molar tooth sign on brain scans, including those with these additional signs and symptoms, are usually considered Joubert syndrome ⁹.

Joubert syndrome signs and symptoms:

• Low muscle tone (hypotonia) in infancy.
• Difficulty to coordinate voluntary muscle movements (ataxia).
• Breathing problems (hyperpnea, apnea).
• Abnormal eye movements (nystagmus, strabismus).
• Developmental delays and intellectual disabilities.
• Possible facial differences.
• Physical deformities (polydactyly, cleft lip or palate, and tongue abnormalities).
• Other symptoms may include kidney and liver disease, and skeletal abnormalities.
• Seizures.

Reliable epidemiological data on Joubert syndrome are lacking ¹⁰. Joubert syndrome is estimated to affect between 1 in 80,000 and 1 in 100,000 newborns ¹⁰. However, this estimate may be too low because Joubert syndrome has such a large range of possible features and is likely underdiagnosed ¹¹, ³, ⁹.

About 94 percent of Joubert syndrome cases is caused by mutations in more than 40 genes ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷. These genetic mutations that cause Joubert syndrome are more common in certain ethnic groups, such as Ashkenazi Jewish, French-Canadian, and Hutterite populations. In the remaining cases, the genetic cause is unknown. In the Askhenazi Jews, the predicted prevalence of Joubert syndrome is increased up to 1 in 34,000 and 1 in 40,000 newborns due to the presence of the founder mutation p.R73L in the TMEM216 gene, with a carrier frequency of 1:90 to 1:100 ¹⁸, ¹⁹. Similarly, in the Hutterite population, about 1:17 healthy subjects carry the founder mutation p.R18X in the TMEM237 gene, leading to a Joubert syndrome prevalence of about 1 in 1150 ²⁰.

Mutations in the genes associated with Joubert syndrome lead to problems with the structure and function of cell structures called primary cilia ²¹, ²², ²³, ²⁴. Primary cilia are microscopic, finger-like projections that stick out from the surface of cells and are involved in sensing the physical environment and in chemical signaling. Primary cilia are important for the structure and function of many types of cells, including brain cells (neurons) and certain cells in the kidneys and liver. Primary cilia are also necessary for the perception of sensory input, which is interpreted by the brain for sight, hearing, and smell. Defects in these cell structures can disrupt important chemical signaling pathways during development. Although researchers believe that defective primary cilia are responsible for most of the features of Joubert syndrome, it is not completely understood how they lead to specific developmental abnormalities.

The diagnosis of Joubert syndrome is based on physical symptoms and the “molar tooth sign” as seen on an MRI. Diagnostic criteria for Joubert syndrome continue to evolve but most experts agree that the neuroradiologic finding of the “molar tooth sign” is necessary to make the diagnosis. The diagnosis of Joubert syndrome is based on the presence of the following three primary criteria ²⁵, ⁶, ²⁶:

1. The “molar tooth sign” based on MRI findings (hypoplasia of the cerebellar vermis)
2. Hypotonia (weak muscle tone) in infancy with later development of ataxia
3. Developmental delays/intellectual disability

A genetic diagnosis of Joubert syndrome can be confirmed via molecular genetic testing, which is available for the many genes that have been shown to cause Joubert syndrome. A molecular genetic diagnosis can be established in about 60% to 90% of patients. Carrier molecular genetic testing and prenatal diagnosis are available if one of these gene mutations has been identified in an affected family member.

The treatment for Joubert syndrome is symptomatic and supportive. Developmental delays are usually treated with physical therapy, occupational therapy, speech therapy and infant stimulation. Children with Joubert syndrome should be evaluated by appropriate specialists including nephrologists, ophthalmologists, geneticists and neurologists. Annual screening is recommended for liver, kidney and retinal abnormalities.

Infants and children with abnormal breathing patterns should be considered for apnea monitoring and supportive therapy may require stimulatory medications or 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. Corrective lenses may be required for optic refractive errors. Nephronophthisis, end-stage renal disease, liver failure and/or fibrosis are treated with standard approaches, which may include dialysis and/or kidney transplantation.

Genetic counseling is recommended for individuals with Joubert syndrome and their families.

Figure 1. Joubert syndrome

Footnotes: Joubert syndrome clinical features.

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

(B) Oral findings in a child with oral-facial-digital features of Joubert syndrome showing midline upper lip cleft (arrowhead), midline groove of tongue, and bumps of the lower alveolar ridge (arrow)

(C) Left hand of an infant with Joubert syndrome and postaxial polydactyly (arrow)

(D) Left foot of an infant with Joubert syndrome and preaxial polydactyly of the hallux (extra big toe)

(E) View from above of an infant with a small occipital encephalocele with protrusion of the occiput of the skull (arrow)

[Source ³ ]

Figure 2. Joubert syndrome brain MRI

Footnotes: Neuroimaging findings in a 2-year-old child with Joubert Syndrome (JS upper panels) compared to a healthy control (N lower panels). Molar tooth sign in Joubert syndrome.

JS upper panels:

(a) Parasagittal T1-weighted image shows the thickened, elongated and horizontally orientated superior cerebellar peduncles (white arrow).

(b) Midsagittal T1-weighted image demonstrates a moderate hypoplasia and dysplasia of the cerebellar vermis (white arrows) with secondary distortion and enlargement of the fourth ventricle with rostral shifting of the fastigium (white arrow head). A deepened interpeduncular fossa is also noted.

(c) Axial T1-weighted image at the level of the pontomesencephalic junction shows the “molar tooth sign” with a deepened interpeduncular fossa (white arrowhead) and elongated, thickened and horizontally orientated superior cerebellar peduncles (white arrows). Additionally, the cerebellar vermis appears to be hypoplastic and its remnants dysplastic.

(d) Coronal T1-weighted image reveals the thickened superior cerebellar peduncles (white arrows).

N lower panels: Healthy control MRI image.

[Source ¹⁰ ]

Figure 3. Joubert syndrome brain MRI

Footnotes: Molar tooth sign (MTS) in Joubert syndrome.

(A) Healthy control brain scan. Axial MRI image through the cerebellum and brain stem showing intact cerebellar vermis (outlined by white arrows)

(B) Axial MRI image through the cerebellum and brain stem of a child with Joubert syndrome. Arrows indicate the three key components of the molar tooth sign.

1. An abnormally deep interpeduncular fossa
2. Prominent, straight, and thickened superior cerebellar peduncles
3. Hypoplasia of the vermis (the midline portion of the cerebellum)

[Source ³ ]

Figure 4. Iris coloboma

Footnotes: A coloboma is a term that is used to describe missing tissue in your eye – the eyelids, iris, lens, ciliary body, zonules, choroid, retina or optic nerve. Colobomas are present in a person’s eye when they’re born. A coloboma can affect one or both eyes. The most recognizable and common colobomas affect your iris (the colored part of your eye) and cause your pupil (the dark center of your eye) to have a keyhole shape. But there are many types of colobomas, most of which you can’t see externally (on the outside). Depending on the location of the coloboma, symptoms may include unusual appearance of the eye or eyelid, blurry vision, blind spots, and sensitivity to light.

[Source ²⁷ ]

Figure 5. Polydactyly (extra fingers or toes)

Is Joubert syndrome more common in people of French Canadian descent?

Yes. There is a relatively high prevalence of Joubert syndrome and related disorders in the French Canadian population, with several founder effects noted ²⁸. A founder effect is the effect on a gene pool that occurs when a new population is formed (founded) by a small number of individuals from a larger population, with limited genetic variation. Founder effects are typically associated with an increase in the frequency of a specific autosomal recessive allele (version of a gene) ²⁹.

The family first described by Joubert et al in 1969 has been traced to a founder who immigrated to Quebec from France in the 1600s. However, it reportedly appears that there are other founder groups in the French Canadian population ²⁸. Scientists are not aware of reports stating the prevalence or carrier frequency of Joubert syndrome in this population.

The exact incidence or prevalence of Joubert syndrome and related disorders in the general population has not been determined, but many authors use a range between 1 in 80,000 and 1 in 100,000. This may be an underestimate ²⁸.

Is there a connection between Joubert syndrome and autism?

There is a connection, but it remains somewhat unclear. Autism is a relatively common condition, occurring in 1 in 500 children, and is more likely in boys with a 4:1 male:female ratio. There are likely many different causes for this increasingly common diagnosis. Features of classical autism include poor eye contact and limited communication skills as well as repetitive or self-stimulatory behaviors. Autism has been reported in a number of children with Joubert syndrome in several publications. However, more recent surveys suggest that these behavioral disturbances do not represent classic autism, but are more likely to be related to the underlying cerebellar disorder, eye movement problems, and associated developmental disabilities ³⁰.

Can steroid use increase the chance to have a child with Joubert syndrome?

No. A person with a history of steroid use does not have a higher chance to have a child with Joubert syndrome. Joubert syndrome is a genetic condition caused by changes (mutations) in genes that can be passed from parent to child. These mutations are present from birth and are not acquired during a person’s lifetime.

Joubert syndrome types

Joubert syndrome have also been described in any related condition showing the “molar tooth sign” (MTS) in brain imaging. Joubert syndrome (JS) was originally described in 1968 in four siblings with agenesis of the cerebellar vermis presenting episodic hyperpnoea, abnormal eye movements, ataxia and intellectual disability ³¹. Several years later, a pathognomonic midbrain-hindbrain malformation, the “molar tooth sign” (MTS), was detected first in Joubert syndrome (JS) ³² and then in several other conditions previously considered as distinct entities ³³:

The term “Joubert Syndrome and Related Disorders” (JSRD) was used as a collective term to represent all conditions sharing the “molar tooth sign” (MTS) in brain imaging with additional specific organ involvement ³⁴, ³⁵, ³⁶, ¹⁰:

• Purely neurological Joubert syndrome (pure JS)
• Joubert syndrome with retinal disease (JS-Ret). 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; however, the retinal disease may not be progressive and is not always present in infancy or early childhood.
• Joubert syndrome with renal disease (JS-Ren). Joubert syndrome with renal disease (JS-Ren) has been described traditionally in two forms – nephronophthisis (kidney inflammation and scarring) and polycystic kidney disease; however, these now appear to be part of a continuum with the specific renal manifestation varying by stage of kidney disease.
• Arima syndrome or Joubert syndrome with oculorenal disease (JS-OR). In Joubert syndrome with oculorenal disease (JS-OR), retinal disease and kidney impairment often occur together in the same individual.
• Joubert syndrome with hepatic disease (JS-H). Joubert syndrome with hepatic disease (JS-H) usually presents with hepatic (liver) fibrosis that is usually progressive but rarely symptomatic at birth.
• COACH syndrome (colobomas, cognitive impairment [“oligophrenia”], ataxia, cerebellar vermis hypoplasia, and hepatic fibrosis)
• Varadi-Papp syndrome or Joubert syndrome with oral-facial-digital features (JS-OFD) (Joubert syndrome with oral-facial-digital features [tongue hamartomas, oral frenulae, and polydactyly with a Y-shaped metacarpal]). In Joubert syndrome with oral-facial-digital features (JS-OFD), oral findings can include midline upper-lip cleft, midline groove of tongue, hamartomas of the alveolar ridge and cleft palate. Craniofacial features often include wide-spaced eyes, low-set ears and small jaw (micrognathia).
• Other less common clinical Joubert syndrome subtypes, e.g., Joubert syndrome with acrocallosal features, Joubert syndrome with Jeune asphyxiating thoracic dystrophy.

Occasional features observed in all subgroups include pre‐, meso‐, or post‐axial polydactyly, which can variably involve hands and feet, and other central nervous system (brain and spinal cord) abnormalities, such as corpus callosum abnormalities, hydrocephalus, encephalocele, or polymicrogyria.

While these complex signs and symptoms had initially been termed “Joubert Syndrome and Related Disorders” (JSRD) ³⁷, ³⁸, nowadays the unifying term “Joubert syndrome” (JS) applies to all patients with the “molar tooth sign” (MTS) in brain imaging, including those with and without any extra‐neurological involvement listed above ¹⁰.

Joubert syndrome causes

About 94 percent of Joubert syndrome is caused by mutations in more than 40 genes ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷. These genetic mutations that cause Joubert syndrome are more common in certain ethnic groups, such as Ashkenazi Jewish, French-Canadian, and Hutterite populations. In the remaining cases, the genetic cause is unknown. Mutations in the genes associated with Joubert syndrome lead to problems with the structure and function of cell structures called primary cilia ²¹, ²², ²³, ²⁴. Primary cilia are microscopic, finger-like projections that stick out from the surface of cells and are involved in sensing the physical environment and in chemical signaling ³⁹, ⁴⁰, ⁴¹. Primary cilia are important for the structure and function of many types of cells, including brain cells (neurons) and certain cells in the kidneys and liver. Primary cilia are also necessary for the perception of sensory input, which is interpreted by the brain for sight, hearing, and smell. Defects in these cell structures can disrupt important chemical signaling pathways during development. Although researchers believe that defective primary cilia are responsible for most of the features of Joubert syndrome, it is not completely understood how they lead to specific developmental abnormalities.

Of note, almost all Joubert syndrome genes have also been implicated in other ciliopathies, such as Meckel syndrome (MKS), isolated nephronophthisis (NPHP), Leber congenital amaurosis (LCA), oral‐facial‐digital syndromes (OFDS), Bardet‐Biedl syndrome (BBS), and others ¹².

Depending on the gene involved, various clinical presentations of Joubert syndrome can occur in an affected individual. A mutation in the AHI1 (JBTS3) gene is responsible for Joubert syndrome in approximately 7% to 10% of families ⁸. Affected individuals with AHI1 (JBTS3) gene mutation often have impaired vision due to retinal dystrophy. A mutation in the NPHP1 (JBTS4) gene causes approximately 1-2% of Joubert syndrome ⁸. Affected individuals with NPHP1 (JBTS4) gene mutation often develop a progressive kidney disease called nephronophthisis ⁸. A mutation in the CEP290 (JBTS5) gene causes about 7 to 10% of Joubert syndrome. Mutations in the CPLANE1, CC2D2A, INPP5E, KIAA0586, MKS1, RPGRIP1L TCTN2, TMEM67 and TMEM216 genes, along with other less common genetic causes are also associated with Joubert syndrome ⁸.

Joubert syndrome inheritance pattern

Joubert syndrome typically has an autosomal recessive pattern of inheritance, which means an individual inherits an abnormal gene from each parent ⁴², ⁸. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they usually do not show signs and symptoms of the condition. If an individual receives one working gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Rare cases of Joubert syndrome caused by mutations in the OFD1 gene are inherited in an X-linked recessive pattern ⁴³, ⁸. In these cases, the abnormal gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome [XY]), one altered copy of the gene in each cell is sufficient to cause Joubert syndrome. In females (who have two X chromosomes [XX]), a mutation would have to occur in both copies of the gene to cause Joubert syndrome. Because it is unlikely that females (who have two X chromosomes [XX]) will have two altered copies of the abnormal gene, males (who have only one X chromosome [XY]) are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.

If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://abgc.learningbuilder.com/Search/Public/MemberRole/Verification) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (https://clinics.acmg.net/) has a searchable database of medical genetics clinic services in the United States.

Figure 6. Joubert syndrome autosomal recessive inheritance pattern

Figure 7. Joubert syndrome X-linked recessive inheritance pattern

Should I have carrier testing if my male partner has a child with Joubert syndrome?

Joubert syndrome is predominantly inherited in an autosomal recessive manner, in which case both parents must be carriers to have an affected child. In rare cases, Joubert syndrome is inherited in an X-linked recessive manner ²⁸.

• If a male child has autosomal recessive Joubert syndrome, it is assumed his father is a carrier. To have another affected child with a different partner, the partner must also be a carrier of autosomal recessive Joubert syndrome. Many genes can be responsible for Joubert syndrome (some of which are unknown), and digenic inheritance is possible ²⁸. This means that children may be at risk if one parent carries a mutation in one responsible gene, and the other parent carries a mutation in a different responsible gene.
• If a male child has X-linked recessive Joubert syndrome, the most likely reason is that his mother is a carrier of X-linked Joubert syndrome, and the father is not a carrier. Males cannot be “carriers” of X-linked recessive conditions; if they have a mutation in the responsible X-linked gene, they will be affected.

Because the genetics of Joubert syndrome can be complex, people with questions about carrier testing are strongly encouraged to speak with a genetic counselor or other genetics professional. Whether to have genetic testing is a personal decision. A genetic counselor can provide more detailed information about the genetic risks to specific family members. They also discuss the risks, benefits, and limitations of genetic testing, and can facilitate the testing process for people who decide to have testing.

Joubert syndrome signs and symptoms

Joubert syndrome is a multisystem neurodevelopmental disorder that affects many parts of the body where most individuals with Joubert syndrome typically present as infants with low muscle tone (hypotonia), abnormal eye movements (ocular motor apraxia), respiratory control disturbances with unusually fast (hyperpnea) or slow (apnea) breathing, and as children or adults with difficulty coordinating movements (ataxia) and/or mild to severe delayed development and intellectual disability ⁴⁴, ¹⁰, ³.

Many of the clinical symptoms of Joubert syndrome are apparent in infancy and most affected children have delays in gross motor developments. The most common features are lack of muscle control (ataxia), abnormal breathing patterns with unusually fast (hyperpnea) or slow (apnea) breathing, sleep apnea, abnormal eye movements (ocular motor apraxia) and tongue movements and low muscle tone (hypotonia). Intellect ranges from normal to severe intellectual disability. Joubert syndrome is characterized by a specific finding on an MRI called a “molar tooth sign” in which the cerebellar vermis of the brain is absent or underdeveloped and the brain stem is abnormal.

In addition to these main features, the majority of individuals with Joubert syndrome also have involvement of other body systems including the eye, kidney, liver, and skeleton ⁴⁵. Joubert syndrome is sometimes associated with other eye abnormalities such as retinal dystrophy (degenerative disorders of the retina), and coloboma (a gap or split in a structure of the eye), which can cause vision loss or blindness and sensitivity to light, abnormal eye movements (nystagmus) and/or oculomotor apraxia (difficulty in smooth ocular pursuit with jerkiness in gaze and tracking), crossed eyes (strabismus) and droopy eyelids (ptosis). Other problems sometimes associated with Joubert syndrome include kidney disease such as polycystic kidney disease and nephronophthisis (a rare genetic disorder that leads to end-stage kidney disease that is characterized by kidney scarring (fibrosis), inflammation, and cyst formation, impairing kidney function that progress to terminal renal failure during the second decade (juvenile form) or before the age of 5 years (infantile form)) and/or liver disease, skeletal abnormalities such as the presence of extra fingers and toes (polydactyly), scoliosis (abnormal sideways curve of the spine), a gap in the skull with protrusion of the membranes that cover the brain (encephalocele) and hormone (endocrine) problems ⁹. Distinctive facial features can also occur in Joubert syndrome, these include a broad forehead, arched eyebrows, widely spaced eyes (hypertelorism), low-set ears, and a triangle-shaped mouth ⁹.

The signs and symptoms of Joubert syndrome vary among affected individuals, even among members of the same family and several of the additional features may be progressive, thereby substantially complicating medical management.

Neonatal period and early infancy

Clinical findings in the neonatal period and early infancy include low muscle tone (hypotonia), abnormal breathing pattern such as unusually fast (hyperpnea) or slow (apnea) breathing that may alternate, and abnormal eye movements including nystagmus and/or oculomotor apraxia (i.e., difficulty in smooth ocular pursuit with jerkiness in gaze and tracking), crossed eyes (strabismus) and droopy eyelids (ptosis). Oculomotor apraxia can sometimes manifest as head thrusting (as a compensatory mechanism for the inability to initiate saccades) or as horizontal head titubation (i.e., a “no-no” head tremor) ³.

Children and adults

Clinical findings that are identified or emerge with time include cognitive impairment (problems with a person’s ability to think, learn, remember, use judgement, and make decisions) and neurologic findings, as well as involvement of the eyes, kidney, liver, and skeleton.

Developmental delay and intellectual disability

Almost all individuals with Joubert syndrome manifest hypotonia and motor delays during infancy and early childhood, frequently evolving to ataxia (impaired balance or coordination) with age. While most reports indicate that patients with Joubert syndrome have substantial cognitive impairment (problems with a person’s ability to think, learn, remember, use judgement, and make decisions), the range of ability is quite broad with a minority of individuals having cognition in the normal range ⁴⁶, ⁴⁷, ⁴⁸, ³. A sample of 32 patients aged 1 to 17 years (mean 6 years) evaluated with the Child Development Inventory displayed a mean developmental age equivalent of 19 months ⁴⁹. IQ (intelligence quotient) between 30 and 80 have been reported in patients with Joubert syndrome ⁵⁰, ⁴⁷. However, difficulties measuring IQ in the presence of significant motor, speech, and visual impairments may be encountered. Ideally, neuropsychological and school evaluations should examine both full-scale intelligence quotient (FSIQ) and the generalized ability index (GAI) or similar measures to best reflect the individual’s intellectual and functional abilities ³.

The range of neurodevelopmental outcomes is very broad. Speech production is impacted out of proportion to language comprehension due to oral motor apraxia. Monitoring of development coupled with standard therapies (physical, occupational, and speech-language) and educational interventions aim to build on individual strengths and address specific weaknesses. Impaired balance or coordination (ataxia) and oculomotor apraxia (difficulty in smooth ocular pursuit with jerkiness in gaze and tracking) often improve as children mature. Most children with Joubert syndrome eventually walk independently, although a subset require assistance such as walkers and wheelchairs for ambulation. Adults with Joubert syndrome are much less well studied, but cognitive and functional impacts are lifelong ⁵¹.

Autism has been reported in children with Joubert syndrome, but the severe oral-motor dyspraxia and oculomotor issues in Joubert syndrome cause speech delay and abnormal eye contact, complicating the assessment of two core features of the diagnosis (communication and social interaction) ⁵², ⁵³, ⁵⁴. Takahashi et al ⁵⁵ reported that none of 31 patients with Joubert syndrome exceeded the Autism Behavior Checklist cutoff for autism, and they did not find increased load of neuropsychiatric issues seen in families of individuals with autism. Furthermore, many patients with Joubert syndrome are very interested in social interaction, engage in pretend play and exhibit theory of mind, features inconsistent with autism ¹⁰.

Eye and vision disorders

Abnormal eye movements are uniformly present in Joubert syndrome though highly variable in severity and may be subtle ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, ⁵⁰, ⁶⁰, ⁶¹, ⁶². The presence of nystagmus, saccades instead of smooth pursuit and tracking/acquiring targets with head movements rather than eye movements are the predominant clinical signs ¹⁰. Quantitative eye movement recordings demonstrate that the gains (target velocity/eye velocity) for smooth pursuit, saccades, optokinetic nystagmus and vestibuloocular reflex are variably reduced ⁵⁷, ⁶³, ⁶⁴. Each of these eye movement deficits reflect abnormalities of specific neural ensembles in the cerebellar vermis (oculomotor, nodulus, uvula), flocculus/paraflocculus, deep cerebellar nuclei, vestibular nuclei, pontine nuclei and/or inferior olives ¹⁰.

Retinal dystrophy (30% of individuals) ranging from congenital retinal blindness diagnosed in infancy with an attenuated or extinguished electroretinogram (ERG) (i.e., Leber congenital amaurosis) to retinitis pigmentosa, a slowly progressive degeneration that can result in nyctalopia (night blindness) or eventual blindness after the second decade ¹⁰, ⁵¹, ⁴³. Early onset of the retinal dystrophy shares overlapping clinical features with Leber congenital amaurosis, and preservation of vision despite markedly abnormal electroretinogram (ERG) findings supports more severe involvement of rod versus cone photoreceptors in some cases ⁶⁵, ⁵⁶.

Chorioretinal coloboma, optic nerve coloboma (17% of individuals) and optic atrophy is associated with significant visual impairment if the macula or optic nerve are involved ⁵¹.

Both chorioretinal coloboma and retinal dystrophy (2%-3% of individuals) ⁶⁶, ⁶⁷.

Microphthalmia (a developmental disorder of the eye in which one or both eyes are abnormally small and have anatomic malformations) and/or anophthalmia (a rare genetic birth defect characterized by the complete absence of one or both eyes), frequently accompanying colobomas, have rarely been identified in few patients with biallelic variants in CELSR2, CEP120, CSPP1, PDE6D, TMEM67, TMEM138, and TMEM216 ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹, ⁷², ⁷³, ⁷⁴, ⁷⁵.

Strabismus (crossed eye) and droopy eyelid (ptosis) (19% of individuals) are additional ocular findings that may be corrected with surgical intervention ⁶⁶, ¹⁰. Amblyopia and refractive errors are also common ⁶⁷.

Kidney disease

Kidney disease is present in 23% to 38% of individuals with Joubert syndrome and was traditionally described as “cystic dysplasia” and “nephronophthisis” with onset in late childhood or later ⁷⁶, ⁷⁷. However, these two findings now appear to be part of a continuum in which the manifestations vary by the stage of kidney disease ⁷⁸, ⁷⁹, ¹², ⁵¹. Nephronophthisis is a rare genetic disorder that leads to end-stage kidney disease that is characterized by kidney scarring (fibrosis), inflammation, and cyst formation, impairing kidney function that progress to terminal renal failure during the second decade (juvenile form) or before the age of 5 years (infantile form) ⁸⁰, ⁸¹. The first sign of later onset kidney disease is often failure to concentrate urine (salt-losing renal insufficiency) followed by echogenic kidneys on ultrasound and eventual renal failure. In patients with AHI1 mutations, onset of kidney disease has been reported in young adults ⁸², ⁸³. Saraiva and Baraitser ⁸⁴ reported kidney disease in 30% of cases in the literature.

In early-onset kidney disease, findings may be consistent with cystic dysplasia (i.e., multiple variably sized cysts in immature kidneys with fetal lobulations). In the first or second decade of life, kidney disease often presents as a urine-concentrating defect that results in polyuria and polydipsia (i.e., juvenile nephronophthisis) that may go undetected until manifestations of end-stage kidney disease (ESKD) become evident, such as fatigue, growth restriction, and/or anemia. Ultrasound examination typically shows small, scarred kidneys with increased echogenicity and occasional cysts at the corticomedullary junction.

Progression to end-stage kidney disease, occurring on average by age 13 years, is the leading cause of death in individuals with Joubert syndrome after age one year ⁷⁸.

Liver disease

Liver disease is typically congenital hepatic fibrosis characterized by developmental anomalies of biliary ductal plate remodeling with elevated transaminases and gamma-glutamyl transferase (GGT) with preserved hepatocellular (synthetic) function ³. COACH syndrome (Cerebellar vermis hypoplasia, Oligophrenia – developmental delay/mental retardation, Ataxia, Colobomas, and Hepatic fibrosis) is considered a sub-type of Joubert syndrome ⁸⁵, ⁸⁶, ³⁸. Clinically, the liver disease can be asymptomatic or present with mildly elevated serum transaminases, but more often, it is identified by liver imaging or signs of portal hypertension (gastroesophageal varices, hepatomegaly, splenomegaly, hypersplenism, ascites and rarely, upper gastrointestinal bleeding) in up to 13% of individuals ⁸⁷, ⁵¹, ¹². Liver biopsy findings are in the spectrum of the ductal plate malformation and congenital liver fibrosis, and the fibrosis is progressive at least in some cases ⁸⁸. Severe liver disease requires transjugular intrahepatic portosystemic shunt (TIPS) or liver transplantation and can result in death ⁸⁷, ⁵¹, ¹².

Skeletal disorder

Extra fingers and toes (polydactyly) is seen in 8% to 19% of Joubert syndrome cases and is a feature of many ciliopathies (a group of genetically inherited disorders caused by defects in cilia, hairlike structures that protrude from the surface of cells) ⁴⁴, ³⁶. Most frequently, it is post-axial polydactyly with (little finger) side of the hand or fibular (little toe) side of the foot, although it can be pre-axial polydactyly with having an extra digit (thumb or big toe) located on the thumb or big toe side (radial or tibial side) of the hand or foot; or very rarely, mesoaxial polydactyly with the presence of an extra finger or toe between the thumb/hallux and little finger/toe. In general, extra fingers and toes (polydactyly) is not functionally significant, and surgical correction is at the discretion of the patient/family.

Although various skeletal features and related short-rib thoracic dysplasias have been reported in Joubert syndrome, it is rare for this to be the primary presentation ⁸⁹, ⁹⁰, ⁹¹, ⁹².

Neuromuscular scoliosis (abnormal sideways curve of the spine) with minimal prevalence of 5% requires close monitoring, especially during puberty and may require further intervention ⁵¹.

Breathing disorder

Children and adults with Joubert syndrome are at increased risk for sleep-related apnea and central sleep apnea and obstructive sleep apnea, especially if obese ⁵¹. Sleep-disordered breathing can worsen neurobehavioral/psychiatric manifestations and if untreated can result in pulmonary hypertension ⁹³.

Oral motor dysfunction

Oral motor dysfunction may include the following ³:

• Difficulty swallowing (dysphagia) that may manifest as excess drooling and feeding difficulties predisposing to aspiration and respiratory complications. A substantial minority of individuals require gastrostomy tube placement.
• Speech apraxia a motor speech disorder that makes it difficult to plan and coordinate the movements needed to produce speech, a nearly universal finding that may account (at least in part) for the discrepancy between expressive and receptive communication abilities ⁹⁴, ⁹⁵.
• Dystonic movements are involuntary, abnormal muscle contractions that cause twisting, repetitive movements, and abnormal postures, which often include facial grimacing and/or biting the tongue and cheeks (perhaps self-injurious), for which there are no established treatments ⁵¹.

Other neurologic signs and symptoms

Other neurologic findings can include the following ³:

• Early hypotonia often evolves with time to become cerebellar ataxia that frequently improves with age ⁵¹
• Neurobehavioral/psychiatric manifestations include inattention, hyperactivity, stereotypies, emotional lability, anxiety, self-injury, aggression, and autism ⁵¹
• Seizures of all types (10% of individuals), which require standard neurologic evaluation and treatment ⁵¹, ¹²
• Temperature dysregulation (prevalence unknown), including episodic unexplained fevers and heat intolerance that can be associated with decreased activity during hot weather.

Infections

A small subset of individuals typically those with OFD1-related Joubert syndrome experience frequent sinopulmonary infections consistent with a primary ciliary dyskinesia (i.e., motile ciliopathy) ⁴³, ⁹⁶. These infections may be severe and require hospitalization.

Other signs and symptoms

While many patients with Joubert syndrome display dysmorphic facial features, no easily recognizable facial appearance has been described ⁹⁷, ⁹⁸. Specific craniofacial findings of oral-facial-digital syndrome type 1 (OFD1) (cleft palate, oral frenulae, and tongue lobulations or hamartomas) may be present in OFD1-related Joubert syndrome (Figure 1B) ¹².

Micropenis and pituitary dysfunction have also been reported in small numbers of patients with Joubert syndrome ⁸⁴, ³⁷.

Endocrine abnormalities seen in <5% of individuals with Joubert syndrome include panhypopituitarism, isolated growth hormone deficiency, or thyroid hormone deficiency ⁶⁶, ⁹⁹, ⁵¹.

Laterality defects sseen in <1% of individuals with Joubert syndrome include situs inversus (a rare congenital condition in which the organs in your chest and abdomen are positioned in a mirror image of their normal location) ⁶⁶.

Hirschsprung’s disease, a congenital disorder where nerve cells are missing in the large intestine, preventing the bowel from properly pushing stool through, manifested by intractable constipation has been described so far in few Joubert syndrome individuals ³⁶, while this condition is significantly associated with another ciliopathy, Bardet–Biedl syndrome ¹⁰⁰.

Joubert syndrome diagnosis

The diagnosis of Joubert syndrome is based on physical symptoms and the “molar tooth sign” as seen on an MRI. Diagnostic criteria for Joubert syndrome continue to evolve but most experts agree that the neuroradiologic finding of the “molar tooth sign” is necessary to make the diagnosis. The diagnosis of Joubert syndrome is based on the presence of the following three primary criteria ²⁵, ⁶, ²⁶:

1. The “molar tooth sign” based on MRI findings (hypoplasia of the cerebellar vermis)
2. Hypotonia (weak muscle tone) in infancy with later development of ataxia
3. Developmental delays/intellectual disability

A genetic diagnosis of Joubert syndrome can be confirmed via molecular genetic testing, which is available for the many genes that have been shown to cause Joubert syndrome. A molecular genetic diagnosis can be established in about 60% to 90% of patients. Carrier molecular genetic testing and prenatal diagnosis are available if one of these gene mutations has been identified in an affected family member.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://abgc.learningbuilder.com/Search/Public/MemberRole/Verification) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (https://clinics.acmg.net/) has a searchable database of medical genetics clinic services in the United States.

Clinical Testing and Work-Up

Because Joubert syndrome is a multisystem neurodevelopmental disorder, and the diagnosis is often made initially in the setting of a neurology, genetics or developmental pediatrics clinic, the frequent involvement of other organ systems means that monitoring for complications is required, with referral to the corresponding subspecialists when specific organ involvement is suspected.

The following baseline evaluations to identify the extent of disease are recommended by a consensus panel:

• Examination of high-quality MRI scan (if not done at the time of diagnosis) to assess for cerebral malformations and other brain abnormalities that may indicate a poorer prognosis or seizures.
• A baseline neurologic evaluation with particular attention to tone, respiratory pattern, eye movements, development and cerebellar function.
• Neuropsychological and developmental evaluation.
• Evaluation by a pediatric ophthalmologist via dilated eye examination for eye abnormalities such as colobomas, retinal changes, strabismus and ptosis.
• Abdominal ultrasound examination for evaluation of possible liver and kidney abnormalities.
• Tests of renal function, including blood pressure, blood urea nitrogen (BUN), serum creatinine concentration, complete blood count (CBC) and urine analysis.
• Liver function tests including serum concentrations of transaminases, albumin, bilirubin and prothrombin time.
• Skeletal survey and/or limb radiographs if there is suspicion of a skeletal dysplasia such as short-rib polydactyly.
• Consultation with a clinical geneticist to document family history, evaluate growth and head size and to evaluate for other physical anomalies such as polydactyly or dysmorphic facial features.

Brain abnormalities

Molar tooth sign (MTS). MRI findings comprise the following (see Figure 3 above) ³, ²⁵, ⁶, ²⁶:

1. An abnormally deep interpeduncular fossa
2. Prominent, straight, and thickened superior cerebellar peduncles
3. Hypoplasia of the vermis (the midline portion of the cerebellum)

An additional proposed near-universal feature is superior cerebellar dysplasia characterized by absence of the superior cerebellar peduncle decussation, which can be identified on fractional anisotropy imaging ⁵¹, ¹².

To ensure the most accurate imaging to establish the diagnosis of molar tooth sign (MTS), both high-quality MRI with thin (≤3 mm) axial cuts through the posterior fossa from the midbrain to the pons and standard axial, coronal, and sagittal cuts are recommended ⁵¹, ¹².

Note:

1. Because a subset of individuals with pathogenic variants in Joubert syndrome-associated genes have MRI findings without obvious molar tooth sign (MTS), the spectrum of brain findings in Joubert syndrome likely extends beyond molar tooth sign (MTS).
2. Conversely, cerebellar and brain stem malformations identified on brain MRI may be interpreted as “mild molar tooth sign” leading to an erroneous diagnosis of Joubert syndrome ¹².

Less common brain anomalies observed with molar tooth sign (MTS) include the following ⁵¹, ¹²:

• Cerebellar hemisphere enlargement
• Malrotation of the hippocampi
• Ventriculomegaly
• Dandy-Walker malformation
• Dysgenesis of the corpus callosum
• Polymicrogyria
• Heterotopia
• Occipital encephalocele (see Figure 1E above)
• Abnormal brain stem and/or hypothalamic hamartomas, particularly in those with oral-facial-digital features ¹⁰¹.

Pre-implantation genetic testing

Pre-implantation Genetic Testing is an early form of prenatal genetic diagnosis where abnormal embryos with specific known single gene condition or chromosome variation are identified, thereby allowing transfer of genetically healthy embryos during an in vitro fertilization (IVF), maximising the chance of a healthy baby. In vitro fertilization (IVF) is a fertility treatment where eggs are fertilized with sperm outside the body in a laboratory, and then a resulting embryo is transferred to the uterus. Pre-implantation Genetic Testing has become an integral part of Assisted Reproductive Technology (ART) procedures ¹⁰².

The option of in vitro fertilization (IVF) and preimplantation genetic diagnosis allows couples to reduce the chance of having a child with a specific genetic condition without having to face the difficult decision of whether to stop a naturally conceived pregnancy that has been shown to be affected by testing during pregnancy. IVF and preimplantation genetic diagnosis can also reduce the chance of repeated miscarriages for couples where for example one partner carries a chromosome translocation.

As with any IVF procedure, stress and sometimes disappointment can arise when undertaking the preimplantation genetic diagnosis process. Success rates for having a child from an IVF cycle followed by preimplantation genetic diagnosis vary from IVF center to center (these are available from the individual IVF provider) but tend to follow standard IVF success rates.

Couples may balance the financial and emotional cost of the IVF procedure followed by preimplantation genetic diagnosis, with that of considering termination of pregnancy or continuing a pregnancy for a child with a genetic condition conceived naturally.

In preparation for pregnancy, reproductive genetic carrier screening is also available for women and their partners. This test screens for whether there is an increased chance for other recessive genetic conditions in pregnancy.

Who is suitable for Pre-implantation Genetic Testing?

You may wish to consider pre-implantation genetic testing if you are concerned about any of the following issues:

• Either or both partners are carriers of single gene mutations that you want to avoid passing on to future children
• Either partner has a chromosome rearrangement (called a translocation) that can result in chromosomal variations in the eggs or sperm that could lead to either miscarriage or health problems in the child
• A previous pregnancy has been affected by a chromosomal variation
• Advanced maternal age (usually to test for Down syndrome where the mother is over 38 years old)
• Recurrent miscarriage
• Repeated IVF failure (where 5 or more embryos have been transferred without pregnancy).

How is Pre-implantation Genetic Testing performed?

In pre-implantation genetic testing, the woman goes through a standard in vitro fertilization (IVF) cycle. Hormones are given to the woman to stimulate her ovaries and allow the collection of a number of her eggs called oocytes. After the eggs are removed, they are fertilized in the laboratory with sperm. Those eggs that are successfully fertilized divide and multiply to form a developing embryo. When the embryo is at the blastocyst stage in the IVF laboratory, a few cells are removed to test for the specific genetic condition in question. In general, the removal of these cells does not appear to harm the developing embryo. Only those embryos that do not have the genetic condition tested for, will be transferred into the woman’s uterus.

Joubert syndrome treatment

Guidelines for the evaluation and management of patients with Joubert syndrome were developed by a consensus panel convened by the Joubert syndrome Foundation and Related Cerebellar Disorders ¹⁰³. The treatment for Joubert syndrome is symptomatic and supportive. Developmental delays are usually treated with physical therapy, occupational therapy, speech therapy and infant stimulation. Children with Joubert syndrome should be evaluated by appropriate specialists including nephrologists, ophthalmologists, geneticists and neurologists. Annual screening is recommended for liver, kidney and retinal abnormalities include yearly ophthalmologic evaluation, urinalysis, renal and liver ultrasounds, as well as serum transaminases, blood urea nitrogen (BUN), and creatinine to monitor for and allow early treatment of the medical complications described above. Lifelong monitoring for obstructive and central sleep apnea is also warranted. Specific developmental and behavioral supports for Joubert syndrome do not exist, and interventions are tailored to the needs of each individual ⁴⁴.

Infants and children with abnormal breathing patterns should be considered for apnea monitoring and supportive therapy may require stimulatory medications or 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. Corrective lenses may be required for optic refractive errors. Nephronophthisis, end-stage renal disease, liver failure and/or fibrosis are treated with standard approaches, which may include dialysis and/or kidney transplantation.

Genetic counseling is recommended for individuals with Joubert syndrome and their families.

Table 1. Joubert Syndrome recommended evaluations following diagnosis

System/Concern	Evaluation	Comment
Constitutional	Measure height, weight, occipitofrontal circumference [OFC]
Neurologic	By neurologist familiar w/neurodevelopmental disorders	Hypotonia, present in infants, often becomes cerebellar ataxia in older persons. Consider EEG if seizures are a concern.
Respiratory	By pulmonologist and/or sleep medicine provider	Include assessment for sleep apnea
Dysphagia / Poor feeding	By gastroenterologist / nutritionist / feeding team	Evaluate aspiration risk & nutritional status. Consider eval for gastrostomy tube placement in persons w/dysphagia &/or when aspiration risk is increased.
Ophthalmologic	By ophthalmologist	Assess for: Ptosis, abnormal ocular movement, reduced vision, best corrected visual acuity, refractive errors, and strabismus; Findings such as coloboma &/or retinal dystrophy. 1
Dysarthria / Speech apraxia	By speech-language pathologist	Focus on speech apraxia when warranted
Ataxia/activities of daily living (ADL)	Physical medicine & rehab / physical therapy (PT) & occupational therapy (OT) eval	Include assessment of: Gross motor & fine motor skills Mobility, activities of daily living (ADL), & need for adaptive devices Need for physical therapy (PT) (to improve gross motor skills) and/or occupational therapy (OT) (to improve fine motor skills)
Skeletal	By primary care provider / orthopedist	Physical exam; if suspicion of skeletal dysplasia, obtain skeletal survey &/or limb radiographs. Evaluate polydactyly re need for surgery. Evaluate for spinal curvature per standard practice. Consult with orthopedist if scoliosis is progressing and/or significant.
Development (infants & young children)	Developmental assessment	To include motor, adaptive, cognitive and speech-language evaluation Evaluate for early intervention / special education.
Cognitive abilities (school-age children & adults)	School-based standardized assessments	Provision of services & resources as directed by educational assessments
Neurobehavioral/ psychiatric manifestations	By developmental pediatrician	For infants and young children: screening for concerns incl sleep disturbances, attention-deficit/hyperactivity disorder (ADHD), anxiety, &/or findings suggestive of autism spectrum disorder
	By mental health specialist	For school-age children & adults
Kidney disease	By nephrologist / primary care provider	Monitor 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). Abdominal ultrasound for kidney size, cysts, and/or findings consistent with nephronophthisis (e.g., loss of corticomedullary differentiation)
Liver disease	By primary care provider	Monitor blood concentrations of transaminases, albumin, bilirubin, & prothrombin time. Abdominal ultrasound to evaluate for hepatic fibrosis, anomalies of bile duct
Recurrent sinopulmonary infections	Pulmonary medicine consultation	Only in persons with OFD1-related Joubert syndrome
Genetic counseling	By genetics professionals 2	Obtain a pedigree & inform affected persons & their families re nature, mode of inheritance, and implications of Joubert syndrome to facilitate medical and personal decision making & reproductive options
Family support & resources	By clinicians, wider care team, & family support organizations	Assessment of family & social structure to determine need for: Community or online resources such as Parent to Parent Social work involvement for parental support Home nursing referral

Footnotes:

1. Now commonly confirmed by ocular coherence tomography (OCT) rather than electroretinogram (ERG)
2. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

[Source ³ ]

Table 2. Joubert Syndrome Treatment Options

Manifestation/Concern	Treatment	Considerations/Other
Seizures	Standardized treatment with anti-seizure medication by experienced neurologist	Many anti-seizure medications may be effective; none has been demonstrated effective specifically for this disorder. Education for parents/caregivers 1
Respiratory	Involve sleep medicine as needed. Infants & children with abnormal breathing may require: Stimulatory medications (e.g., caffeine) and/or supplemental oxygen (particularly newborns); Rarely, mechanical support and/or tracheostomy.	By pulmonologist
Dysphagia/poor feeding	Assure adequate dietary intake. Consider gastrostomy tube placement if aspiration risk is increased.	By nutritionist / speech-language pathologist / gastroenterologist
Ophthalmologic	Surgery for symptomatic ptosis and/or strabismus	By ophthalmologist
	Low vision services	Children: through early intervention programs and/or school district Adults: low vision clinic &/or community vision services /occupational therapy (OT) / mobility services
Dysarthria / Speech apraxia	By speech-language pathologist	For oral motor dysfunction Consider augmentative or alternate means of communication.
Ataxia/Spasticity/activities of daily living (ADL)	Physical therapy (PT)/occupational therapy (OT)	Include stretching to help avoid contractures and falls Consider need for positioning and mobility devices, disability parking placard.
Skeletal involvement	Scoliosis detection and monitoring Surgical repair as recommended by orthopedist	By orthopedist or primary care provider
Development (infants & young children)	Age-related individualized educational support	If needed, incl special programs for visually impaired. Determine if individual education plan (IEP) or 504 plan is needed.
Cognitive abilities (school-age children & adults)
Neurobehavioral and psychiatric problems	Medication management per standard care Counsel regarding ↑ risk for emotional lability, anxiety, and attention-deficit/hyperactivity disorder (ADHD)	By mental health specialist
Kidney disease	Standard practices for complications of cystic kidney disease and end-stage kidney disease (ESKD)	By nephrologist familiar w/nephronophthisis Agents/circumstances to avoid incl nephrotoxic agents/medications for those w/molecular diagnosis that puts them at ↑ risk (see Table 1).
Liver disease	Standard practices for liver failure &/or hepatic fibrosis	By gastroenterologist familiar with congenital hepatic fibrosis
Family/Community	Ensure appropriate social work involvement to connect families with local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, and supplies.	Ongoing assessment of need for palliative care involvement and/or home nursing Consider involvement in adaptive sports or Special Olympics.

Footnotes:

1. Education of parents/caregivers regarding common seizure presentations is appropriate.

[Source ³ ]

Table 3. Joubert Syndrome recommended monitoring

System/Concern	Evaluation		Frequency
Feeding/Growth	Measure growth parameters. Assess nutritional status & safety of oral intake.		At each visit
Respiratory	Clinical surveillance for apnea
	Involve sleep medicine if new manifestations emerge.		As needed
Neurologic	Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, & ataxia.		Per treating neurologist
Development	Monitor developmental & educational progress.		At each visit
Neurobehavioral/psychiatric manifestations	Assessment for anxiety, ADHD, autism spectrum disorder, aggression, & self-injury
Musculoskeletal/ADL	OT/PT assessment of mobility, self-help skills
Scoliosis	For those under care of orthopedist or for children during period of rapid growth		Per treating clinician
Ophthalmologic involvement	Eye eval for known ophthalmologic involvement & those w/molecular diagnosis that places them at ↑ risk for retinal dystrophy (See Table 1.)		Per treating ophthalmologist
	Low vision services		Per treating clinician
Dysarthria / Speech apraxia	Per treating speech-language pathologist		Per treating speech-language pathologist
Kidney disease	For those w/molecular diagnosis that places them at ↑ risk for kidney disease (see Table 1) who are not manifesting kidney disease:	Clinical monitoring for polyuria, polydipsia, & fatigue	Yearly until at least age 20 yrs
		Estimate creatine & hematocrit; consider urine osmolarity & cystatin C	Every 1-2 yrs
	For those w/kidney disease: per treating nephrologist		Per treating nephrologist
Liver involvement	For those w/molecular diagnosis that places them at ↑ risk for age-related liver disease (see Table 1):	Monitor for hepatic disease (abdominal ultrasound for spleen size).	Yearly during childhood (until at least age 20 yrs)
		Monitor platelets, GGT, & ALT.	Every 1-2 yrs
	For those w/liver disease: per treating hepatologist		Per treating hepatologist
Endocrine	Assess pubertal development.		When age appropriate
Family/Community	Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning). 1		At each visit

Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ALT = alanine transaminase; ASD = autism spectrum disorder; GGT = gamma-glutamyl transferase; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist

[Source ³ ]

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 ¹⁰⁴;
  • Alpha-2 agonists such as clonidine or dexmedetomidine to avoid respiratory depression and other complications of opioids while achieving motion-free images ¹⁰⁵.
• 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 central nervous system 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 antiepileptic drugs.
• 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.

Eye problems

• 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 renal disease (ESRD) resulting from nephronophthisis frequently requires dialysis and/or kidney transplantation during the teenage years or later.
• Hypertension, anemia, and other complications of ESRD 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 Bilevel Positive Airway Pressure (BiPAP) or continuous positive airway pressure/power (CPAP) 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:

• 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 and 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.

Joubert syndrome prognosis

The prognosis for infants with Joubert syndrome depends on whether or not the cerebellar vermis is partially developed or entirely absent, as well as on the extent and severity of other organ involvement, such as the kidneys and liver. Some children have a mild form of the disorder, with minimal motor disability and good mental development, while others may have severe motor disability, moderate impaired mental development, and multi-organ impairments. Some patients may have a shortened lifespan due to complications of the disease, including kidney or liver abnormalities.

Little is known about mortality in Joubert syndrome. After the first months of life, Joubert syndrome prognosis varies considerably among Joubert syndrome subgroups, depending on the extent and severity of organ involvement ³⁶. A wide range of central nervous system (brain and spinal cord) malformations are described in association to the molar tooth sign (MTS) that can dramatically affect the clinical outcome and prognosis of patients with Joubert syndrome ³⁶. These include hydrocephalus, cystic enlargement of the posterior fossa, abnormalities of the corpus callosum, white matter cysts, hypothalamic hamartoma, and absence of the pituitary gland ¹⁰⁶, ¹⁰⁷, ¹⁰⁸, ¹⁰⁹. Abnormal migration defects, mainly periventricular nodular heterotopia, and cortical organization defects such as polymicrogyria have also been reported ¹¹⁰, ¹¹¹. Patients with these brain malformations present a higher incidence of epilepsy, which is otherwise a rare feature of Joubert syndrome ¹¹⁰, ¹⁰⁸. A small number of cases present with occipital (meningo) encephalocele of variable severity ¹¹², ¹¹³, ³¹.

Poretti et al ¹¹⁴ reported that neuroimaging may predict the neurodevelopmental outcome, as a high degree of vermis hypoplasia was found to correlate with worse prognosis. In the University of Washington cohort, 40 of 565 patients with Joubert syndrome were deceased, mainly due to extra‐neurological involvement, such as kidney disease or liver fibrosis ¹¹⁵. The underlying genetic defects had been identified in 80% (32/40) of the deceased cohort. Although the numbers were too small for any statistical analyses, six of nine individuals with biallelic variants in CEP290 had died from complications of kidney disease, while two of the three with molecular defects in TMEM67 had died from liver fibrosis, and all three individuals with TCTN2‐related Joubert syndrome died from respiratory complications. Therefore, a close monitoring of these issues should be considered in patients with these additional risk factors ⁷⁸.

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