Joubert syndrome

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Disease Profile

Joubert syndrome

1-9 / 100 000

US Estimated

Europe Estimated

Age of onset

Antenatal

ICD-10

Q04.3

Inheritance

Joubert syndrome is predominantly inherited in an autosomal recessive manner.^[4] This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

25% chance to be affected
50% chance to be an unaffected carrier like each parent
25% chance to be unaffected and not a carrier.

In rare cases, when Joubert syndrome is caused by mutations in the OFD1 gene on the X chromosome, it is inherited in an X-linked recessive manner.^[5] X-linked recessive conditions usually occur in males, who only have one X chromosome (and one Y chromosome). Females have two X chromosomes, so if they have a mutation on one X chromosome, they still have a working copy of the gene on their other X chromosome and are typically unaffected. While females can have an X-linked recessive condition, it is very rare.

If a mother is a carrier of an X-linked recessive condition and the father is not, the risk to children depends on each child's sex.

Each male child has a 50% chance to be unaffected, and a 50% chance to be affected
Each daughter has a 50% chance to be unaffected, and a 50% chance to be an unaffected carrier

If a father has the X-linked recessive condition and the mother is not a carrier, all sons will be unaffected, and all daughters will be unaffected carriers.

People with specific questions about the inheritance of Joubert syndrome for themselves or family members are encouraged to speak with a genetic counselor or other genetics professional. A genetics professional can help by:

thoroughly evaluating the family history
addressing questions and concerns
assessing recurrence risks
facilitating genetic testing if desired
discussing reproductive options

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Other names (AKA)

Cerebelloparenchymal disorder 4; Cerebellar vermis agenesis; Joubert-Boltshauser syndrome;

Summary

Joubert syndrome is disorder of brain development that may affect many parts of the body. It is characterized by the absence or underdevelopment of the cerebellar vermis (a part of the brain that controls balance and coordination) and a malformed brain stem (connection between the brain and spinal cord). Together, these cause the characteristic appearance of a molar tooth sign on MRI. Signs and symptoms can vary but commonly include weak muscle tone (hypotonia); abnormal breathing patterns; abnormal eye movements; ataxia; distinctive facial features; and intellectual disability.^[1]^[2]^[3] Various other abnormalities may also be present. Joubert syndrome may be caused by mutations in any of many genes. Inheritance is usually autosomal recessive, but rarely it may be X-linked recessive.^[1]^[4]^[5] Treatment is supportive and depends on the symptoms in each person.^[1]

Symptoms

Most infants with Joubert syndrome have weak muscle tone (hypotonia), which evolves into difficulty coordinating movements (ataxia) in early childhood.^[3] Affected children may have episodes of unusually fast or slow breathing (hyperpnea), which tends to occur shortly after birth. This may intensify with emotional stress, but progressively improves with age and usually disappears around 6 months of age.^[3]^[6]

Abnormal eye movements are also common. Oculomotor apraxia occurs frequently and causes difficulty moving the eyes from side to side. People with oculomotor apraxia have to turn their heads to see things in their peripheral vision.^[6]

Developmental abilities, in particular language and motor skills, are delayed with variable severity. Mild to severe intellectual disability is common, but some people with Joubert syndrome have normal intellectual abilities.^[6]

Distinctive facial features are also characteristic. These include a broad forehead, arched eyebrows, droopy eyelids (ptosis), widely spaced eyes, low-set ears, and a triangular-shaped mouth.^[3]

Joubert syndrome can cause a wide range of additional signs and symptoms. The condition is sometimes associated with other eye abnormalities (such as retinal dystrophy, which can cause vision loss); kidney disease; liver disease; skeletal abnormalities (such as extra fingers and toes); and hormone (endocrine) problems. When the characteristic features of Joubert syndrome occur with one or more of these additional features, researchers refer to the condition as "Joubert syndrome and related disorders (JSRD)"^[3] or as a subtype of Joubert syndrome.^[6]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms

Other Names

Learn More:

HPO ID

80%-99% of people have these symptoms

Apnea

0002104

Ataxia

0001251

Cerebellar vermis hypoplasia

0001320

Episodic tachypnea

0002876

Global developmental delay

0001263

Intellectual disability

Mental deficiency

Mental retardation

Mental retardation, nonspecific

Mental-retardation

[ more ]

0001249

Muscular hypotonia

Low or weak muscle tone

0001252

Oculomotor apraxia

0000657

30%-79% of people have these symptoms

Biparietal narrowing

0004422

Feeding difficulties in infancy

0008872

Gait disturbance

Abnormal gait

Abnormal walk

Impaired gait

[ more ]

0001288

Long face

Elongation of face

Increased height of face

Increased length of face

Vertical elongation of face

Vertical enlargement of face

Vertical overgrowth of face

[ more ]

0000276

Nystagmus

Involuntary, rapid, rhythmic eye movements

0000639

5%-29% of people have these symptoms

Abnormal form of the vertebral bodies

0003312

Abnormality of the hypothalamus-pituitary axis

0000864

Aganglionic megacolon

Enlarged colon lacking nerve cells

0002251

Anteverted nares

Nasal tip, upturned

Upturned nasal tip

Upturned nose

Upturned nostrils

[ more ]

0000463

Aplasia/Hypoplasia of the corpus callosum

0007370

Encephalocele

0002084

Foot polydactyly

Duplication of bones of the toes

0001829

Hand polydactyly

Extra finger

0001161

Highly arched eyebrow

Arched eyebrows

Broad, arched eyebrows

High, rounded eyebrows

High-arched eyebrows

Thick, flared eyebrows

[ more ]

0002553

Hydrocephalus

Too much cerebrospinal fluid in the brain

0000238

Iris coloboma

Cat eye

0000612

Low-set ears

Low set ears

Lowset ears

[ more ]

0000369

Occipital myelomeningocele

0007271

Oral cleft

Cleft of the mouth

0000202

Polymicrogyria

More grooves in brain

0002126

Prominent nasal bridge

Elevated nasal bridge

High nasal bridge

Prominent bridge of nose

Prominent nasal root

Protruding bridge of nose

Protruding nasal bridge

[ more ]

0000426

Ptosis

Drooping upper eyelid

0000508

Renal cyst

Kidney cyst

Retinal dysplasia

Scoliosis

Seizure

Situs inversus totalis

All organs on wrong side of body

0001696

Strabismus

Cross-eyed

Squint

Squint eyes

[ more ]

0000486

Tremor

0001337

Percent of people who have these symptoms is not available through HPO

Abnormal foot morphology

Abnormal feet structure

Abnormality of the feet

Abnormality of the foot

Foot deformities

Foot deformity

[ more ]

0001760

Abnormal saccadic eye movements

0000570

Abnormality of ocular smooth pursuit

0000617

Agenesis of cerebellar vermis

0002335

Aggressive behavior

Aggression

Aggressive behaviour

Aggressiveness

[ more ]

0000718

Autosomal recessive inheritance

0000007

Brainstem dysplasia

0002508

Central apnea

0002871

Chorioretinal coloboma

Birth defect that causes a hole in the innermost layer at the back of the eye

0000567

Dysgenesis of the cerebellar vermis

0002195

Elongated superior cerebellar peduncle

0011933

Enlarged fossa interpeduncularis

0100951

Epicanthus

Eye folds

Prominent eye folds

[ more ]

0000286

Generalized hypotonia

Decreased muscle tone

Low muscle tone

[ more ]

0001290

Hemifacial spasm

Spasms on one side of the face

0010828

Hepatic fibrosis

0001395

Hyperactivity

More active than typical

0000752

Hypoplasia of the brainstem

Small brainstem

Underdeveloped brainstem

Cause

Joubert syndrome and related disorders may be caused by changes (mutations) in any of many genes (some of which are unknown). The proteins made from these genes are either known or thought to affect cell structures called cilia. Cilia are projections on the cell surface that play a role in signaling. They are important for many cell types, including neurons, liver cells and kidney cells. Cilia also play a role in the senses such as sight, hearing, and smell.

Mutations in the genes responsible for Joubert syndrome and related disorders cause problems with the structure and function of cilia, likely disrupting important signaling pathways during development. However, it is still unclear how specific developmental abnormalities result from these problems.^[7]

Diagnosis

The diagnosis of Joubert syndrome is based on the presence of characteristic clinical features as well as the MRI finding of the molar tooth sign.^[8]

The diagnosis of "classic" or “pure” Joubert syndrome is based on the presence of the following three primary criteria:

the molar tooth sign on MRI
hypotonia (weak muscle tone) in infancy with later development of ataxia
developmental delays / intellectual disability

Additional features often identified in people with Joubert syndrome include an abnormal breathing pattern (alternating tachypnea and/or apnea) and abnormal eye movements.

The term “Joubert syndrome and related disorders” (JSRD) refers to those with Joubert syndrome who have additional findings such as retinal dystrophy, renal (kidney) disease, ocular colobomas, occipital encephalocele (protruding tissue at the back of the skull), fibrosis of the liver, polydactyly, and/or other abnormalities. A significant proportion of people diagnosed with classic Joubert syndrome in infancy or early childhood will eventually have additional findings that represent JSRD.^[8]

While mutations in many genes are known to be associated with Joubert syndrome, they are only identified in about 50% of affected people who have genetic testing. Therefore, genetic testing is not required for a diagnosis of Joubert syndrome or JSRD.^[8]

Testing Resources

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Treatment

The resources below provide information about treatment options for this condition. If you have questions about which treatment is right for you, talk to your healthcare professional.

Management Guidelines

Project OrphanAnesthesia is a project whose aim is to create peer-reviewed, readily accessible guidelines for patients with rare diseases and for the anesthesiologists caring for them. The project is a collaborative effort of the German Society of Anesthesiology and Intensive Care, Orphanet, the European Society of Pediatric Anesthesia, anesthetists and rare disease experts with the aim to contribute to patient safety.

Related diseases

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet

Differential diagnoses include Joubert syndrome-related disorders (JSRD), cerebellar vermis malformations without the MTS (which include Dandy-Walker malformation), X-linked cerebellar hypoplasia, ataxia with oculomotor apraxia types 1 and 2 (AOA1, AOA2), congenital disorders of glycosylation (CDG), 3-C syndrome, pontocerebellar hypoplasias/atrophies, orofaciodigital syndromes II and III, and Meckel-Gruber syndrome (see these terms).

Visit the Orphanet disease page for more information.

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Joubert Syndrome & Related Disorders Foundation (JSRDF)
9 Dorenfeld CT
Petaluma, CA 94952
Telephone: +1-614-864-1362
E-mail: info@jsrdf.org
Website: https://jsrdf.org/

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

Genetics Home Reference (GHR) contains information on Joubert syndrome. This website is maintained by the National Library of Medicine.
The National Institute of Neurological Disorders and Stroke (NINDS) collects and disseminates research information related to neurological disorders. Click on the link to view information on this topic.
The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.
The University of Washington's Hindbrain Malformation Research Program has more information on this condition.

In-Depth Information

GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Joubert syndrome. Click on the link to view a sample search on this topic.

References

NINDS Joubert Syndrome Information Page. NINDS. January 21, 2016; https://www.ninds.nih.gov/disorders/joubert/joubert.htm.
Overview. Joubert Syndrome & Related Disorders Foundation. 2016; https://jsrdf.org/what-is-js/.
Joubert syndrome. Genetics Home Reference. January 2011; https://ghr.nlm.nih.gov/condition/joubert-syndrome.
What is Joubert Syndrome?. Hindbrain Malformation Research Program. 2016; https://depts.washington.edu/joubert/joubertsyndrome.php.
Cassandra L. Kniffin. JOUBERT SYNDROME 10; JBTS10. OMIM. December 2, 2015; https://www.omim.org/entry/300804.
Brancati, Francesco, et.al.. Joubert Syndrome and related disorders. Orphanet Journal of Rare Diseases. July 2010; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913941/pdf/1750-1172-5-20.pdf.
Joubert syndrome. Genetics Home Reference. January, 2011; https://ghr.nlm.nih.gov/condition/joubert-syndrome.
Melissa Parisi and Ian Glass. Joubert Syndrome and Related Disorders. GeneReviews. April 11, 2013; https://www.ncbi.nlm.nih.gov/books/NBK1325/.

Rare Hematology News

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Antenatal

Q04.3

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Other names (AKA)

Categories

Summary

Symptoms

Cause

Diagnosis

Testing Resources

Treatment

Management Guidelines

Related diseases

Organizations

Organizations Supporting this Disease

Learn more

Where to Start

In-Depth Information

References

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.