Joubert Syndrome and Related Disorders

Implications for Nurse Practitioners

Laurie Anne Ferguson, FNP-C; Maritza Salgado, FNP-BC


Journal for Nurse Practitioners. 2012;8(4):316-322. 

In This Article

Joubert Syndrome

JS and JSRD are rare autosomal recessive disorders typified by a distinctive cerebellar and brainstem malformation. The neuroradiological-specific MTS (Figure 1) found on magnetic resonance imaging (MRI) is required to diagnose JSRD.[9] In addition to cerebellar and brainstem malformation, JS and JSRD are characterized by hypotonia, developmental delays, intermittent hyperpnea or apnea, and atypical eye movements, including nystagmus. Many children affected with the disorder die in infancy before diagnosis. Its prevalence is estimated to be between 1:80,000 to 1:100,000 live births for genetic screening purposes, although this condition is probably under-reported.[10,11] Research into rare genetic conditions is continuing to evolve, and its implications for practice are evolving as well.

Figure 1.

Molar Tooth Sign
Used with permission from Michael V. Huppman Medpix®.


JS was first identified in 1969 by French neurologist Marie Joubert, who described 4 siblings with hyperpnea, abnormal eye movements, ataxia, mental retardation, and absent cerebellar vermis. A founder effect or the loss of genetic variation has been identified in the French-Canadian population. The term founder effect refers to a genetic alteration where subsequent generations are related to a small group of people. The genetic pool becomes much smaller. Genes that were not prominent in the larger group may become more prominent in a small community of people. Founder effect is associated with geographic or religiously isolated communities, where individuals are at higher risk of developing diseases or syndromes because there is a higher probability of recessive disorders. The family first described by Joubert traced their linage to an immigrant from France to Quebec in the 1600s.[10–13] However, JS and JSRD are found worldwide in all individuals of all races and ethnic backgrounds.


Early in fetal development, the human embryo comprises 3 germ layers called the ectoderm, endoderm, and mesoderm. These structures give rise to all body organs and tissues.[12] The ectoderm subsequently develops into a neural plate, which leads to the neural tube and the embryonic brain. This primitive embryonic brain comprises the prosencephalon, midbrain, and hindbrain. The hindbrain further divides into separate anatomic structures called rhombomeres. It is believed that these rhombomeres play a critical role in gene expression. Rhombomeres with deep cerebellar nuclei further morph into Cranial Nerves V and X. It is believed that an error in development of these structures results in an absent or underdeveloped vermis and the physical findings seen in JS.[12]


Many syndromes with genetic mutations share similar physical manifestations. Although it was originally thought that the MTS was specific to JS, this is no longer the case. Other autosomal recessive disorders also demonstrate the MTS, including Dekaban-Arima syndrome, severe retinal dysplasia, COACH syndrome, Senior Laken syndrome, Varadi-Papp syndrome, nephronophthisis and Cogan oculomotor apraxia syndrome, and Bardet-Biedi syndrome. Hypoplastic cerebellar vermis is associated with Dandy-Walker malformation, X-linked cerebellar hypoplasia, ataxia and oculomotor apraxia type 1 (AOA1, characterized by lack of muscle coordination during voluntary movement and difficulty moving eyes), congenital disorders of glycosylation, 3-C syndrome, pontocerebellar hypoplasias, oral-facial-digital syndromes II and III, as well as Meckel-Gruber syndrome.[10]

Classic findings associated with JS and JSRD are hypotonia in infancy, developmental delays and intellectual disability, abnormal breathing, either hyperpnea or apnea, and/or abnormal eye movements.[9,14] Hypotonia in the neonatal period is not specific to JSRD, but when associated with irregular breathing and abnormal eye movements, the PCP should order an MRI.[9] Developmental delay always warrants further evaluation.

The diagnosis of JSRD is not made by the PCP, because an accurate diagnosis of JS and JSRD is difficult to establish as a result of the genotypic-phenotypic variations of the disorders. As with any rare disorder, nonspecific symptoms may delay recognition of varying clinical findings.[9] As with all clinical encounters, an initial evaluation should include a complete health history, examination, and extensive family history. The family history is considered an instrumental tool for diagnosis and risk assessment in medical genetics and serves as a critical element in making appropriate, timely referrals for genetic testing in primary care.[15] When a genetic disorder is suspect, the PCP should immediately refer to a genetics specialist for definitive diagnosis and counseling. The genetic referral should occur in conjunction with referral to appropriate specialists, such as neurology, nephrology, ophthalmology, etc, as needed for specific interventions.

Clinical Findings

Individuals with JS and JSRD display some clinical heterogeneity and some variation as well. Central nervous system (CNS) findings comprise the largest area of symptoms associated with JS and JSRD. Neurologic findings are variable in severity and include cognitive abilities ranging from profound mental retardation to normal intelligence.[9,10] Speech difficulties are common as a result of tongue thrust and speech apraxia. An abnormal electroencephalogram and seizures have been found in some individuals with JS.[9]

Furthermore, an increased occurrence, as high as 40%, of autism spectrum disorders has been found in some patients with JSRD. This is specifically associated with AHI1 gene deletion.[16] Behavioral problems, including tantrums, are common. Other CNS abnormalities include increased cerebrospinal fluid in the fourth ventricle, occipital encephalocele or meningocele, and hydrocephalus. Additional findings may include the absence of the corpus collosum, neuroepithelial cysts, and a rare finding of polymocrogyria or an excessive number of convolutions (gyri) on the brain.

Heterotopias or misplacement of grey matter is also sometimes associated with JSRD.[10] Although hypotonia in infancy is associated with JSRD, ataxia and a broad-based gait are often seen as children develop independent ambulation.[9]

Ophthalmologic pathology is commonly found in individuals with JSRD. Pathology ranges from nystagmus to blindness, along with ptosis, strabismus, and amblyopia.[9,14] However, nystagmus found in infancy may diminish over time. Retinal disease associated with JSRD can resemble retinitis pigmentosa, which is characterized by a progressive loss of vision. In JSRD the retinal disease and subsequent vision loss is not usually progressive. Atypical head movements or posturing as the child attempts to compensate for vision loss may be an early indicator of underlying pathology.

Renal disease often occurs in 25% of individuals with JSRD. The renal diseases associated with this condition include cystic dysplasia and juvenile nephronophthisis, a form of chronic tubulointerstitial nephropathy.[9] Renal function should be monitored by the PCP in collaboration with the nephrologist.

Some individuals with JSRD have congenital hepatic fibrosis as a result of anomalies of biliary structures and portal tracts during embryonic development.[9] Liver function tests with hepatic ultrasound are recommended biannually in children and at diagnosis in adults.[9] Polydactyly and micropenis have also been found in some individuals with JSRD.[10]

Some stereotypical facial features are associated with JSRD and include a long face, prominent forehead, bitemporal narrowing, high-arched eyebrows, occasional ptosis, prominent nasal bridge, triangular-shaped mouth, upturned nose, protruding jaw, and low-set ears. However, many physical features are less evident as the child ages (Box 1). [10,13]

Children with JSRD who survive infancy meet developmental milestones later, if at all. Ambulation presents a particular challenge for JSRD. The ataxia and disequilibrium of JSRD frequently require assistive devices when independent ambulation is achieved. Relative independence with ambulation and activities of daily living are worthy goals. Caregiver fatigue with growing children who may achieve adult height and weight is a common problem.


PCPs may be the first to suspect that a patient has a syndrome. Advances in genetics afford opportunities for improved understanding and treatment of common illnesses and rare disorders. PCPs need to know how to incorporate the genetic impact on disease and syndromes in primary care to better use the information gained by advances in genetics. Determining genetic risk requires a comprehensive family history that includes a 3-generation detailed pedigree. Ideally, this includes age of disease onset and age at death for each family member. Furthermore, PCPs should be proficient in recognizing common inheritance patterns and the impact of ethnicity and be able to communicate risk and counseling without bias.[17]

If JSRD is suspected, then a complete work-up is indicated, including an MRI, complete neurologic evaluation, sleep study, kidney ultrasound, and lab work evaluating liver and kidney function. A complete genetic evaluation and assessment by a speech pathologist, neuropsychiatric specialist, physical therapist, and ophthalmologist should also be included. Male children exhibiting micropenis or growth abnormalities should be referred to an endocrinologist for evaluation. PCPs should order specialized laboratory and radiological studies only in consultation with specialists to avoid unnecessary or superlative testing.

The management of individuals with JSRD is supportive and related to the different manifestations of the syndrome. The PCP can play a critical role in coordinating care. Respiratory problems require apnea monitoring and may include medications and supplemental oxygen. Occasionally, mechanical ventilator support is required. Speech, occupational, and physical therapy should be ordered to improve swallowing and speech difficulties and physical challenges. Neurosurgery is rarely indicated, but referral should be considered if appropriate, especially if VP shunting or encephalocele closure is required. Medication management to control seizures may be required. All hepatotoxic or nephrotoxic medications should be avoided if organ function is impaired.[9,10]

Individuals with NPHP1 deletion, CEP290 mutations, and some with AHI1 mutations are considered high risk for nephronophthisis and should be followed by a nephrologist. Referrals to correct anomalies such as ptosis, strabismus, amblyopia, and polydactyly may be required (Box 2).

The role of PCPs in caring for patients with genetic disorders includes monitoring in conjunction with a genetic specialist and coordinating the care of individuals with complex specialty needs. Additionally, PCPs are the initial source of information and guidance for patients and families in understanding the disease and making informed decisions.[17]


The prognosis for individuals with JSRD varies. Some individuals are able to live independent, productive lives. However, most will require various degrees of supportive care for their whole lives. Individuals who have severe renal or hepatic impairment have a shortened life expectancy.

Genetic Counseling

Parents of a child with JSRD, although asymptomatic themselves, are heterozygotes by definition and carry at least 1 mutant allele. At conception the offspring of these parents have a 25% chance of having a child affected with JSRD, a 50% chance of having a child who is an unaffected carrier, and a 25% chance of not being affected or a carrier. No known offspring from individuals with JSRD have been reported.[10]

Information regarding carrier status and risk should be provided before pregnancy if possible. Family members should be provided with information and resources if they desire to have genetic testing and counseling. The Joubert Syndrome Foundation and Related Cerebellar Disorders ( is one of the founding members of the BioBank established by the Genetic Alliance. Affected families have the opportunity to contribute to the BioBank. DNA banking can be very helpful for future research since the current sensitivity of available testing is less than 100%.

Prenatal Testing

Prenatal evaluation of pregnancies that are of increased risk for JS and JSRD can be evaluated for AHI1-, CEP290-, TMEM67-, NPHP1-, and CC2DA-related JSRD via amniocentesis or chorionic villus sampling. However, in order for this testing to be of value, the disease-causing alleles of the affected family member have to be identified.[10]

Serial ultrasounds may be useful in identifying anomalies starting at 11–12 weeks gestation. Fetal MRI has been used to diagnose some posterior fossa anomalies and the classic diagnostic MTS.[18]


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