Joubert Syndrome and Related Disorders: Implications for Nurse Practitioners

Joubert Syndrome and Related Disorders: Implications for Nurse Practitioners Laurie Anne Ferguson, FNP-C, and Maritza Salgado, FNP-BC ABSTRACT Joubert syndrome (JS) and related disorders (JSRD) are rare autosomal recessive disorders typified by a distinctive cerebellar and brainstem malformation. The diagnosis of JSRD requires the neuroradiological “molar tooth sign” found on magnetic resonance imaging. Many children affected with the disorder die in infancy before diagnosis. Rare diseases or syndromes can pose unique challenges for primary care providers who participate in the day-to-day care of chronically ill and physically and mentally challenged children. This article discusses JS and JSRD to provide insight for primary care providers caring for these special children and adults. Keywords: developmental delay, genetic disorder, Joubert syndrome, Joubert syndrome related disorders, molar tooth sign © 2012 American College of Nurse Practitioners

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urse practitioners play an essential role in health promotion, disease prevention, and identification of risk factors for various conditions. Experience and expertise contribute to practitioners’ ability to successfully diagnose and treat patients with both common and rare conditions. Unfortunately, many primary care providers (PCPs) may not have sufficient exposure or knowledge of genetics.1 A growing body of evidence demonstrates the contribution of genetic risk factors to many common disorders that are managed in primary care settings, such as cardiovascular disease, diabetes, renal disease, and cancer.2 One in 10 patients seen in the primary care setting may have a disorder with a genetic component. With advances in genetics, PCPs need to become more familiar with genetic conditions for referral, diagnosis, and counseling.3 Genetic disorders often encountered in primary care include familial hyperlipidemia, Down syndrome, cystic fibrosis, and sickle cell disease; 316

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however, rare genetic disorders may also present to the PCP. Joubert Syndrome (JS) and Related Disorders (JSRD) is an example of a rare genetic disorder. PCPs play an important role in early identification, referral, and care coordination for individuals with physical and mental challenges, as well as chronic illness. Psychosocial support is critical to ensure optimal outcomes. This article discusses genetics and the challenges faced by families in the context of this rare genetic disorder. GENETIC OVERVIEW A key factor to early identification of genetic disorders is for PCPs to have a working knowledge of inheritance patterns. Mendelian modes of inheritance include autosomal dominant, autosomal recessive, and X-linked inheritance. Autosomal dominant is a pattern in which an affected individual has 1 copy of a mutant gene and 1 normal gene on a pair of autosomal chromosomes. Individuals with autosomal dominant diseases have a Volume 8, Issue 4, April 2012

Figure 1. Molar Tooth Sign Used with permission from Michael V. Huppman Medpix®.

50:50 chance of passing the mutant gene and, therefore, the disorder to their children.4 Autosomal recessive inheritance requires 2 mutant genes for the disease to occur. The affected individual is said to be homozygous and is usually the offspring of 2 heterozygous parents. Autosomal recessive diseases are rare and often occur in the context of parental consanguinity. X-linked inheritance refers to disorders that are caused by genes on the X sex chromosome. The Y chromosome contains only a few dozen genes; therefore, most sex-linked traits are located on the X chromosome and are said to be X-linked. Because of the presence of 1 X chromosome in males (versus 2 X chromosomes in females), males are said to be hemizygous and are more likely to inherit mutant genes carried on the X chromosome and develop the mutant phenotype. A female with 2 X chromosomes may be either heterozygous or homozygous for the mutant gene.4 GENOTYPE AND PHENOTYPE ASSOCIATIONS Two classic methods are used in the study of genetics and inheritance. The first is linkage analysis and is family based, which includes the review of family pedigrees to study disease patterns. Linkage analysis screens the entire genome and aims to discover the location of the causative gene(s). The assumption is made that family members with the disease phenotype have the affected allele or genotype. www.npjournal.org

The other approach is association analysis, which is population based.5 Since JSRD is so rare, the populationbased approach is challenging in terms of finding the causative genes associated with the syndrome. The population-based approach focuses on examining the frequency of a specific allele or genotype in patients versus those in controls. In other words, the purpose of association analysis is to determine the causative gene.6 The classic radiographic findings of absent or severely underdeveloped cerebellar vermis with its classic “molar tooth sign” (MTS), along with the typical neurologic signs of hypotonia, ataxia, and developmental delay, are used to diagnose patients with JSRD. Genetic causality has been less clear because of genetic overlap in clinical symptoms and syndromes. The first JSRD locus on chromosome 9q was identified as recently as 1999. All the current genes associated with JSRD encode for proteins, which are expressed in the primary cilium or the centrosome. Primary cilia are structures found in several tissues, including renal tubules, bile ducts, retinal photoreceptors, and neuronal cells in both the fetal and adult brain. Cilia act like sensors and are involved in both the development and accurate function of such organs as kidneys, brains, eyes, and liver. Ciliopathies or abnormalities in the cilia may explain why there is an overlap between JSRD and other genetic disorders with common gene expressions and is an emerging field of genetic research.7 While there has been remarkable progress in explaining the genetic basis of JSRD and identifying genes, it appears that all these genes explain for only 25% of JSRD families.7 No curative genetic therapies exist for these ciliopathic syndromes.8 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 underThe Journal for Nurse Practitioners - JNP

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reported.10,11 Research into rare genetic conditions is continuing to evolve, and its implications for practice are evolving as well.

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 Løken History syndrome, Varadi-Papp syndrome, nephronophthisis and JS was first identified in 1969 by French neurologist Marie Cogan oculomotor apraxia syndrome, and Bardet-Biedi Joubert, who described 4 siblings with hyperpnea, abnormal syndrome. Hypoplastic cerebellar vermis is associated eye movements, ataxia, mental retardation, and absent cerewith Dandy-Walker malformation, X-linked cerebellar bellar vermis. A founder effect or the loss of genetic variahypoplasia, ataxia and oculomotor apraxia type 1 (AOA1, tion has been identified in the French-Canadian population. characterized by lack of muscle coordination during volThe term founder effect refers to a genetic alteration where untary movement and difficulty moving eyes), congenital subsequent generations are related to a small group of peodisorders of glycosylation, 3-C syndrome, pontocerebellar ple. The genetic pool becomes hypoplasias, oral-facial-digital much smaller. Genes that were syndromes II and III, as well as not prominent in the larger Meckel-Gruber syndrome.10 Many syndromes with group may become more promiClassic findings associated nent in a small community of with JS and JSRD are hypotonia genetic mutations share people. Founder effect is associin infancy, developmental delays similar physical ated with geographic or reliand intellectual disability, abnormanifestations. giously isolated communities, mal breathing, either hyperpnea where individuals are at higher or apnea, and/or abnormal eye movements.9,14 Hypotonia in the risk of developing diseases or neonatal period is not specific to JSRD, but when associated syndromes because there is a higher probability of recessive with irregular breathing and abnormal eye movements, the disorders. The family first described by Joubert traced their PCP should order an MRI.9 Developmental delay always linage to an immigrant from France to Quebec in the warrants further evaluation. 1600s.10-13 However, JS and JSRD are found worldwide in all individuals of all races and ethnic backgrounds. The diagnosis of JSRD is not made by the PCP, because an accurate diagnosis of JS and JSRD is difficult Pathophysiology to establish as a result of the genotypic-phenotypic variaEarly in fetal development, the human embryo comprises 3 tions of the disorders. As with any rare disorder, nonspegerm layers called the ectoderm, endoderm, and mesoderm. cific symptoms may delay recognition of varying clinical 12 These structures give rise to all body organs and tissues. findings.9 As with all clinical encounters, an initial evaluThe ectoderm subsequently develops into a neural plate, ation should include a complete health history, examinawhich leads to the neural tube and the embryonic brain. tion, and extensive family history. The family history is This primitive embryonic brain comprises the prosenconsidered an instrumental tool for diagnosis and risk cephalon, midbrain, and hindbrain. The hindbrain further assessment in medical genetics and serves as a critical eledivides into separate anatomic structures called rhomment in making appropriate, timely referrals for genetic bomeres. It is believed that these rhombomeres play a crititesting in primary care.15 When a genetic disorder is suscal role in gene expression. Rhombomeres with deep pect, the PCP should immediately refer to a genetics cerebellar nuclei further morph into Cranial Nerves V and specialist for definitive diagnosis and counseling. The X. It is believed that an error in development of these strucgenetic referral should occur in conjunction with referral tures results in an absent or underdeveloped vermis and the to appropriate specialists, such as neurology, nephrology, physical findings seen in JS.12 ophthalmology, etc, as needed for specific interventions. Diagnosis Many syndromes with genetic mutations share similar physical manifestations. Although it was originally 318

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Clinical Findings Individuals with JS and JSRD display some clinical heterogeneity and some variation as well. Central nervous system Volume 8, Issue 4, April 2012

(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 broadbased 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 www.npjournal.org

Box 1. Physical Examination Findings Associated With JSRD • Hypotonia (⫹⫹ neonatal period) • Breathing abnormalities (⫹⫹ neonatal period) • Oculomotor apraxia/other abnormal eye movements • Psychomotor delay • Ataxia (childhood) • Polydactyly • Facial dysmorphisms • Lobulated tongue, multiple oral frenula • Cleft lip/palate • Scoliosis Adapted from Bracanti et al9

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. Management 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, The Journal for Nurse Practitioners - JNP

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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 Prognosis 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 320

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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 (www.joubertsyndrome.org) 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 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS The challenges of having a special needs child are great, starting with the associated stigma. A mother of JRSD children recently related a story of flying to New York to attend an international JSRD conference in which other passengers wanted the children moved to the rear of the plane, as if the syndrome was catching. Genetic science has advanced to the stage that its power to improve or diminish the quality of life is significant. Issues surrounding testing will continually evolve as science and technology advances improve the ability to detect and treat genetic illnesses. An appropriate fear of the misuse of genetic information serves to provide caution as society boldly embraces new technologies. As science continues to increase our ability to identify and treat genetic illnesses, we must remain ever vigilant in protecting individual rights and freedoms. The controversy surrounding genetic risk disclosure will be debated Volume 8, Issue 4, April 2012

Box 2. Diagnosis and Management of JSRD Brain MRI (molar tooth sign) Central Nervous System & Development • In neonates and infants, prevent respiratory and feeding problems related to breathing abnormalities and hypotonia • Perform developmental, neuropsychological, and behavioral testing and plan rehabilitation strategy • Order electroencephalogram if seizures are suspected Eye • At diagnosis, plan ophthalmologic evaluation Kidney • Children (0-16), monitor renal function, urinary specific gravity, and renal ultrasound every 2 years • Adults, check renal function, renal function, urinary specific gravity, and renal ultrasound at diagnosis • Refer to nephrologist as appropriate Liver • Children (0-16), liver function and hepatic ultrasound every 2 years • Adults, check liver function and hepatic ultrasound at diagnosis • Refer to hepatologist as appropriate Miscellaneous • Check once for congenital heart defects, situs inversus, and Hirschsprung’s Disease Adapted from Bracanti et al9

well into the futures as society attempts to establish ethical guidelines for the implementation of genetic and technological advances. Other issues faced by parents of chronically ill children include insurance coverage and respite assistance. The physical, emotional, and psychological burdens of caring for individuals with special needs often preclude parental employment. Government-sponsored insurance programs, such as Medicaid, are often the only choice for chronically ill and special needs children and adults. Paradoxically, many specialty health care providers do not participate in Medicaid programs, further limiting access. PCPs can be very effective in recognizing psychosocial issues affecting a family, making appropriate referrals, and providing information on available resources. The 24-hour-a-day burden of physical and emotional care is very stressful for parents and caregivers. The difficulties of accessing individuals trained to assist with special needs children for respite is indeed challenging. Sadly, even when respite services are available, the lack of staff continuity further adds to the problem. Many parents and caregivers of special needs individuals become socially isolated.19 www.npjournal.org

Special needs individuals require planning for future care as they may outlive their parents and caregivers. While no individual with JS has been known to have a child, parents of JSRD children also face birth control or sterilization decisions. CONCLUSION JS and JSRD are rare conditions with a wide spectrum of clinical symptoms. A few affected individuals may not demonstrate any clinical anomalies, and the variety of outcomes may be difficult to predict. Although great progress has been made in the identification of genes responsible for JSRD, a clear genetic cause cannot be identified for most patients with the current state of the science. Affected families with JSRD need the most current and up-to-date information regarding this syndrome to make decisions regarding care. The sad reality is that, for many families experiencing the consequences of a rare syndrome, the PCP may not have sufficient understanding or knowledge to assist them. For patients who live in rural areas, the geographic barriers may make referral to university medical centers difficult, if not impossible. The Journal for Nurse Practitioners - JNP

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Box 3. Resource Organizations Joubert Syndrome Foundation and Related Cerebellar Disorders 414 Hungerford Dr, Suite 252 Rockville, MD 20850 614-864-1362 [email protected] www.jsfrcd.org Arc of the United States 1010 Wayne Ave, Suite 650 Silver Spring, MD 20910 800-433-5255 [email protected] www.thearc.org National Organization for Rare Disorders PO Box 1968 55 Kenosia Ave Danbury, CT 06813 800-999-6673 [email protected] www.rarediseases.org The implications for primary care practice are great. Providers need to stay current with the emerging technology and science of genetics and genomics and provide information and assistance through appropriate referrals and support. Electronic medical records would greatly enhance the continuity of care between specialty providers, especially where specialists whose expertise in treating rare syndromes may be separated by large geographical distances (Box 3). Technological advances have produced earlier identification of rare syndromes. As the identification of the genetic cause of disorders increases, the need for integrating genetics into primary care will also increase. Nurse practitioners, as primary care providers, can play pivotal roles in providing support and guidance for families with special needs. References 1. Hayward J. Common genetic conditions in primary care. Pulse. 2011;26:824825. 2. McCahon D, Holder R, Metcalf A, et al. General practitioners’ attitudes to assessment of genetic risk of common disorders in routine primary care. Clin Genet. 2009;76:544-551. 3. Burke S, Martyn M, Stone A, Bennett C, Thomas H, Farndon P. Developing a curriculum statement based on clinical practice: Genetics in primary care. Br J Gen Pract. 2009;59:99-103. 4. Gunder L, Martin S. Essentials of medical genetics for health professionals. Sudbury: Jones and Bartlett; 2011.

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5. Nussbaum RL, McInnes RR, Willard HF, eds. Thompson and Thompson Genetics in Medicine. 7th ed. Philadelphia: Saunders Elsevier; 2007. 6. Hodge S. Linkage analysis versus association analysis: Distinguishing between two models that explain disease marker associations. Am J Human Genet. 1993;53:367-384. 7. Valente EM, Brancati F, Dallapiccola B. Genotypes and phenotypes of joubert syndrome and related disorders. Europ J Med Genet. 2008;51:1-23. 8. Sattar S, Gleeson J. The ciliopathis in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndromerelated disorders. Developmental Med Child Neurol. 2011;53:793-798. 9. Brancati F, Dallapiccola B, Valente EM. Joubert Syndrome and related disorders. Orphanet J Rare Dis. 2010;5(20). http://www.ncbi.nlm.nih.gov/ pmc/articles/PMC2913941/. Accessed February 8, 2012. 10. Parisi M, Glass I. Joubert syndrome. Gene Reviews. http://www.ncbi.nlm.nih. gov/books/NBK1325/. Accessed February 8, 2012. 11. Choh AS, Choh NA, Bhat SA, Jehangir M. MRI findings in joubert syndrome. Indian J Ped. 2009;76:231-235. 12. Merritt L. Recognition of the clinical signs and symptoms of joubert syndrome. Adv Neonat Care. 2003;3:178-188. 13. Maria BL, Boltshauser E, Palmer SC, Tran TX. Clinical features and revised diagnostic criteria in joubert syndrome. J Child Neurol. 1999;14:583-590. 14. Khan AO, Oystreck DT, Seidahmed MZ, et al. Ophthalmic features of joubert syndrome. Ophthalmology. 2008;115:2286-2289. 15. Rich E, Burke W, Heaton CJ, Haga S, Pinsky L, Short MP, Acheson L. Reconsidering the family history in primary care. J Gen Intern Med. 2004;19:273-280. 16. Retruerto AIA, Cantor RM, Gleeson JG, et al. Association of common variants in the joubert syndrome gene (AHI1) with autism. Hum Mole Genet. 2008;17:3887-3896. 17. Emery J, Hayflick S. The challenge of integrating genetics into primary care. Br Med J. 2001;322:1027-1030. 18. Pugash D, Oh T, Godwin K, et al. Sonographic “molar tooth” sign in the diagnosis of Joubert Syndrome. Ultrasound Obstet Gynecol. 2011;38:598602. 19. Farmer JE, Deidrick KM, Kitten JC, Fennell FB, Maria BL. Parenting stress and its relationship to the behavior of children with Joubert syndrome. J Child Neurol. 2006;21:163-167.

Laurie Anne Ferguson, DNP, APRN, ANP-BC, FNP-C, CPNP, is an associate professor at Loyola University in New Orleans and practices at Varnado Family Practice in Greensburg, LA. She can be reached at [email protected]. Maritza Salgado, DNP, APRN, FNP-BC, is an assistant professor of nursing at Loyola and practices as a family nurse practitioner at a local community health clinic. In compliance with national ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest.

Acknowledgment The authors thank AT and LT’s family for insight into living with JSRD and for granting permission to share photographs. Additional information regarding Joubert Syndrome can be found at http://www.ncbi.nlm.nih.gov/books/NBK1325/. 1555-4155/12/$ see front matter © 2012 American College of Nurse Practitioners doi: 10.1016/j.nurpra.2012.01.019

Volume 8, Issue 4, April 2012