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1999-12-17-11 Joubert syndrome © Jeanty www.thefetus.net/
Joubert Syndrome

Philippe Jeanty, MD, PhD, Nashville, TN and Gianluigi Pilu, MD. Bologna, Italy

Definition

Marie Joubert described the syndrome in 1968 [18] -69 [19] . It is a rare developmental defect of the cerebellar vermis, with autosomal recessive inheritance. The phenotype is highly variable and may include episodic hyperpnea, abnormal eye movements, hypotonia, ataxia, developmental delay, and mental retardation 

Etiology

Unknown.

Prenatal diagnosis

The first ultrasonic diagnosis was made by Campbell in 1984 [20] . The following findings have been found in fetus with Joubert syndrome [21] , [22] :

  1. vermian agenesis
  2. abnormal cerebellar shape
  3. hydrocephalus
  4. renal anomalies
  5. nuchal lucency [23]

Interestingly there is another report of a fetus in which the vermis was considered abnormal, had a normal postnatal examination and the diagnosis was only made later22 .

These are 9 images from 2 midtrimester exams (3 weeks apart) on a little baby boy. The spine was normal. The fetus was then referred elsewhere where he was considered normal. A CT at birth was also read as normal.

Findings

The images demonstrated a small degree of ventriculomegaly and an abnormal posterior fossa. The first six images do not demonstrate the vermis. Instead there is a great big cleft in between lateral lobes of the cerebellum. 

  

  

 

 Image 7 demonstrates a small amount of ventriculomegaly but also notice the appearance of the cerebellum: the "buttock sign" 

 

 

            3. Picture 8: mild ventriculomegaly

            4. Picture 9 shows  the cavum of the septi pellucidi, thus excluding dysgenesis of the corpus callosum.

A CT done after birth was read as normal. However, when the child was one year old, a geneticist put together the clinical findings of this baby and obtained a MRI:

 

 

Several axial views that demonstrate the absence of the vermis and the “molar tooth” sign (see below)

 

 

Coronal views with absence of the vermis and demonstration of the corpus callosum

 

 

Sagittal views with absence of the vermis and demonstration of the corpus callosum

Diagnosis

The diagnosis is based on the clinical findings and supported by the pathognomonic “molar tooth” sign on MRI.

MRI findings:

The recently described “molar tooth” sign on axial sections results from a combination of midbrain, vermian, and superior cerebellar peduncle abnormalities [24] . Other findings include [25] , [26] :

  1. thinned optic tracts,
  2. enlarged temporal horns in the absence of hydrocephalus,
  3. high-signal of the cerebral periventricular white matter,
  4. abnormal signal in the decussation of the superior cerebellar peduncles,
  5. abnormal embryonic vessels associated with the dysplastic folia of the cerebellar hemispheres
  6. dilatation of the fourth ventricle with some appearing bat-wing shaped,
  7. elongation and stretching of the superior cerebellar peduncles,
  8. dysplasia of the vermis,
  9. widening of the foramen of Magendie and the posterior cistern

On postnatal diagnosis the following findings can be recognized [27] :

  1. molar tooth sign
  2. dysgenesis of the isthmic portion of the brain stem at the pontomesencephalic junction,
  3. abnormally thick superior cerebellar peduncles perpendicular to the brain stem,
  4. hypoplasia of the cerebellar vermis with enlargement of the 4th ventricle and rostral shift of the fastigium,
  5. sagittal vermis clefting
  6. mild prominence of the ventricles and subarachnoid spaces

Not all findings are present in all babies

Clinical findings:

Include:

  1. hypotonia
  2. truncal ataxia
  3. developmental delay
  4. tachy/hyperpnea/apnea
  5. abnormal eye movements
  6. tongue protrusion  

And less commonly [28] :

  1. seizures
  2. hemifacial spasms
  3. polydactyly 8%
  4. colobomas 4%
  5. renal cysts 2%
  6. soft tissue tumors of the tongue2%
  7. occipital meningocele [29]

Phenotypes

Siblings from the same family and even monozygotic twins [30] with Joubert syndrome may present with phenotypes ranging from severely handicapped to minimally handicapped. The motor handicap varies from wheelchair bound to being able to walk and run and the mental handicap from severely retarded, nonverbal, and autistic to verbal.

Genetics

A recent report (this week) suggests that the anomaly is genetically heterogeneous and that one locus maps to the telomeric region of chromosome 9q, close to the marker D9S158, with a multipoint LOD score of Z=+3.7 [31] .

Associated anomalies

The following cculomotor anomalies have been described [32] :

  1. decreased smooth pursuit gain
  1. hypometric volitional saccades
  2. optic nerve dysplasia
  3. severe visual loss
  4. oculomotor apraxia
  5. pendular nystagmus
  6. gaze-holding nystagmus
  7. pigmentary changes in the fundus
  8. decreased vestibulo-ocular reflexes

Cognitive functions:

A variety of deficits in cognition, verbal memory, visuomotor, motor, and language-related tasks are described as well as problems in temperament, hyperactivity, aggressiveness, and dependency [33] . The degree of developmental delay (DG: 30-85)41 in Joubert syndrome and the severity of gross central nervous system malformations appear independent [34] . In one case there was no mental retardation [35] and in another marked improvement appeared after some delay [36] .

Other anomalies like ectodermal dysplasia [37] , Gaucher disease [38] , multicystic kidney disease, hepatic fibrosis [39] , hypertension [40] have also been associated.

Prognosis

A decreased life span has been found in many patients [41]

Autopsy findings

The following anomalies have been reported [42] , [43] :

  1. aplasia or agenesis of the cerebellar vermis
  1. fragmentation several brainstem nuclei (dentate nuclei, inferior olives, and basis pontis)
  2. dysplasia of structures at the pontomesencephalic junction and caudal medulla
  3. abnormal decussation of the superior cerebellar peduncles
  4. enlarged iter (rostral 4th ventricle)
  5. elongated tegmental nuclei (including the locus coeruleus)
  6. reduction of the neurons of the basis pontis and reticular formation
  7.  malformations of the medulla (hypoplasia of the inferior olivary nuclei, solitary nuclei and tracts, and the nucleus and spinal tracts of trigeminal nerve (cranial nerve V).
  8. dysplasia of the caudal medulla at the cervicomedullary junction (absence of a posterior median sulcus, neuronal swelling and axonal spheroids in the region of malformed nuclei gracilis and cuneatus, and absence of pyramidal decussation)

Thus aside from vermal agenesis, Joubert syndrome may be associated with malformation of multiple brainstem structures. This could explain the hyperpnea and oculomotor anomalies.

Differential diagnosis

Vermian cleft without Joubert [44] , Dandy-Walker, Dandy-Walker variant, Down’s syndrome [45]

Social support

There is a support group in the department of Marie Joubert and she can be contacted at : mida@musica.mcgill.ca . Other resource include the Joubert Syndrome Resource and Joubert Syndrome at the National Institute of Neurological Disorders and Stroke Kris, the mom of this baby just started another list at joubertsyndrome@onelist.com .

In view of the few cases diagnosed there is not much support for parents of affected kids. It has been shown that the “parental burden depends more on the parents" coping skills and the level of family functioning rather than on the degree of the child"s impairment” [46] .

References

[18] Joubert M, Eisenring JJ, Andermann F Familial dysgenesis of the vermis: a syndrome of hyperventilation, abnormal eye movements and retardation. Neurology 1968 Mar;18(3):302-3

[19] Joubert M, Eisenring JJ, Robb JP, Andermann F Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 1969 Sep;19(9):813-25

[20] Campbell S, Tsannatos C, Pearce JM The prenatal diagnosis of Joubert"s syndrome of familial agenesis of the cerebellar vermis. Prenat Diagn 1984 Sep-Oct;4(5):391-5

[21] Anderson JS, Gorey MT, Pasternak JF, Trommer BL Joubert"s syndrome and prenatal hydrocephalus. Pediatr Neurol 1999 May;20(5):403-5

[22] Ni Scanaill S, Crowley P, Hogan M, Stuart B Abnormal prenatal sonographic findings in the posterior cranial fossa: a case of Joubert"s syndrome. Ultrasound Obstet Gynecol 1999 Jan;13(1):71-4

[23] Reynders CS, Pauker SP, Benacerraf BR First trimester isolated fetal nuchal lucency: significance and outcome. J Ultrasound Med 1997 Feb;16(2):101-5

[24] Maria BL, Hoang KB, Tusa RJ, Mancuso AA, Hamed LM, Quisling RG, Hove MT, Fennell EB, Booth-Jones M, Ringdahl DM, Yachnis AT, Creel G, Frerking B "Joubert syndrome" revisited: key ocular motor signs with magnetic resonance imaging correlation. J Child Neurol 1997 Oct;12(7):423-30

[25] Sener RN MR imaging of Joubert"s syndrome. Comput Med Imaging Graph 1995 Nov-Dec;19(6):481-6

[26] Shen WC, Shian WJ, Chen CC, Chi CS, Lee SK, Lee KR MRI of Joubert"s syndrome. Eur J Radiol 1994 Feb;18(1):30-3

[27] Quisling RG, Barkovich AJ, Maria BL Magnetic resonance imaging features and classification of central nervous system malformations in Joubert syndrome. J Child Neurol 1999 Oct;14(10):628-35

[28] Pellegrino JE, Lensch MW, Muenke M, Chance PF Clinical and molecular analysis in Joubert syndrome. Am J Med Genet 1997 Oct 3;72(1):59-62

[29] Suzuki T, Hakozaki M, Kubo N, Kuroda K, Ogawa A A case of cranial meningocele associated with Joubert syndrome. Childs Nerv Syst 1996 May;12(5):280-2

[30] Raynes HR, Shanske A, Goldberg S, Burde R, Rapin I Joubert syndrome: monozygotic twins with discordant phenotypes. J Child Neurol 1999 Oct;14(10):649-54

[31] Saar K, Al-Gazali L, Sztriha L, Rueschendorf F, Nur-E-Kamal M, Reis A, Bayoumi R Homozygosity Mapping in Families with Joubert Syndrome Identifies a Locus on Chromosome 9q34.3 and Evidence for Genetic Heterogeneity. Am J Hum Genet 1999 Dec;65(6):1666-1671

[32] Tusa RJ, Hove MT Ocular and oculomotor signs in Joubert syndrome. J Child Neurol 1999 Oct;14(10):621-7

[33] Fennell EB, Gitten JC, Dede DE, Maria BL Cognition, behavior, and development in Joubert syndrome. J Child Neurol 1999 Sep;14(9):592-6

[34] Gitten J, Dede D, Fennell E, Quisling R, Maria BL Neurobehavioral development in Joubert syndrome. J Child Neurol 1998 Aug;13(8):391-7

[35] Vaquerizo Madrid J, Galan Gomez E, Hernandez Rastrollo R, Cardesa Garcia JJ Joubert syndrome without mental retardation. An Esp Pediatr 1991 Apr;34(4):329-30

[36] Ziegler AL, Deonna T, Calame A Hidden intelligence of a multiply handicapped child with Joubert syndrome. Dev Med Child Neurol 1990 Mar;32(3):261-6   

[37] Nuri Sener R A patient with ectodermal dysplasia, Joubert"s syndrome, and brain cysts. Comput Med Imaging Graph 1998 Jul-Aug;22(4):349-51

[38] van Royen-Kerkhof A, Poll-The BT, Kleijer WJ, van Diggelen OP, Aerts JM, Hopwood JJ, Beemer FA Coexistence of Gaucher disease type 1 and Joubert syndrome. J Med Genet 1998 Nov;35(11):965-6

[39] Silverstein DM, Zacharowicz L, Edelman M, Lee SC, Greifer I, Rapin I Joubert syndrome associated with multicystic kidney disease and hepatic fibrosis. Pediatr Nephrol 1997 Dec;11(6):746-9

[40] Gonzalez Echeverria FJ, Garcia Blanco A, Carbayo Tardaguila L, Sanchez Garcia M, Pricto Figuero A, Cimadevilla Sanchez C, Gomez Cabrera G, Yague Sanz L Joubert"s syndrome in a girl with hypertensive crisis. An Esp Pediatr 1993 Nov;39(5):455-6

[41] Steinlin M, Schmid M, Landau K, Boltshauser E Follow-up in children with Joubert syndrome. Neuropediatrics 1997 Aug;28(4):204-11

[42] Yachnis AT, Rorke LB Neuropathology of Joubert syndrome. J Child Neurol 1999 Oct;14(10):655-9; discussion 669-72

[43] Yachnis AT, Rorke LB Cerebellar and brainstem development: an overview in relation to Joubert syndrome. J Child Neurol 1999 Sep;14(9):570-3

[44] Sener RN Cerebellar vermian clefts disconnecting the hemispheres: a different entity unassociated with Joubert"s syndrome. Comput Med Imaging Graph 1997 Jan-Feb;21(1):71-5

[45] Keogan MT, DeAtkine AB, Hertzberg BS Cerebellar vermian defects: antenatal sonographic appearance and clinical significance. J Ultrasound Med 1994 Aug;13(8):607-11

[46] Luescher JL, Dede DE, Gitten JC, Fennell E, Maria BL Parental burden, coping, and family functioning in primary caregivers of children with Joubert syndrome. J Child Neurol 1999 Oct;14(10):642-8

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