Download A Turkish Adulthood Joubert Syndrome and Review of the Literature

A Turkish Adulthood Joubert
Syndrome and Review of the
Literature
Mehmet Noyan Zenger1,5, Serdar Kabatas2,4, Ali Fuat Baykiz3, Yang D. Teng4
Departments of 1Radiology,
2
Neurosurgery, and 3Psychiatry, Elazig
Military Hospital, Elazig, Turkey
4
Department of Neurosurgery,
Brigham and Women’s Hospital,
Harvard Medical School, Boston, USA
5
Department of Radiology, Ozel Nakiboglu Hastanesi, Konya, Turkey
Eur J Gen Med 2009;6(2):119-122
ABSTRACT
Joubert Syndrome (JS) in adult population is extremely rare. Here,
we describe the first adult case seen in the Republic of Turkey.
Our patient, a 19-year-old male, was diagnosed primarily by magnetic resonance imaging (MRI) finding of the typical “molar tooth
sign”, in addition to JS clinical features such as mental retardation, hypotonia, dysarthria, nystagmus and ataxia. Detailed images
of high resolution MRI, a review of the literature and a brief
discussion are reported.
Keywords: Adult, Joubert Syndrome, MRI.
INTRODUCTION
Correspondence: Mehmet Noyan
Zenger, MD
Department of Radiology, Ozel Nakiboglu Hastanesi, Ahmetdede Mah.
Nuraniye Sok. No:3 42030 Konya,
Turkey, Tel.: +903323537200 (121);
fax: +903323537497
E-mail: [email protected]
Disclaimer
The authors have no financial interest in the subject presented in this
paper.
European Journal of General Medicine
Joubert Syndrome (JS) is a rare neurological disorder with agenesis or hypoplasia of the cerebellar vermis and a distorted brain
stem. Primary clinical features include hypotonia, developmental
delays, and either abnormal eye movements (i.e., nystagmus) or
an abnormal breathing pattern (1,2). Additional deformities such
as extra fingers and toes, cleft lip or palate, tongue abnormalities,
and seizures may also occur. Many patients die in infancy or childhood, but some survive into adulthood with variable cognitive and
motor impairments, depending on whether the cerebellar vermis is
entirely absent or partially developed (3). JS is mostly presented
as sporadic cases. However, there are some familial incidents which
appear to be inherited via recessive genes. Here, we discuss an
adult case which was diagnosed principally by magnetic resonance
imaging (MRI) finding of the typical “molar tooth sign”, and by
manifestation of other related clinical symptoms, including mental retardation, hypotonia, dysarthria, nystagmus and longstanding
ataxia (4). To the best of our knowledge, this is the first report on
an adult JS male individual in the Republic of Turkey.
119
A Turkish Adulthood Joubert Syndrome
CASE REPORT
A 19 years old male was admitted to our clinic with
parental complaints on his difficulties in speech, walk
and vision. His developmental history could not be
followed up entirely in detail levels. It was, therefore, difficult to verify the time-course evolvement
of the main complaint related problems. Physical examination showed right eye rhythmic oscillation into
different directions, atrophic changes in both arms
and feet, and mild hypotonia, especially in his lower
extremities. The patient, however, was not found
with discernable problems of breathing and other
congenital anomalies. Neurological examination found
rotatory nystagmus which was more definitive in the
right eye, prolongation of bilateral strabismus that
might be caused by bilateral nervus abducens paresis,
truncal ataxia (i.e., when standing under either open
or closed eye condition, his trunk gradually inclined
towards the right side), mild dysarthria, and global
hypereflexes (5). Ophtalmologic observations did not
find retinal anomalies or degeneration. In psychiatric consulting evaluation, he was deemed as lack of
appropriate awareness to surrounding environmental
changes. He was found to have a mild mental retardation that was mainly judged by his Intelligence
Quotient (IQ) level of 70. During the entire clinic
visit his communication with physicians and staff
was done with help of his father. Thus, his verbal
communication appeared largely functional to people
who are familiar with his life. His speech, however,
was consistently slow, and includes dysarthric components. The patient showed nearly normal gait but had
major difficulty in running that triggered appearance
of staggering-like gait disorder, followed shortly by
falling (4). He expressed through his father that he
was not capable to play sports that were common
for his peers. Conversely, he could perform his own
personal care activities, such as independent bathing, dressing and toileting. Due to the circumstantial
limits, we were not able to conduct any genetic
analysis for the patient and his family. The overall
clinical symptoms in addition to the main complaint
of the patient indicated that this might be a very
rare adult case of Joubert syndrome. We therefore
focused on seeking systematical neuroradiological evidence. Transverse MRI images obtained at the level
of the midbrain showed a “molar tooth sign” typical in patients with JS (Figure 1). (6). Further MRI
image analysis revealed a bat wing-shaped fourth
ventricle, vermian atrophy and a deep cerebellar
midline cleft (Figure 2). Sagittal images additionally
120
Figure 1. Transverse spin-echo T2-weighted MRI
(repetition time msec/echo time msec, 2000/80) obtained at the level of the pontomedullary junction
demonstrates elongated and thinned superior cerebellar peduncles (indicated by arrows) that result
in the molar tooth configuration, retrocerebellar cyst
and apposition of cerebellar hemispheres to each
other (black arrow).
Figure 2. Transverse spin-echo T2-weighted MRI (repetition time msec/echo time msec, 440/12) depicts
the fourth ventricle deformation (arrow).
European Journal of General Medicine
Zenger et al.
demonstrated hypoplasia of the superior cerebeller
hemisphere, hypoplastic cerebellar peduncles and the
disgenesis of the corpus callosum (Figure 3). Together
the examination outcomes supported our notion, and
the patient was diagnosed with JS. The patient was
later discharged with his father being given general
information on JB prognosis and patient support.
DISCUSSION
JS was first described by Dr. Marie Joubert in 1969.
It has been estimated to occur in approximately 1
in 100,000 individuals and associated with retinal
coloboma and dystrophy in approximately 50% of patients, and multicystic kidney disease in 30% of patients (1,2). The congenital brain malformation also
comprises abnormalities of axonal decussation affecting the corticospinal tract and superior cerebellar
peduncles. Thus, individuals with JS have motor and
behavioral disorders, including an inability to walk
due to severe clumsiness and mirror movements, and
cognitive and behavioral disturbances (7). The main
imaging findings, in all patients, are partial or complete absence of the vermis, hypoplastic cerebellar
peduncles, and the fourth ventricular deformity. The
cerebellar hemispheres are usually normal. In our
case, cerebellar hemispheres are in direct contact in
the midline due to severe hypoplasia of the vermis
Figure 3. Sagittal spin-echo T1-weighted MRI (repetition time msec/echo time msec, 440/12) revealed
hypoplasia of the superior cerebeller hemisphere,
hypoplastic cerebellar peduncle (thin arrow) and the
disgenesis of the corpus callosum (bold arrow).
European Journal of General Medicine
(Figure 1). The cerebrum is mostly not affected, although moderate lateral ventricular enlargement due
to atrophy was described in 6%–20% of JB cases, with
corpus callosum dysgenesis present in 6%–10% patients
(Figure 3). (1). The term “molar tooth” refers to the
characteristic appearance of an enlarged and horizontally directed tubular structure on each side of the
midline emerging from the midbrain. In one earlier
study, “the molar tooth sign” was identified in 85%
of patients with JS, and thus was considered pathognomonic of this disorder (6). In our case, radiological
evidence of JB is suggested by the combination of
hypoplasia of the cerebellar peduncles that results
in the molar tooth sign and severe hypoplasia of
the vermis that gives a bat-wing appearance to the
fourth ventricle and leads to a midline cleft between
the two cerebellar hemispheres (Figure 2) (1,2).
Regarding differential diagnosis, Arima and SeniorLoken syndromes with posterior fossa malformations
often add difficulties in making clinical diagnosis
of JS. Nevertheless, molar tooth sign, though to a
less degree existing in other hindbrain/midbrain syndromes, is still considered virtually diagnostic of JS.
Tectocerebellar dysplasia, rhomboencephalosynapsis,
and Dandy-Walker syndrome are additional source of
confusion, and they may also accompany JS (8). But
in Dandy-Walker syndrome, a large cystic abnormality
of the posterior fossa is seen and is often accompanied by posterior fossa enlargement. In rhombonencephalosysnapsis, unlike in JS, a midline cerebellar
cleft is not present because of the cerebellar hemispheres fusion (2).
Inheritance of this disease is said to be autosomal
recessive. Studies have shown that it is a genetically heterogenous disorder with one locus pointing to
chromosome 9q (9). More recently, Walsh and Gleeson
labs studying families from Middle East identified mutations in AHI1 gene that caused the disease in these
families (9,10). In JS patients with progressive kidney
disease, mutation of NPHP1 gene was determined.
There is a generally held perception that the genetic
foundation of JS may eventually be determined to
be equally as varied and heterogeneous as the clinical presentations (10,11). Thus, Saraiva and Baraitser
defined diagnostic criteria (vermian hypoplasia, hypotonia, developmental delay, and either eye movement
or respiratory abnormalities) are still highly valuable
for diagnosing JS. In regions that lack genetic tests
accessibility, neuroradiology exams should be used to
assist final diagnosis (1,5,10).
121
A Turkish Adulthood Joubert Syndrome
In the absence of general biochemical or genetic
markers and animal models for the JS, currently little
can be known in terms of the pathogenic mechanisms. Hence, there is no specific treatment for JS.
Prognosis differs from age and associated anomalies,
but is generally very poor due to the severe mental retardation in most cases. The main causes of
death are severe feeding difficulties and respiratory
infections with associated anomalies such as cranial
meningocele (12). Respiratory abnormalities typically
improve with age advancing, but cognitive and motor function typically decline (3). Treatment for JS is
therefore symptomatic and supportive. Infant stimulation, physical, occupational and speech therapy may
have beneficial effects (13).
In conclusion, in addition to prenatal and child JB
cases that were reported previously (14), we have
now presented the first adult case of JS in the
Republic of Turkey. Given the region novelty and age
rareness of our patient, follow-up genetic investigations are highly desirable to determine if this is a
case of AHI1 mutation, or perhaps a different genotype that has not been identified in Middle Eastern
families. Such studies may reveal new genes that are
linked with this developmental disorder.
Acknowledgments
We thank Dr. Dou Yu (the Spinal Cord Injury & Neural
Stem Cell Biology Laboratory, BWH/HMS) for his generous help with preparation of the figures.
REFERENCES
1. Peter McGraw. The Molar Tooth Sign. Radiology 2003;
229:671-2.
4. Gunzler SA, Jon Stoessl A, Egan RA, et al. Joubert
syndrome surviving to adulthood associated with a progressive movement disorder. Movement Disorders 2007;
22:262-4.
5. Saraiva JM, Baraitser M. Joubert syndrome: A review.
Am J Med Genet 1992;43:726-31.
6. Maria BL, Quisling RG, Rosainz LC, et al. Molar tooth
sign in Joubert syndrome: clinical, radiologic, and
pathologic significance. J Child Neurol 1999;14:368-76.
7. Ferland RJ, Eyaid W, Collura RV, et al. Abnormal cerebellar development and axonal decussation due to
mutations in AHI1 in Joubert syndrome. Nat Genet
2004;36:1008-13.
8. Maria BL, Boltshauser E, Palmer SC, Tran TX. Clinical
features and revised diagnostic criteria in Joubert syndrome. J Clin Neurol 1999;14:583–90.
9. Chance PF, Cavalier L, Satran D, et al. Clinical nosologic and genetic aspects of Joubert and related
syndromes. J Child Neurol 1999;14:660–6.
10. National Institute of Neurologic Disorders and Stroke
(NINDS). Researchers Identify Joubert Syndrome Genes.
National Institutes of Health; 2005. p. 1-2. (Website:
http://www. ninds. nih. gov/news_and_events/news_
article news_article_Joubert_genes. htm)
11. National Institute of Neurologic Disorders and Stroke
(NINDS). Future Research Directions in Joubert
Syndrome. National Institutes of Health; 2002. p. 1-11.
(Website: http//www. ninds .nih gov/news_and_events/
proceedings/joubert_syndrome_2002. htm)
12. Suzuki T, Hakozaki M, Kubo N, et al. A Case of cranial
meningocele associated with Joubert Syndrome. Child’s
Nerv Syst 1996;12:280-2.
13. Spinella GM. Research directions. Follow up of the
Joubert syndrome. J Child Neurol 1999;14:667-72.
14. Kumandas S, Akcakus M, Coskun A, Gumus H. Joubert
syndrome: Review and report of seven new cases. Eur
J Neurol 2004;11:505-10.
2. van Beek EJ, Majoie CBL. Case 25: Joubert syndrome.
Radiology 2000;216:379-82.
3. Steinlin M, Schmid M, Landau K, Boltshauser E. Followup in children with Joubert syndrome. Neuropediatrics
1997;28:204-11.
122
European Journal of General Medicine