Dokkyo Journal of Medical Sciences
39（2）：119〜122，2012

119

Case Report

Clinically Mild form of Joubert Syndrome-related Disorderin a 7-year-old Female：A case report
George Imataka, Yoshiyuki Watabe, Osamu Arisaka
Department of Pediatrics, Dokkyo Medical University School of Medicine

SUMMARY
Joubert syndrome-related disorders（JSRD）is a very rare syndrome observed with agenesis of the vermis, episodic hyperpnea, abnormal eye movements, and cerebellar ataxia and mental retardation. There
have been many reports on the image-based diagnosis using MRI/CT, but not many clinical reports on theintelligence of subjects with JSRD. We herein report a clinically mild form of JSRD in a 7-year-old female.
The patient did not have any clinical abnormalities in the neonatal period.
She initially visited the neurology outpatient department at 6 months of age because her neck was still
unstable. A brain MRI was conducted to assess symptoms of abnormal eye movements and body trunk cerebellar ataxia, and she was diagnosed with JSRD based on the observation of agenesis of the vermis andcharacteristic molar tooth signs. Regarding her motor development, she was able to hold her head up at 7months of age, and was able to sit up at 1 year and 2 months old. She underwent rehabilitation, and a widebase cerebellar gait was observed when she was 5 years old. In addition, at 5 years of age, she could intermittently speak two-word sentences, draw pictures with an understanding of color, and was able to engage
in actions such as throwing a ball. At 6 years of age, her conversation became better. She entered elementary school at 7 years of age, was able to go up and down stairs, read words, do single-digit addition, andwrite many Chinese characters with a pencil. The intellectual dysfunction of subjects with JSRD is generally
moderate to severe. Thus, this case was diagnosed to be a clinically mild form of JSRD, because the patient
exhibited limited effects on her intelligence.
Key Words：cerebellar hypoplasia, molar tooth malformation, Jouber syndrome-related disorders

INTRODUCTION

superior cerebellar peduncle）. In clinical terms, abnormal breathing with repeated tachypnea and apnea areIn 1969, Joubert reported five cases where the pa-

generally exhibited from the neonatal period, and ocu-

tients had episodic hyperpnea, abnormal eye move-lar motor apraxia, ataxia, mental retardation, as well as1）

ments, ataxia, and mental retardation . Patients withautism were observed as the patients aged 2〜4）. A few

Joubert syndrome have characteristic imaging findings

causative genes have been identified, for example,

with impairment/hypoplasia of the cerebellar vermis

AHI 1（ Jouberin）, NPHP 1（ nephrocystin）, NPHP 6 ,and molar tooth signs（ the mid pons transition looks

CEP290, and TMEM67（MSK3）,the hereditary form

like molars on horizontal MRI/CT slicing due to theof which is due to autosomal recessive inheritance, andthese were classified as Joubert syndrome-related dis-Received March 7, 2012；accepted May 24, 2012
Reprint requests to：George Imataka MD, PhD
880 Kitakobayashi, Mibu, Shimotsuga, Tochigi
321-0293 Japanorder（JSRD）nosologically 5〜7）. The impairment of theintellectual development of patients with JSRD is generally moderate to severe. We herein report the clinical course of a clinically mild case with JSRD.

120George ImatakaFigure 1DJMS

A drawing made by the patient at 5 years of age. The
mother is drawn on the left side, while the doctor is drawn
on the right side.

CASE REPORT

such as“mom,”“dad,”etc., at 2 years of age. Rehabilitation was conducted, and actions such as throwing aA female infant weighing 3,790 g and that was 50.5

ball were possible from a walker at 2 years old, andcm in height at 4 0 weeks 4 days gestation was bornwith an ankle-foot orthosis at 5 years old, which wereby natural delivery. The mother was multiparous. She

accompanied by the observation of a wide base cere-

has no family history of any diseases. There were nobellar gait and cerebellar ataxia. This patient intermit-

external malformations such as polydactyly, etc. Photo-tently spoke two-word sentences and drew pictures

therapy was conducted 5 days after birth for neonatal（ Figure 1）. A molar tooth sign was observed upon

jaundice. The results of health examinations at 1 and 3

brain CT（Figure 2A/2B）. The patient’s conversation

months were normal, and the infant’s weight increase

became smooth at 6 years old. She was able to enter

was also good. However, neck instability was observed

elementary school at 7 years old, was able to go up

at 5 months after birth. A brain MRI was conducted,and down stairs, read words, and was able to do sin-

and impairment of the cerebellar vermis, an elongatedgle-digit addition, moreover, she could write many

front superior cerebellar peduncle, and interpeduncu-Chinese characters（ Figure 3）. A tic was observed

lar cistern of the deep anterior midbrain, that is to say,when she practiced words due to psychological stress.

molar tooth signs, were observed. A diagnosis wasThis case was diagnosed as an intellectually mild form

made of JSRD-associated disease. The G-band chromo-of JSRD.

some banding was a normal karyotype. A genetic analysis was not performed. Differentiation of the associat-DISCUSSION

ed diseases is required for JSRD, and therefore, aA patient cannot be diagnosed with Joubert syn-careful examination of the entire body was conducted.

drome based on a molar tooth sign alone. There areFindings of congenital amaurosis and retinal dystrophy

other classifications of diseases observed with abnor-

were not observed. The patient’s visual evoked poten-

malities of the brain stem, cerebellum and with thetial and eye retinograms both showed normal respons-molar tooth sign that need to be included in the differ-

es. There were no abnormalities in the patient’s mouth.

ential diagnosis 8〜1 3）. These include Arima syndrome

Facial blepharoptosis was not noted. With regard to（Dekaban-Arima syndrome）, Senior-Loken syndrome,

subsequent motor development, the neck became sta-COACH syndrome（cerebellar vermis hypoplasia/apla-ble at 7 months from birth, and the infant was able tosia, oligophrenia, congenital nonprogressive ataxia,

sit at 1 year and 2 months old. The infant spoke words

coloboma, hepatic fibrosis）, Varadi-Papp Syndrome39（2）（2012）

Figure 2 A/B

Clinically mild form of JSRD in a 7-year-old female

121

A Brain CT scan performed at 5 years of age. An axial image at the level of the midbrainshows the enlarged superior cerebellar peduncles and the absence of the vermis. This has
been called the“molar tooth sign.”

Figure 3

At 7 years of her age, the patient was able to write many
Chinese characters using a pencil.

（ orofaciodigital syndrome type IV）, etc. As indicated

JSRD is moderate to severe. Thus, our patient was di-in Table 1, other complications were ruled out in thisagnosed with an intellectually mild form of JSRD.

case, and a clinical diagnosis of JSRD was made. In thisThere have been many reports on causative genes,

case, the patient was able to speak, and she was able

such as AHI 1（ Jouberin）, NPHP 1（ nephrocystin）,

to walk up and down stairs, although she had a wide

NPHP6, CEP290, TMEM67（MSK3）and/or MRI/

base cerebellar gait. Because of her progress and abili-

CT results and reports on the ways to differentiate

ties, the patient was diagnosed with a relatively mild

similar symptoms and complications regarding JSRD；

case of JSRD. The patient could also not only perform

however, there are not many reports regarding the in-simple addition and draw pictures, but after she en-tellectual clinical manifestations associated with JSRD.

tered elementary school at 7 years of age, could read

Therefore, reports on relatively intellectually mild cas-words, and was able to write many Chinese characters.

es of JSRD, such as this report, are clinically very im-

Generally, the intellectual dysfunction of subjects withportant. This case was concluded to be due to auto-

George Imataka

122
Table 1

DJMS

Joubert syndrome related disorders associated with the molar tooth molformation
Joubert

ArimaSenior-Loken

COACH

Varadi-Papp

syndrome

syndrome

syndrome

syndrome

syndrome−−−−＋−＋/−＋＋−−＋−−＋−−＋−−

retinopathy
tumor of the togune
hepatic fibrosis
nephronophthisis

somal recessive inheritance, and genetic counselingmutations in meckelin （ MKS 3 /TMEM 6 7） cause

regarding their next child is planned for the family. Innephronophthisis with liver fibrosis（NPHP11）.J Med

the long term, a case in which renal insufficiency ad-Genet 46：663-670, 2009.

vanced after the age of 20 was reported in congenital7）Tory K, Lacoste T, Burglen L, et al：High NPHP 1

ocular motor apraxia exhibiting similar findings asand NPHP 6 mutation rate in patients with Joubert

JSRD1 4）

. Therefore, periodic examinations of the kid-

neys will be performed in the future.

syndrome and nephronophthisis：potential epistatic
effect of NPHP6 and AHI1 mutations in patients withNPHP1 mutations. J Am Soc Nephrol 18：1566-1575,

Acknowledgement

We would like to thank Profes-2007.

sor Ohno Kousaku（ Department of Child Neurology,8）Sattar S, Gleeson JG：The ciliopathies in neuronal de-Institute of Neurological Sciences）, and Professor

velopment：a clinical approach to investigation ofHideo Yamanouchi（Department of Pediatrics, Saitama

Joubert syndrome and Joubert syndrome-related dis-Medical University）, who gave us valuable suggestions

orders. Dev Med Child Neirol 53：793-798, 2011.

regarding the clinical diagnosis of this case.
REFERENCES
1）Joubert M, Eisenring JJ, Robb JP, Andermann F：Fa-9）Kumada S, Hayashi M, Arima K, et al：Retinal disease in Arima syndrome is nephronopathisis as inother Joubert-related Cerebello-oculo-retinal syndromes. Am J Med Genet A 131：71-76, 2004.

milial agenesis of the cerebellar vermis. A syndrome10）Stone EM, Cideciyan AV, Aleman TS, et al：Varia-of episodic hyperpnea, abnormal eye movements,

tions in NPHP 5 in patients with nonsyndromic leberataxia, and mental retardation. Neurology 1 9：8 1 3 -congenital amaurosis and Senir-Loken syndrome.

825, 1969.

Arch Opththalmol 129：81-87, 2011.

2）King MD, Dudgeon J, Stephenson JBP：Joubert’s syn-11）Weiland MD, Nowicki MJ, Jones JK, Giles HW：drome with retinal dysplasia：neonatal tachypnea as

COACH syndrome：an unusual cause of neonatal

the clue to a genetic brain-eye malformation. Archcholestasis. J Pediatr 158：858-858.e.1, 2011.

Dis Child 59：709-718, 1984.

12）Chodirker BN, Shah NS, Bunge MK, Reed MH：An-3）Kendall B, Kingsley D, Lambert SR, Taylor D, Finn P：

other case of Varadi-Papp Syndrome with molar

Joubert syndrome：a clinical-radiological study. Neu-tooth sign. Am J Med Genet A 136A：416-417, 2005.

roradiology 31：502-506, 1990.

13）Stephan MJ, Brooks KL, Moore DC, et al：Hypotha-4）Boltshauser E, Herdon M, Dumermuth G, Isler W：

lamic hamartoma in oral-facial-digital syndrome type

Joubert syndrome：clinical and polygraphic observa-Ⅳ（Varadi syndroe）. Am J Med Genet 51：131-136,

tions in a further case. Neuropediatrics 12：181-191,1994.

1981.

14）Kondo A, Saito Y, Floricel F, Maegaki Y, Ohno K：

5）Valente EM, Brancati F, Silhavy JL, et al：AHI1 gene

Congenital ocular motor apraxia：clinical and neuro-mutations cause specific forms of Joubert syndrome

radiological findings, and long-term intellectual prog-related disorders. Ann Neurol 59：527-534, 2006.

nosis. Brain Dev 29：431-438, 2007.

6）Otto EA, Tory K, Attanasio M, et al：Hypomorphic