American Journal of Medical Genetics 43:726-73 1 (1992)
Joubert Syndrome: A Review Jorge M. Saraiva and Michael Baraitser Paediatric Hospital (J.M.S.), Coimbra, Portugal and Unit of Clinical Genetics and Fetal Medicine (M.B.), Institute of Child Health, London, England
We review 72 previously reported and 29 new patients with the possible diagnosis of Joubert syndrome. We define diagnostic criteria for this syndrome and present the data available in 94 patients that fulfill our criteria. We present the data regarding the clinical, neuroradiological, and ophthalmological manifestations and the prognosis of these 94 patients. We propose a classification of the patients with this diagnosis in 2 groups: those with retinal dystrophy and those without. Retinal dystrophy runs true in families and was never absent when renal cysts were reported. o 1992 Wiley-Liss, Inc.
KEY WORDS: Joubert syndrome, JoubertBoltshauser syndrome, retinal dystrophy, vermis hypoplasia INTRODUCTION The Joubert (Joubert-Boltshauser) syndrome is a well known but rare autosomal recessive condition and no prevalence estimate is available. It is a syndrome with variable phenotype: partial or complete absence of the cerebellar vermis is seen in all patients; the other cardinal findings are the episodic tachypnoea and apnoea in the neonatal period,jerky eye movements, hypotonia, severe mental handicap, ataxia, and impaired equilibrium [Baraitser, 1990; Brett, 1991; Casamassima and Pfeiffer, 1990;Harding, 1990;Winter and Baraitser, 19911. Marie Joubert (whose name is linked to the condition) and co-workers [Joubert et al., 19691provided the earliest detailed analysis of the syndrome. They described 4 sibs, 3 males and 1 female, and an isolated case, and called the condition a “familial syndrome of episodic hyperpnea, abnormal eye movements, ataxia, mental retardation, agenesis of the vermis” and absence
of cerebellar vermis observed in one case at autopsy. Cerebellar vermis hypoplasia had previously been observed at autopsy in one of 3 affected brothers [De Haene, 19551 but the clinical description was incomplete. All the original cases had vermis hypoplasia, developmental delay, episodic hyperpnoea, abnormal eye movements, and hypotonia and some had an occipital meningoencephalocele, polydactyly, tongue protrusion, hemifacial spasms, and ataxia. Later there were reports of additional manifestations: self-mutilation [Boltshauser and Isler, 19771, chorioretinal coloboma [Lindhout et al., 19801, tongue tumours [Egger et al., 19821, ptosis [Harmant-van Rijckevorsel et al., 19831, retinal dystrophy [Aicardi et al., 19831,cystic kidneys [King et al., 19841,and duodenal atresia [Lambert et al., 1989bl. Chromosomes were reported as normal. Because of the difficulty in establishing the boundaries of Joubert syndrome regarding its diagnosis, classification, and prognosis, a study was undertaken to address the following: could we define the diagnostic criteria of Joubert syndrome? Is it possible to distinguish different groups of patients with different prognoses and inheritance patterns taking into account the presence of some of the associated features? What information is available regarding the prognosis of these patients?
MATERIALS AND METHODS We included in our study all the reports from the literature either diagnosed by the authors as having Joubert syndrome or where such a diagnosis had been suggested by others. We analyzed the data described in 72 case reports: 34 isolated cases and 38 sibs in 17 families [Aicardi et al., 1983; Appleton et al., 1989; Beemer and Gooskens, 1985; Boltshauser and Isler, 1977; Boltshauser et al., 1981; Burroni et al., 1980; Calogero, 1977; Campbell et al., 1984; Casaer et al., 1985; Casamassima et al., 1987; Curatolo et al., 1980; Da Silva et al., 1984; Dekaban, 1969; Dralle and Schmidt-Sommerfeld, 1979; Egger et al., 1982; Fernandez et al., 1979; Fierro et al., 1977;Friede and Boltshauser, 1978; Gustavson et al., 1971; Hartmant-van Rijckevorsel et al., 1983; Haumont and Pelc, 1983;Houdou Received for publication June 6,1991; revision received October et al., 1986; Jourbert et al., 1969; King et al., 1984; 3, 1991. Lambert et al., 1989b;Laverda et al., 1984; Lindhout et Address reprint requests to Dr. M. Baraitser, Unit of Clinical Genetics and Fetal Medicine, Institute of Child Health, 30 Guilford al., 1980; Matsuzaka et al., 1985; Meix and Castroviejo, 1980;Menezes and Coker, 1990;Moore andTaylor, 1984; Street, London WClN lEH, England. 0 1992 Wiley-Liss, Inc.
Joubert Syndrome Pfeiffer et al., 1974; Pierquin et al., 1989; Rossi et al., 1988;Sempere and Serano, 1982;Verloes and Lambotte, 1989; Yacoub et al., 1987; Ziegler et al., 19901. We also included 39 patients, 16 isolated cases and 13 sibs in 6 families with the diagnosis of Joubert syndrome or query Joubert syndrome. These patients were known to clinical geneticists working in London whom we approached and we analyzed the data available in their hospital files. For each of the 101 cases we compiled the following data: sex; isolated case in the family or affected sib(s); ethnic origin; coefficient of relationship of the parents if consanguineous; results of neuroradiological imaging, presence or absence of abnormal pattern of breathing, abnormal eye movements, hypotonia, ataxia, hemifacial spasms, tongue protrusion, occipital meningocele, polydactyly, renal cysts, and other malformations; results of ophthalmological assessment, electroencephalogram (EEG), and karyotype; age of death or age when last seen alive, and postmortem studies. The cardinal diagnostic criteria of Joubert syndrome have already been described and were our guide when assessing each case. These are as follows. The abnormal pattern of breathing is an alternating episodic hyperpnoea that has been compared to the panting of a dog [Boltshauser and Isler, 19771, and periods of apnoea usually first noticed soon after birth. The pattern of breathing may improve and subsequently disappear [Joubert et al., 19691. The respiratory rate may increase up to 200/min [Boltshauser et al., 19811 and the apnoea may last up to 90 sec [Calogero, 19771 but cyanosis and bradycardia are not usually seen. The tachypnoea has been observed while the patients are awake particularly if stimulated and it occurs in both nonrapid and rapid eye movement sleep whereas the apnoea is more frequent in nonrapid eye movement sleep [Hartmant-van Rijckevorsel et al., 19831. The abnormal eye movements were initially described as irregular jerky [Joubert et al., 19691or as oscillatory eye movements [Dekaban, 19691. In a recent ophthalmological reappraisal of 7 patients with Joubert syndrome [Lambert et al., 1989bl the authors described a range of ocular motor abnormalities: all had nystagmus and 5 had abnormalities of saccades but there was no constant abnormality. The diagnosis of cerebellar vermis dysplasia by computed tomography can be difficult and this was discussed soon after the first report of a case of Joubert syndrome confirmed by computed tomography [Curatolo et al., 19801. The tomographic criteria suggestive of the diagnosis are (1)dilated cisterna magna, (2) lack of parenchyma in the midline between cisterna magna and fourth ventricle, and (3) enlarged communication between cisterna magna and fourth ventricle. These findings do not exclude other diagnoses [Curatolo and Cotroneo, 19821. The retinal dystrophy of patients with Joubert syndrome is accompanied by a nonrecordable or significantly attenuated electroretinogram but, unlike Leber congenital amaurosis, with present flash and pattern visual evoked potentials [Lambert et al., 1989bl. The fundi may be normal or show chorioretinal pigmentary
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changes [Lambert et al., 1989al. The abnormal electroretinograms were first described in 1969 and the histopathological description mentioned absent rod photoreceptors and short cone receptors [Dekaban, 19691.We considered evidence of electroretinographic attenuation as a criterion for retinal dystrophy and a normal electroretinogram as excluding it. Our criteria for defining the presence or absence of renal cysts was the evidence on renal ultrasonography, intravenous pyelogram, or histopathological studies. Chorioretinal coloboma was assessed only when there was a description of a proper ocular fundal examination. We classified the polydactyly according to the limbs affected, unilateral or bilateral and as preaxial or postaxial. We also tried to estimate the incidence of the Joubert syndrome taking into account the frequency of first cousin marriages among parents of affected individuals.
RESULTS Diagnosis There were 22 sibships with classical Joubert syndrome on whom data were available regarding the presence or absence of vermis hypoplasia, abnormal breathing, abnormal eye movement, hypotonia, and developmental delay. All the index cases had evidence of vermis hypoplasia, hypotonia, and developmental delay, as did their 26 affected sibs. In 19 index cases there was evidence of abnormal breathing, as well as in their 23 sibs. In 3 index cases there was no mention of abnormal breathing, nor was this present in their 3 sibs. Sixteen index cases had abnormal eye movements, which were present in their 19 sibs. In 3 index cases with abnormal breathing there was no mention of abnormal eye movements, nor was this noted in their 3 sibs. In 3 index cases there was a description of abnormal eye movements, but this was not noted in 3 of their 4 sibs. However, 1of these 3 sibs died when he was 2 days old [Casamassima et al., 19871, there is only a short description of another [Egger et al., 19821, and the third was only seen when he was 3 years old [Boltshauser and Isler, 19771and spontaneous resolution of the ocular motor abnormalities has been reported [Dekaban, 1969; Lambert et al., 1989bl. Therefore we had good reasons to think that vermis hypoplasia, abnormal breathing, abnormal eye movements, hypotonia, and developmental delay ran true in families and we decided to see if there was any difference between the clinical features and prognosis of the patients with all 5 traits (vermis hypoplasia, hypotonia, developmental delay, abnormal breathing, and abnormal eye movements) as opposed to those who had only 4, excluding either the abnormal breathing or the abnormal eye movements. We did not find any significant difference between the 2 groups (data not shown) and we decided to define the diagnostic criteria of Joubert syndrome as evidence of vermis hypoplasia, hypotonia, developmental delay, and at least 1 of 2 additional abnormalities: abnormal breathing and abnormal eye movements; 94 of the 101 cases fulfilled these criteria.
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Clinical Variability We decided to look in our personal series of patients at the concordance between sibs of some of the associated manifestations of Joubert syndrome. We looked at the presence or absence of retinal dystrophy, renal cysts, chorioretinal coloboma, polydactyly, and occipital meningocele in the 26 affected sibs of 22 index cases. The retinal dystrophy was present in 6 index cases and was concordant in all of their 6 affected sibs. The renal cysts were present in 2 index cases and were concordant in their 3 sibs. Coloboma was present in 4 index cases and was concordant in 1 sib and nonconcordant in 3. Polydactyly was present in 7 index cases and was concordant in 6 sibs and nonconcordant in 2. An occipital meningocele was present in 6 index cases and was concordant in 2 sibs and nonconcordant in 8 sibs. There was good evidence that retinal dystrophy was a distinct abnormality and we decided to classify the 94 cases of Joubert syndrome in 2 groups: Group A, including 17 cases without retinal dystrophy; and group B, including 36 cases with retinal dystrophy. We excluded 41 cases where retinal dystrophy had not been described or excluded. We present the data available on both groups in Tables I and 11. The fact that none of the patients without retinal dystrophy had renal cysts and that they were present in 7 out of the 20 patients with retinal dystrophy where they were looked for was a striking difference. This, together with the concordance between sibs, supports the classification of the patients with Joubert syndrome into 2 groups, with and without retinal dystrophy.
TABLE I. Comparison of the 17 Patients Without Retinal Dystrophy (Group A) With the 36 Patients With Retinal Dystrophy (Group B) Manifestations Isolated cases Sibs affected Males Females Consanguinity Chorioretinal coloboma Renal cysts Polydactyly Occipital meningocele Hemifacial spasms Tongue protrusion Abnormal EEG
Group A (n= 17) 7 10 in 5 families 12 5 0 in 12 families 4 in 14
Group B (n= 36) 19 17 in 8 families 23 13 4 in 27 families 3 in 33
Total (n= 94) 46 48 in 22 families 60 34 6 in 68 families 14 in 65
0 in 4 3 in 17 0 in 17
7 in 20 3 in 36 5 in 36
10 in 37 15 in 94 15 in 94
0 in 17 3 in 17
3 in 36 11 in 36
5 in 94 28 in 94
4 in 15
7 in 21
19 in 58
There are occasional references to an abnormal liver histopathology described as fatty infiltration, cholangitis, or periportal fibrosis in 2 patients with, and 3 patients without renal cysts. Retinal dystrophy was present in 1patient and was not looked for in the other 4. Polydactyly was present only in the fingers of 3 patients, and only in the toes in 2 patients. It was present in the fingers and toes in 10 patients. It was unilateral in the 3 patients with polydactyly of the fingers only and in the toes of one patient with polydactyly of both fingers Manifestations and Prognosis and toes. It was postaxial in 11 patients and 4 had The abnormalities of the central nervous system were bilateral preaxial polydactyly of the toes. The occipital meningocele was described as a mendescribed in the autopsies of 13 cases. The cerebellar vermis was absent in 5 and there was severe hypoplasia ingoencephalocele (3) or as a reducible meningocele in the others, affecting mainly the postero-inferior part. (121, one of which was only 3 mm in diameter. In 6 cases neuronal heterotopias in the cerebellum were described. There was evidence of moderate dilatation of the ventricular system in 4 cases, of large cisterna TABLE 11. Comparison of the Survival of the 17 Patients magna and fourth ventricle in 3 cases, of a narrow pons Dystrophy (Group A) With the 36 Patients in 1 case, and of absence of pyramidal decussation in the Without Retinal With Retinal Dvstrophv (Group B) medulla in 2 cases. Group B Group A Total The chorioretinal coloboma was unilateral in 3 pa- Age (n= 17) (n= 36) (n= 94) tients and bilateral in l l. It was unilateral in the only 2 (years) 1 16 in 17 34 in 34 females with chorioretinal coloboma. 76 in 87 13 in 14 29 in 30 60 in 72 The occurrence of renal pathology in the Joubert syn- 2 9 in 10 24 in 26 44 in 61 drome was reported in the probable first cases [De 3 4 9 in 10 19 in 22 35 in 53 Haene, 19551 as one of the patients died from renal 5 15 in 20 8 in 9 30 in 50 disease. The renal cysts were only present in 10 out of 37 6 14 in 19 6 in 7 27 in 47 patients and were described at autopsy as multiple thin11 in 16 7 5 in 6 23 in 43 9 in 14 3 in 4 walled cortical cysts. 8 19 in 39 9 7 in 13 3 in 4 14 in 35 However, 2 of the patients without renal cysts had 3 in 4 7 in 13 14 in 35 abnormal kidney function and the description of the 10 7 in 13 2 in 3 13 in 34 renal biopsy of one mentioned focal glomerular obsoles- 11 7 in 13 12 2 in 3 11 in 32 cence, interstitial chronic inflammation, and fibrosis. A 13 6 in 13 1 in 2 9 in 31 renal biopsy of one patient with normal kidney function 14 1 in 2 3 in 11 6 in 29 showedthickened tubular basal lamina, moderate inter- 15 1 in 2 2 in 10 4 in 27 1 in 2 1 in 9 3 in 26 stitial fibrosis, and amyloid deposit. The first 2 patients 16 1 in 2 1 in 9 2 in 24 had retinal dystrophy but this was not looked for in the 17 1 in 2 18 0 in 8 0 in 23 last patient.
Joubert Syndrome The EEG abnormalities were always described as a delay in maturation and irregular slow activity. In 38 patients the chromosomes were described as normal. The associated malformations were unilateral or bilateral ptosis (71, one of them in a patient with histidinemia and histidinuria [Appleton et al., 19891, minor tongue abnormalities (5) described as small soft tissue tumours containing adipose tissue and occasional normal mucous glands, self-mutilation (4 cases), congenital heart defect (21, cleft palate (21, duodenal atresia (21, choanal atresia (l),and pyloric stenosis (1). Consanguinity There was consanguinity in 6 of 68 families. The coefficients of relationship of these 6 families were 9 132, 118,118,118,118, and 1164. In 5 of these 6 families the parents were first cousins and they were from Pakistan (21, Bangladesh (11, Algeria (l),and Laos (1).The only consanguineous parents of European origin were a Swiss couple who had common ancestors four generations back [Boltshauser and Isler, 19771 and a French Canadian couple who had common ancestors nine generations back [Joubert et al., 19691. The fact that none of the 20 European couples was first cousins strongly suggests that the recessive allele frequency is not very low, but this sample is quite small and from a population with a small cousin marriage rate. Male/Female Ratio One of the first reports of patients with the possible diagnosis of Joubert syndrome described 3 males [De Haene, 19551 and Joubert described 4 males and 1 female [Joubert et al., 19691.The fact that Joubert syndrome has been reported much more often in males was first commented on in 1982 [Sempere and Serano, 19821 and the ratio of 2 males to 1 female is well recognised [Cantani, 19891 but remains unexplained. In the 94 patients (those from the literature plus the present series) with Joubert syndrome there was a male/ female ratio of 1.8 : 1 (60 males and 34 females). This ratio was similar in all the groups: 2.4 : 1(12 males and 5 females) in the patients without retinal dystrophy, and 1.8 : 1 (23 males and 13 females) in the patients with retinal dystrophy. There was no evidence in any family of another affected male among the brothers or the maternal uncles of the mother of the patient. No significant difference was found between the manifestations in males and females, except that 12 out of 45 males had a chorioretinal coloboma, in contrast to only 2 out of 20 females. Both females had a unilateral coloboma whereas only 1of the 12 colobomas in males was unilateral. DISCUSSION The Joubert syndrome has a worldwide distribution: there are reports of cases of French Canadian [Joubert et al., 19691, Jewish [Joubert et al., 19691, Swedish [Gustavson et al., 19711, German [Pfeiffer et al., 1974; Boltshauser and Isler, 1977; Dralle and SchmidtSommerfeld, 1979; Boltshauser et al., 19811, Swiss
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[Bolshauser and Isler, 1977; Friede and Boltshauser, 1978; Da Silva et al., 19841, Spanish [Fernandez et al., 1979; Meix and Castroviejo, 1980; Sempere and Serano, 19821, Dutch [Lindhout et al., 1980; Beemer and Gooskens, 19851,Italian [Curatolo et al., 1980; Burroni et al., 1980; Laverda et al., 1984; Rossi et al., 19883, Indian [Egger et al., 19821, Belgian (Harmant-van Rijckevorsel et al., 1983; Casaer et al., 1985; Pierquin et al., 19891, Moroccan [Haumont and Pelc, 19831,Laotian [Aicardi et al., 19831, Algerian [Aicardi et al., 19831, Scottish [King et al., 19841, Turkish [Da Silva et al., 19841, Indonesian [Beemer and Gooskens, 19851,Japanese [Matsuzaka et al., 1985; Houdou et al., 19861, and Portuguese [Yacoub et al., 19871 origin. Several papers have addressed the problem of the differential diagnosis of vermis agenesis [Bordarier and Aicardi, 19901, defining the ophthalmological findings [King et al., 1984; Moore and Taylor, 1984; Lambert et al., 1989bl and the neuroradiology [Curatolo et al., 1980; Curatolo and Cotroneo, 1982; Kendall et al., 19901. In a recent review of 45 [Cantani, 19891 and later 53 cases [Cantani et al., 19901 the authors mentioned the association of ocular abnormalities and renal malformations and the possibility that the cases with retinal coloboma could be an X-linked variant [Pfeiffer, 1981;Beemer and Gooskens, 19851but no conclusions were made about the diagnostic criteria or the heterogeneity of this group of patients. The diagnosis of Joubert syndrome should not be made on the evidence of vermis hypoplasia alone. Hypotonia and developmental delay are always present and at least 1of the 2 additional manifestations, abnormal breathing or abnormal eye movements, should be present. Therefore the presence of 4 of the 5 criteria is sufficient for the diagnosis. Patients who fulfill all 5 or only 4 criteria have similar traits and prognosis and the recurrence risk are identical. We propose that patients with Joubert syndrome should be classified in 2 groups: those with retinal dystrophy and those without. The former group could be called Dekaban syndrome as he was the first to describe it [Dekaban, 19691. Both groups share the cardinal abnormalities but differ not only in the presence of retinal dystrophy, but also in the presence of renal cysts in the Dekaban group. These changes are concordant in sibs. The fact that 2 females had a chorioretinal coloboma makes it unlikely that an X-linked variant exist with associated chorioretinal coloboma [Pfeiffer, 19811. It might be that this abnormality is influenced by the sex of the patient and is less common in females and, when present, unilateral. No chromosomes were studied in the 2 females with a chorioretinal coloboma, but the absence of any pedigree suggestive of X-linked inheritance gives no support to the X-linked variant hypothesis. The cases of Joubert syndrome with retinal dystrophy have highly attenuated electroretinograms and present visual evoked potentials. The presence of pattern-reversal visual evoked potentials suggests that the rod receptors are more severely affected than the cone receptors [Lambert et al., 1989bl and this is supported by the
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histopathological findings of the retina [Dekaban, 19691. The differential diagnosis of Joubert syndrome includes the Varadi syndrome [Varadi et al., 19801.Only 1 of the six patients reported had evidence of vermis hypoplasia, and there is no mention of abnormal pattern of breathing or of abnormal eye movement. All had bilateral polydactyly of fingers and toes and 4 in 6 had a cleft lip and/or cleft palate. The inheritance is autosomal recessive. The oro-facial-digital syndrome type I1 (Mohr syndrome) includes tongue nodules, cleft lip and palate, and bilateral duplication of the hallux and occasionally of the thumbs, but does not have an abnormal pattern of breathing or abnormal eye movements. Usually intelligence is normal and severe brain pathology is often absent [Baraitser, 19861.However the case described by Reardon [Reardon et al., 19891had a thin superior cerebellar vermis, abnormal pattern of breathing, roving eye movements, hypotonia, developmental delay, bilateral hallucal reduplication, and unilateral ptosis. In a report of 15 children with Joubert syndrome studied by computed tomography [Kendall et al., 19901 all had dysplasia of the inferior vermis, a fourth ventricle with the floor convex towards the brainstem, and small inferior and superior cerebellar peduncles. Five of these 15 patients had magnetic resonance imaging which showed vermis dysplasia, dilatation of the fourth ventricle also with convexity of the floor toward a small brainstem. However, the results of neuroradiological studies are not always similar in affected siblings [Aicardi et al., 19831. Especially difficult is the differential diagnosis from the Dandy-Walker syndrome by using the neuroradiological imaging alone. This is of major importance because the recurrence rate of the Dandy-Walker syndrome is only 1to 2% [Bordarier and Aicardi, 19841. The criteria of (1)partial or complete agenesis of the vermis, (2) cystic formation in the posterior fossa communicating with the fourth ventricle, (3) hydrocephalus, (4) enlargement of the posterior fossa, and (5) elevation of the torcular and lateral sinuses are said to be diagnostic of the Dandy-Walker malformation [Bordarier and Aicardi, 19901. In a patient with Joubert syndrome we would expect to find different degrees of vermis dysplasia, usually most pronounced posteriorly and inferiorly. The brain stem can also be small and its involvement could explain some of the symptoms in the syndrome. The abnormal pattern of breathing and the abnormal eye movements are likely to be due to both cerebellar and brainstem abnormalities. The cerebellar vermis hypoplasia cannot explain the mental retardation but no constant association of hemispheric malformation has been described. In a few cases the intelligence level was better than expected given the early developmental delay [Casaer et al., 1985; Ziegler et al., 19901. The hypotonia, the ataxia, the hemifacial spasms, and the protrusion of the tongue are also a result of the central nervous system abnormalities. The renal cysts, present only in the group with retinal dystrophy, are multiple, small, and cortical and the affected kidneys also have interstitial chronic inflamma-
tion and fibrosis. These latter changes may be present in the absence of renal cysts and may explain the abnormal kidney function of some patients. The histopathological changes had not been reported in patients without retinal dystrophy. A similar pattern of interstitial inflammation and fibrosis has been reported in the liver of some patients, with [Dekaban, 19691 and without renal cysts [Verloes and Lambotte, 19891 but never without retinal dystrophy. In the group with retinal dystrophy there seems to be a predisposition for these changes and not only for renal cysts. The most frequent associated anomaly is polydactyly. It was usually postaxial and bilateral and affected both fingers and toes. Our data also enable us to provide the parents of the affected children with more accurate information regarding the prognosis of the disease. Although it reflects the bias of report of the cases with earlier death and postmortem studies it provides for the first time reliable estimates of survival. The possibility of prenatal diagnosis by ultrasound remains difficult. There is only one case report of a prenatal diagnosis of Joubert syndrome by ultrasound [Campbell et al., 19841, and it should be stressed that the diagnosis was probably apparent only from 22 weeks gestation. The polydactyly was concordant in 6 of 8 sibs and its presence, as well as the presence of renal cysts, are findings that may help prenatal diagnosis although the abnormalities of the posterior fossa remain the most important change.
ACKNOWLEDGMENTS J.M. Saraiva was supported by a grant from the Fundapio Calouste Gulbenkian, Lisbon, Portugal. We thank Dr. C. Berry, SE Thames Regional Genetics Centre, Guy’s Hospital, London, and Dr. B. Kendall, Department of Neuroradiology, The Hospital for Sick Children, Great Ormond Street, London for the referral of patients with Joubert syndrome. REFERENCES Aicardi J , Castello-Branco ME, Roy CL (1983): Le syndrome de Joubert. A propos de cinq observations. Arch Fr P6diatr 40:625-629. AppletonRE, Chitayat D, J a n JE,KennedyR,Hall J G (1989):Joubert’s syndrome associated with congenital ocular fibrosis and histidinemia. Arch Neurol 46:579-582. Baraitser M (1986): The orofaciodigital (OFD)syndromes.J Med Genet 23: 116-1 19. Baraitser M (1990): “The Genetics of Neurological Disorders.” Oxford Oxford University Press, 2nd ed, pp 176-177. Beemer FA, Gooskens R (1985): Chorioretinal coloboma and Joubert syndrome (letter). J Pediatr 107:158-159. Boltshauser E, Isler W (1977): Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia, associated with dysplasia of the cerebellar vermis. Neuropediatrics 8:57-66. Boltshauser E, Herdan M, Dumermuth G, Isler W (1981): Joubert syndrome: Clinical and polygraphic observations in a further case. Neuropediatrics 12:181-191. Bordarier C, Aicardi J (1990): Dandy-Walker syndrome and agenesisof the cerebellar vermis: Diagnostic problems and genetic counselling. Dev Med Child Neurol 32:285-294. Brett EM (1991): Ataxia. In Brett EM (ed): “Paediatric Neurology.” Edinburgh: Churchill Livingstone, 2nd ed, pp 263-270.
Joubert Syndrome Burroni M, Perrotta F, Rossolini V (1980): Sindrome di Joubert, contributo clinico. Minerva Pediatr 32:763-766. Calogero JA (1977): Vermian agenesis and unsegmented midbrain tectum. J Neurosurg 47:605-608. Campbell S, Tsannatos C, Pearce J M (1984):The prenatal diagnosis of Joubert’s syndrome of familial agenesis of the cerebellar vermis. Prenat Diagn 4:391-395. Cantani A (1989): A proposito dei 45 casi della sindrome di Joubert (letter). Riv Ital Pediatr 15:102-103. Cantani A, Lucenti P, Ronzani GA, Santoro C (1990): Joubert syndrome-review of the fifty-three cases so far published. Ann Genet 33:96-98. Casaer P, Vles JSH, Devlieger H, Eggermont E, Boel M (1985): Variability of outcome in Joubert syndrome. Neuropediatrics 16:43-45. Casamassima AC, Mamunes P, Gladstone IM, Solomon S, Moncure C (1987): A new syndrome with features of the Smith-Lemli-Opitz and Meckel-Gruber syndromes in a sibship with cerebellar defects. Am J Med Genet 26:321-336. Casamassima AC, Pfeiffer RA (1990):Joubert syndrome. In Buyse ML (ed): “Birth Defects “Encyclopedia.” Dover: Center for Birth Defects Information Services, Inc., pp 995-996. Curatolo P, Mercuri S, Cotroneo E (1980):Joubert syndrome: A case confirmed by computerized tomography. Dev Med Child Neurol 22:362-378. Curatolo P, Cotroneo E (1982):Cerebellar vermis dysplasia: Diagnostic problems by CT. Neuropediatrics 13:50. Da Silva V, Boltshauser E, Lange B, Gugler E (1984): Joubert-Syndrom-Beobachtungen a n 2 Patienten. Helv Paediatr Acta 39(suppl 50): 3. De Haene A (1955): Agenesie partielle du vermis du cervelet a carac@re familial. Acta Neurol Belg 55:622-628. Dekaban AS (1969):Hereditary syndrome of congenital retinal blindness (Leber), polycystic kidneys and maldevelopment of the brain. Am J Ophthalmol 68:1029-1036. Dralle D, Schmidt-Sommerfeld E (1979): Zusammenhange zwischen Atemregulation und paradoxem Schlaf bei einem Patienten mit Joubert-Syndrom. Klin Padiatr 191233-90. Egger J, Bellman MH, Ross EM, Baraitser M (1982): Joubert-Boltshauser syndrome with polydactyly in siblings. J Neurol Neurosurg Psychiatry 45737-739. Fernandez CC, Costa TR, Perez JS, Janer BR, Lopez FR (1979): Sindrome de Joubert-a prop6sito de un caso. Arch Neurobiol (Madr) 42~299-308. Fierro M, Martinez AJ, Harbison JW, Hay SH (1977): Smith-LemliOpitz syndrome: Neuropathological and ophthalmological observations. Dev Med Child Neurol 1957-62. Friede RL, Boltshauser E (1978): Uncommon syndromes of cerebellar vermis aplasia. I: Joubert syndrome. Dev Med Child Neurol 20:758-763. Gustavson K-H, Kreuger A, Peterson PO (1971): Syndrome characterized by lingual malformation, polydactyly, tachypnea, and psychomotor retardation (Mohr syndrome). Clin Genet 2:261-266. Harding AE (1990):The hereditary ataxias and paraplegias. In Emery AEH, Rimoin DL (eds): “Principles and Practice of Medical Genetics.’’ Edinburgh: Churchill Livingstone, 2nd ed, pp 383-396. Hartmant-van Rijckevorsel G, Aubert-Tulkens G, Moulin D, Lyon G (1983): Le syndrome de Joubert. ktude clinique et anatomopathologique.Hypotheses Btiopathogeniques. Rev Neurol (Paris) 12~715-724. Haumont D, Pelc S (1983): The Mohr syndrome: Are there two variants? Clin Genet 24:41-46. Houdou S, Ohno K, Takashima S, Takeshita K (1986): Joubert syn-
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drome associated with unilateral ptosis and Leber congenital amaurosis. Pediatr Neurol 2:102-105. Joubert M, Eisenring J J , Robb JP, Andermann F (1969): Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia;and retardation.Neurbiogy 19:813-815. Kendall B, Kingsley D, Lambert SR, Taylor D, Finn P (1990):Joubert syndrome: A clinico-radiological study. Neuroradiology 31:502506. King MD, Dudgeon J , Stephenson J B P (1984):Joubert’s syndrome with retinal dysplasia: Neonatal tachypnoea as the clue to a genetic brain-eye malformation. Arch Dis Child 59:709-718. Lambert SR, Kriss A, Taylor D, Coffey R, Pembrey M (1989a):Follow-up and diagnostic reappraisal of 75 patients with Leber’s congenital amaurosis. Am J Ophthalmol 107524-631. Lambert SR, Kriss A, Gresty M, Benton S, Taylor D (1989b):Joubert syndrome. Arch Ophthalmol 107:709-713. Laverda AM, Saia DS, Drigo P, Danieli E, Clementi M, Tenconi R (1984):Chorioretinal coloboma and Joubert syndrome: A nonrandom association. J Pediatr 105282-284. Lindhout D, Barth PG, Valk J , Boen-Tan TN (1980): The Joubert syndrome associated with bilateral chorioretinal coloboma. Eur J Pediatr 134:173-176. Matsuzaka T, Kono Y, Sakuragawa N, Nonaka I, Ando K (1985): A syndrome of congenital blindness (Leber), agenesis of the vermis, congenital polycystic kidneys and mental retardation. Brain Dev 7:153. Menenzes M, Coker SB (1990):CHARGE and Joubert syndromes-are they a single disorder? Pediatr Neurol (3428-430. Meix JMA, Castroviejo IP (1980):Sindrome de Joubert. Estudio de un nuevo caso y revisi6n de la literatura. An Esp Pediatr 13525-632. Moore AT, Taylor DSI (1984):A syndrome of congenital retinal dystrophy and saccade palsy-a subset of Leber’s amaurosis. Br J Ophthalmol 68:421-431. Pfeiffer RA (1981): The Joubert syndrome associated with bilateral chorioretinal coloboma (letter). Eur J Pediatr 137:lOl. Pfeiffer RA, Palm D, Mann GJ (1974): Nosology of congenital nonprogressive cerebellar ataxia: Report on six cases in three families. Neuropediatrics 591-102. Pierquin G , Deroover J , Levi S, Masson T, Hayez-Delatte F, van Regemorter N (1989): Dandy-Walker malformation with postaxial polydactyly: A new syndrome? Am J Med Genet 33:483-484. Reardon W, Harbord MG, Hall-Craggs MA, Kendall B, Brett EM, Baraitser M (1989): Central nervous system malformations in Mohr’s syndrome. J Med Genet 26:659-663. Rossi A, Sangermani R, Zuccarini C, Dellafiore L (1988):Sindrome di Joubert-descrizione in due fratelli. Riv Ital Ped 14:435-437. Sempere TL, Serano MS (1982): Sindrome de Joubert. Estudio de un nuevo caso y revisi6n de la literatura. An Esp Pediatr 17:310-316. Varadi V, Szabo L, Papp Z (1980): Syndrome of polydactyly, cleft lip/ palate or lingual lump, and psychomotor retardation in endogamic gypsies. J Med Genet 17:119-122. Verloes A, Lambotte C (19891: Further delineation of a syndrome of cerebellar vermis hypoplasia, oliogophrenia, congenital ataxia, coloboma and hepatic fibrosis. Am J Med Genet 32:227-232. Winter RM, Baraitser M (1991): “Multiple Congenital Anomalies-A Diagnostic Compendium.” London: Chapman and Hall Medical, p 321. Yacoub M, Beauvais P, Richardet J M (1987):Syndrome de Joubertdeux nouvelles observations. Med Infantile 94:803-807. Ziegler A-L, Deonna T, Calame A (1990): Hidden intelligence of a multiply handicapped child with Joubert syndrome. Dev Med Child Neurol 32:261-266.
Joubert Syndrome: A Review Jorge M. Saraiva and Michael Baraitser Paediatric Hospital (J.M.S.), Coimbra, Portugal and Unit of Clinical Genetics and Fetal Medicine (M.B.), Institute of Child Health, London, England
We review 72 previously reported and 29 new patients with the possible diagnosis of Joubert syndrome. We define diagnostic criteria for this syndrome and present the data available in 94 patients that fulfill our criteria. We present the data regarding the clinical, neuroradiological, and ophthalmological manifestations and the prognosis of these 94 patients. We propose a classification of the patients with this diagnosis in 2 groups: those with retinal dystrophy and those without. Retinal dystrophy runs true in families and was never absent when renal cysts were reported. o 1992 Wiley-Liss, Inc.
KEY WORDS: Joubert syndrome, JoubertBoltshauser syndrome, retinal dystrophy, vermis hypoplasia INTRODUCTION The Joubert (Joubert-Boltshauser) syndrome is a well known but rare autosomal recessive condition and no prevalence estimate is available. It is a syndrome with variable phenotype: partial or complete absence of the cerebellar vermis is seen in all patients; the other cardinal findings are the episodic tachypnoea and apnoea in the neonatal period,jerky eye movements, hypotonia, severe mental handicap, ataxia, and impaired equilibrium [Baraitser, 1990; Brett, 1991; Casamassima and Pfeiffer, 1990;Harding, 1990;Winter and Baraitser, 19911. Marie Joubert (whose name is linked to the condition) and co-workers [Joubert et al., 19691provided the earliest detailed analysis of the syndrome. They described 4 sibs, 3 males and 1 female, and an isolated case, and called the condition a “familial syndrome of episodic hyperpnea, abnormal eye movements, ataxia, mental retardation, agenesis of the vermis” and absence
of cerebellar vermis observed in one case at autopsy. Cerebellar vermis hypoplasia had previously been observed at autopsy in one of 3 affected brothers [De Haene, 19551 but the clinical description was incomplete. All the original cases had vermis hypoplasia, developmental delay, episodic hyperpnoea, abnormal eye movements, and hypotonia and some had an occipital meningoencephalocele, polydactyly, tongue protrusion, hemifacial spasms, and ataxia. Later there were reports of additional manifestations: self-mutilation [Boltshauser and Isler, 19771, chorioretinal coloboma [Lindhout et al., 19801, tongue tumours [Egger et al., 19821, ptosis [Harmant-van Rijckevorsel et al., 19831, retinal dystrophy [Aicardi et al., 19831,cystic kidneys [King et al., 19841,and duodenal atresia [Lambert et al., 1989bl. Chromosomes were reported as normal. Because of the difficulty in establishing the boundaries of Joubert syndrome regarding its diagnosis, classification, and prognosis, a study was undertaken to address the following: could we define the diagnostic criteria of Joubert syndrome? Is it possible to distinguish different groups of patients with different prognoses and inheritance patterns taking into account the presence of some of the associated features? What information is available regarding the prognosis of these patients?
MATERIALS AND METHODS We included in our study all the reports from the literature either diagnosed by the authors as having Joubert syndrome or where such a diagnosis had been suggested by others. We analyzed the data described in 72 case reports: 34 isolated cases and 38 sibs in 17 families [Aicardi et al., 1983; Appleton et al., 1989; Beemer and Gooskens, 1985; Boltshauser and Isler, 1977; Boltshauser et al., 1981; Burroni et al., 1980; Calogero, 1977; Campbell et al., 1984; Casaer et al., 1985; Casamassima et al., 1987; Curatolo et al., 1980; Da Silva et al., 1984; Dekaban, 1969; Dralle and Schmidt-Sommerfeld, 1979; Egger et al., 1982; Fernandez et al., 1979; Fierro et al., 1977;Friede and Boltshauser, 1978; Gustavson et al., 1971; Hartmant-van Rijckevorsel et al., 1983; Haumont and Pelc, 1983;Houdou Received for publication June 6,1991; revision received October et al., 1986; Jourbert et al., 1969; King et al., 1984; 3, 1991. Lambert et al., 1989b;Laverda et al., 1984; Lindhout et Address reprint requests to Dr. M. Baraitser, Unit of Clinical Genetics and Fetal Medicine, Institute of Child Health, 30 Guilford al., 1980; Matsuzaka et al., 1985; Meix and Castroviejo, 1980;Menezes and Coker, 1990;Moore andTaylor, 1984; Street, London WClN lEH, England. 0 1992 Wiley-Liss, Inc.
Joubert Syndrome Pfeiffer et al., 1974; Pierquin et al., 1989; Rossi et al., 1988;Sempere and Serano, 1982;Verloes and Lambotte, 1989; Yacoub et al., 1987; Ziegler et al., 19901. We also included 39 patients, 16 isolated cases and 13 sibs in 6 families with the diagnosis of Joubert syndrome or query Joubert syndrome. These patients were known to clinical geneticists working in London whom we approached and we analyzed the data available in their hospital files. For each of the 101 cases we compiled the following data: sex; isolated case in the family or affected sib(s); ethnic origin; coefficient of relationship of the parents if consanguineous; results of neuroradiological imaging, presence or absence of abnormal pattern of breathing, abnormal eye movements, hypotonia, ataxia, hemifacial spasms, tongue protrusion, occipital meningocele, polydactyly, renal cysts, and other malformations; results of ophthalmological assessment, electroencephalogram (EEG), and karyotype; age of death or age when last seen alive, and postmortem studies. The cardinal diagnostic criteria of Joubert syndrome have already been described and were our guide when assessing each case. These are as follows. The abnormal pattern of breathing is an alternating episodic hyperpnoea that has been compared to the panting of a dog [Boltshauser and Isler, 19771, and periods of apnoea usually first noticed soon after birth. The pattern of breathing may improve and subsequently disappear [Joubert et al., 19691. The respiratory rate may increase up to 200/min [Boltshauser et al., 19811 and the apnoea may last up to 90 sec [Calogero, 19771 but cyanosis and bradycardia are not usually seen. The tachypnoea has been observed while the patients are awake particularly if stimulated and it occurs in both nonrapid and rapid eye movement sleep whereas the apnoea is more frequent in nonrapid eye movement sleep [Hartmant-van Rijckevorsel et al., 19831. The abnormal eye movements were initially described as irregular jerky [Joubert et al., 19691or as oscillatory eye movements [Dekaban, 19691. In a recent ophthalmological reappraisal of 7 patients with Joubert syndrome [Lambert et al., 1989bl the authors described a range of ocular motor abnormalities: all had nystagmus and 5 had abnormalities of saccades but there was no constant abnormality. The diagnosis of cerebellar vermis dysplasia by computed tomography can be difficult and this was discussed soon after the first report of a case of Joubert syndrome confirmed by computed tomography [Curatolo et al., 19801. The tomographic criteria suggestive of the diagnosis are (1)dilated cisterna magna, (2) lack of parenchyma in the midline between cisterna magna and fourth ventricle, and (3) enlarged communication between cisterna magna and fourth ventricle. These findings do not exclude other diagnoses [Curatolo and Cotroneo, 19821. The retinal dystrophy of patients with Joubert syndrome is accompanied by a nonrecordable or significantly attenuated electroretinogram but, unlike Leber congenital amaurosis, with present flash and pattern visual evoked potentials [Lambert et al., 1989bl. The fundi may be normal or show chorioretinal pigmentary
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changes [Lambert et al., 1989al. The abnormal electroretinograms were first described in 1969 and the histopathological description mentioned absent rod photoreceptors and short cone receptors [Dekaban, 19691.We considered evidence of electroretinographic attenuation as a criterion for retinal dystrophy and a normal electroretinogram as excluding it. Our criteria for defining the presence or absence of renal cysts was the evidence on renal ultrasonography, intravenous pyelogram, or histopathological studies. Chorioretinal coloboma was assessed only when there was a description of a proper ocular fundal examination. We classified the polydactyly according to the limbs affected, unilateral or bilateral and as preaxial or postaxial. We also tried to estimate the incidence of the Joubert syndrome taking into account the frequency of first cousin marriages among parents of affected individuals.
RESULTS Diagnosis There were 22 sibships with classical Joubert syndrome on whom data were available regarding the presence or absence of vermis hypoplasia, abnormal breathing, abnormal eye movement, hypotonia, and developmental delay. All the index cases had evidence of vermis hypoplasia, hypotonia, and developmental delay, as did their 26 affected sibs. In 19 index cases there was evidence of abnormal breathing, as well as in their 23 sibs. In 3 index cases there was no mention of abnormal breathing, nor was this present in their 3 sibs. Sixteen index cases had abnormal eye movements, which were present in their 19 sibs. In 3 index cases with abnormal breathing there was no mention of abnormal eye movements, nor was this noted in their 3 sibs. In 3 index cases there was a description of abnormal eye movements, but this was not noted in 3 of their 4 sibs. However, 1of these 3 sibs died when he was 2 days old [Casamassima et al., 19871, there is only a short description of another [Egger et al., 19821, and the third was only seen when he was 3 years old [Boltshauser and Isler, 19771and spontaneous resolution of the ocular motor abnormalities has been reported [Dekaban, 1969; Lambert et al., 1989bl. Therefore we had good reasons to think that vermis hypoplasia, abnormal breathing, abnormal eye movements, hypotonia, and developmental delay ran true in families and we decided to see if there was any difference between the clinical features and prognosis of the patients with all 5 traits (vermis hypoplasia, hypotonia, developmental delay, abnormal breathing, and abnormal eye movements) as opposed to those who had only 4, excluding either the abnormal breathing or the abnormal eye movements. We did not find any significant difference between the 2 groups (data not shown) and we decided to define the diagnostic criteria of Joubert syndrome as evidence of vermis hypoplasia, hypotonia, developmental delay, and at least 1 of 2 additional abnormalities: abnormal breathing and abnormal eye movements; 94 of the 101 cases fulfilled these criteria.
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Clinical Variability We decided to look in our personal series of patients at the concordance between sibs of some of the associated manifestations of Joubert syndrome. We looked at the presence or absence of retinal dystrophy, renal cysts, chorioretinal coloboma, polydactyly, and occipital meningocele in the 26 affected sibs of 22 index cases. The retinal dystrophy was present in 6 index cases and was concordant in all of their 6 affected sibs. The renal cysts were present in 2 index cases and were concordant in their 3 sibs. Coloboma was present in 4 index cases and was concordant in 1 sib and nonconcordant in 3. Polydactyly was present in 7 index cases and was concordant in 6 sibs and nonconcordant in 2. An occipital meningocele was present in 6 index cases and was concordant in 2 sibs and nonconcordant in 8 sibs. There was good evidence that retinal dystrophy was a distinct abnormality and we decided to classify the 94 cases of Joubert syndrome in 2 groups: Group A, including 17 cases without retinal dystrophy; and group B, including 36 cases with retinal dystrophy. We excluded 41 cases where retinal dystrophy had not been described or excluded. We present the data available on both groups in Tables I and 11. The fact that none of the patients without retinal dystrophy had renal cysts and that they were present in 7 out of the 20 patients with retinal dystrophy where they were looked for was a striking difference. This, together with the concordance between sibs, supports the classification of the patients with Joubert syndrome into 2 groups, with and without retinal dystrophy.
TABLE I. Comparison of the 17 Patients Without Retinal Dystrophy (Group A) With the 36 Patients With Retinal Dystrophy (Group B) Manifestations Isolated cases Sibs affected Males Females Consanguinity Chorioretinal coloboma Renal cysts Polydactyly Occipital meningocele Hemifacial spasms Tongue protrusion Abnormal EEG
Group A (n= 17) 7 10 in 5 families 12 5 0 in 12 families 4 in 14
Group B (n= 36) 19 17 in 8 families 23 13 4 in 27 families 3 in 33
Total (n= 94) 46 48 in 22 families 60 34 6 in 68 families 14 in 65
0 in 4 3 in 17 0 in 17
7 in 20 3 in 36 5 in 36
10 in 37 15 in 94 15 in 94
0 in 17 3 in 17
3 in 36 11 in 36
5 in 94 28 in 94
4 in 15
7 in 21
19 in 58
There are occasional references to an abnormal liver histopathology described as fatty infiltration, cholangitis, or periportal fibrosis in 2 patients with, and 3 patients without renal cysts. Retinal dystrophy was present in 1patient and was not looked for in the other 4. Polydactyly was present only in the fingers of 3 patients, and only in the toes in 2 patients. It was present in the fingers and toes in 10 patients. It was unilateral in the 3 patients with polydactyly of the fingers only and in the toes of one patient with polydactyly of both fingers Manifestations and Prognosis and toes. It was postaxial in 11 patients and 4 had The abnormalities of the central nervous system were bilateral preaxial polydactyly of the toes. The occipital meningocele was described as a mendescribed in the autopsies of 13 cases. The cerebellar vermis was absent in 5 and there was severe hypoplasia ingoencephalocele (3) or as a reducible meningocele in the others, affecting mainly the postero-inferior part. (121, one of which was only 3 mm in diameter. In 6 cases neuronal heterotopias in the cerebellum were described. There was evidence of moderate dilatation of the ventricular system in 4 cases, of large cisterna TABLE 11. Comparison of the Survival of the 17 Patients magna and fourth ventricle in 3 cases, of a narrow pons Dystrophy (Group A) With the 36 Patients in 1 case, and of absence of pyramidal decussation in the Without Retinal With Retinal Dvstrophv (Group B) medulla in 2 cases. Group B Group A Total The chorioretinal coloboma was unilateral in 3 pa- Age (n= 17) (n= 36) (n= 94) tients and bilateral in l l. It was unilateral in the only 2 (years) 1 16 in 17 34 in 34 females with chorioretinal coloboma. 76 in 87 13 in 14 29 in 30 60 in 72 The occurrence of renal pathology in the Joubert syn- 2 9 in 10 24 in 26 44 in 61 drome was reported in the probable first cases [De 3 4 9 in 10 19 in 22 35 in 53 Haene, 19551 as one of the patients died from renal 5 15 in 20 8 in 9 30 in 50 disease. The renal cysts were only present in 10 out of 37 6 14 in 19 6 in 7 27 in 47 patients and were described at autopsy as multiple thin11 in 16 7 5 in 6 23 in 43 9 in 14 3 in 4 walled cortical cysts. 8 19 in 39 9 7 in 13 3 in 4 14 in 35 However, 2 of the patients without renal cysts had 3 in 4 7 in 13 14 in 35 abnormal kidney function and the description of the 10 7 in 13 2 in 3 13 in 34 renal biopsy of one mentioned focal glomerular obsoles- 11 7 in 13 12 2 in 3 11 in 32 cence, interstitial chronic inflammation, and fibrosis. A 13 6 in 13 1 in 2 9 in 31 renal biopsy of one patient with normal kidney function 14 1 in 2 3 in 11 6 in 29 showedthickened tubular basal lamina, moderate inter- 15 1 in 2 2 in 10 4 in 27 1 in 2 1 in 9 3 in 26 stitial fibrosis, and amyloid deposit. The first 2 patients 16 1 in 2 1 in 9 2 in 24 had retinal dystrophy but this was not looked for in the 17 1 in 2 18 0 in 8 0 in 23 last patient.
Joubert Syndrome The EEG abnormalities were always described as a delay in maturation and irregular slow activity. In 38 patients the chromosomes were described as normal. The associated malformations were unilateral or bilateral ptosis (71, one of them in a patient with histidinemia and histidinuria [Appleton et al., 19891, minor tongue abnormalities (5) described as small soft tissue tumours containing adipose tissue and occasional normal mucous glands, self-mutilation (4 cases), congenital heart defect (21, cleft palate (21, duodenal atresia (21, choanal atresia (l),and pyloric stenosis (1). Consanguinity There was consanguinity in 6 of 68 families. The coefficients of relationship of these 6 families were 9 132, 118,118,118,118, and 1164. In 5 of these 6 families the parents were first cousins and they were from Pakistan (21, Bangladesh (11, Algeria (l),and Laos (1).The only consanguineous parents of European origin were a Swiss couple who had common ancestors four generations back [Boltshauser and Isler, 19771 and a French Canadian couple who had common ancestors nine generations back [Joubert et al., 19691. The fact that none of the 20 European couples was first cousins strongly suggests that the recessive allele frequency is not very low, but this sample is quite small and from a population with a small cousin marriage rate. Male/Female Ratio One of the first reports of patients with the possible diagnosis of Joubert syndrome described 3 males [De Haene, 19551 and Joubert described 4 males and 1 female [Joubert et al., 19691.The fact that Joubert syndrome has been reported much more often in males was first commented on in 1982 [Sempere and Serano, 19821 and the ratio of 2 males to 1 female is well recognised [Cantani, 19891 but remains unexplained. In the 94 patients (those from the literature plus the present series) with Joubert syndrome there was a male/ female ratio of 1.8 : 1 (60 males and 34 females). This ratio was similar in all the groups: 2.4 : 1(12 males and 5 females) in the patients without retinal dystrophy, and 1.8 : 1 (23 males and 13 females) in the patients with retinal dystrophy. There was no evidence in any family of another affected male among the brothers or the maternal uncles of the mother of the patient. No significant difference was found between the manifestations in males and females, except that 12 out of 45 males had a chorioretinal coloboma, in contrast to only 2 out of 20 females. Both females had a unilateral coloboma whereas only 1of the 12 colobomas in males was unilateral. DISCUSSION The Joubert syndrome has a worldwide distribution: there are reports of cases of French Canadian [Joubert et al., 19691, Jewish [Joubert et al., 19691, Swedish [Gustavson et al., 19711, German [Pfeiffer et al., 1974; Boltshauser and Isler, 1977; Dralle and SchmidtSommerfeld, 1979; Boltshauser et al., 19811, Swiss
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[Bolshauser and Isler, 1977; Friede and Boltshauser, 1978; Da Silva et al., 19841, Spanish [Fernandez et al., 1979; Meix and Castroviejo, 1980; Sempere and Serano, 19821, Dutch [Lindhout et al., 1980; Beemer and Gooskens, 19851,Italian [Curatolo et al., 1980; Burroni et al., 1980; Laverda et al., 1984; Rossi et al., 19883, Indian [Egger et al., 19821, Belgian (Harmant-van Rijckevorsel et al., 1983; Casaer et al., 1985; Pierquin et al., 19891, Moroccan [Haumont and Pelc, 19831,Laotian [Aicardi et al., 19831, Algerian [Aicardi et al., 19831, Scottish [King et al., 19841, Turkish [Da Silva et al., 19841, Indonesian [Beemer and Gooskens, 19851,Japanese [Matsuzaka et al., 1985; Houdou et al., 19861, and Portuguese [Yacoub et al., 19871 origin. Several papers have addressed the problem of the differential diagnosis of vermis agenesis [Bordarier and Aicardi, 19901, defining the ophthalmological findings [King et al., 1984; Moore and Taylor, 1984; Lambert et al., 1989bl and the neuroradiology [Curatolo et al., 1980; Curatolo and Cotroneo, 1982; Kendall et al., 19901. In a recent review of 45 [Cantani, 19891 and later 53 cases [Cantani et al., 19901 the authors mentioned the association of ocular abnormalities and renal malformations and the possibility that the cases with retinal coloboma could be an X-linked variant [Pfeiffer, 1981;Beemer and Gooskens, 19851but no conclusions were made about the diagnostic criteria or the heterogeneity of this group of patients. The diagnosis of Joubert syndrome should not be made on the evidence of vermis hypoplasia alone. Hypotonia and developmental delay are always present and at least 1of the 2 additional manifestations, abnormal breathing or abnormal eye movements, should be present. Therefore the presence of 4 of the 5 criteria is sufficient for the diagnosis. Patients who fulfill all 5 or only 4 criteria have similar traits and prognosis and the recurrence risk are identical. We propose that patients with Joubert syndrome should be classified in 2 groups: those with retinal dystrophy and those without. The former group could be called Dekaban syndrome as he was the first to describe it [Dekaban, 19691. Both groups share the cardinal abnormalities but differ not only in the presence of retinal dystrophy, but also in the presence of renal cysts in the Dekaban group. These changes are concordant in sibs. The fact that 2 females had a chorioretinal coloboma makes it unlikely that an X-linked variant exist with associated chorioretinal coloboma [Pfeiffer, 19811. It might be that this abnormality is influenced by the sex of the patient and is less common in females and, when present, unilateral. No chromosomes were studied in the 2 females with a chorioretinal coloboma, but the absence of any pedigree suggestive of X-linked inheritance gives no support to the X-linked variant hypothesis. The cases of Joubert syndrome with retinal dystrophy have highly attenuated electroretinograms and present visual evoked potentials. The presence of pattern-reversal visual evoked potentials suggests that the rod receptors are more severely affected than the cone receptors [Lambert et al., 1989bl and this is supported by the
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histopathological findings of the retina [Dekaban, 19691. The differential diagnosis of Joubert syndrome includes the Varadi syndrome [Varadi et al., 19801.Only 1 of the six patients reported had evidence of vermis hypoplasia, and there is no mention of abnormal pattern of breathing or of abnormal eye movement. All had bilateral polydactyly of fingers and toes and 4 in 6 had a cleft lip and/or cleft palate. The inheritance is autosomal recessive. The oro-facial-digital syndrome type I1 (Mohr syndrome) includes tongue nodules, cleft lip and palate, and bilateral duplication of the hallux and occasionally of the thumbs, but does not have an abnormal pattern of breathing or abnormal eye movements. Usually intelligence is normal and severe brain pathology is often absent [Baraitser, 19861.However the case described by Reardon [Reardon et al., 19891had a thin superior cerebellar vermis, abnormal pattern of breathing, roving eye movements, hypotonia, developmental delay, bilateral hallucal reduplication, and unilateral ptosis. In a report of 15 children with Joubert syndrome studied by computed tomography [Kendall et al., 19901 all had dysplasia of the inferior vermis, a fourth ventricle with the floor convex towards the brainstem, and small inferior and superior cerebellar peduncles. Five of these 15 patients had magnetic resonance imaging which showed vermis dysplasia, dilatation of the fourth ventricle also with convexity of the floor toward a small brainstem. However, the results of neuroradiological studies are not always similar in affected siblings [Aicardi et al., 19831. Especially difficult is the differential diagnosis from the Dandy-Walker syndrome by using the neuroradiological imaging alone. This is of major importance because the recurrence rate of the Dandy-Walker syndrome is only 1to 2% [Bordarier and Aicardi, 19841. The criteria of (1)partial or complete agenesis of the vermis, (2) cystic formation in the posterior fossa communicating with the fourth ventricle, (3) hydrocephalus, (4) enlargement of the posterior fossa, and (5) elevation of the torcular and lateral sinuses are said to be diagnostic of the Dandy-Walker malformation [Bordarier and Aicardi, 19901. In a patient with Joubert syndrome we would expect to find different degrees of vermis dysplasia, usually most pronounced posteriorly and inferiorly. The brain stem can also be small and its involvement could explain some of the symptoms in the syndrome. The abnormal pattern of breathing and the abnormal eye movements are likely to be due to both cerebellar and brainstem abnormalities. The cerebellar vermis hypoplasia cannot explain the mental retardation but no constant association of hemispheric malformation has been described. In a few cases the intelligence level was better than expected given the early developmental delay [Casaer et al., 1985; Ziegler et al., 19901. The hypotonia, the ataxia, the hemifacial spasms, and the protrusion of the tongue are also a result of the central nervous system abnormalities. The renal cysts, present only in the group with retinal dystrophy, are multiple, small, and cortical and the affected kidneys also have interstitial chronic inflamma-
tion and fibrosis. These latter changes may be present in the absence of renal cysts and may explain the abnormal kidney function of some patients. The histopathological changes had not been reported in patients without retinal dystrophy. A similar pattern of interstitial inflammation and fibrosis has been reported in the liver of some patients, with [Dekaban, 19691 and without renal cysts [Verloes and Lambotte, 19891 but never without retinal dystrophy. In the group with retinal dystrophy there seems to be a predisposition for these changes and not only for renal cysts. The most frequent associated anomaly is polydactyly. It was usually postaxial and bilateral and affected both fingers and toes. Our data also enable us to provide the parents of the affected children with more accurate information regarding the prognosis of the disease. Although it reflects the bias of report of the cases with earlier death and postmortem studies it provides for the first time reliable estimates of survival. The possibility of prenatal diagnosis by ultrasound remains difficult. There is only one case report of a prenatal diagnosis of Joubert syndrome by ultrasound [Campbell et al., 19841, and it should be stressed that the diagnosis was probably apparent only from 22 weeks gestation. The polydactyly was concordant in 6 of 8 sibs and its presence, as well as the presence of renal cysts, are findings that may help prenatal diagnosis although the abnormalities of the posterior fossa remain the most important change.
ACKNOWLEDGMENTS J.M. Saraiva was supported by a grant from the Fundapio Calouste Gulbenkian, Lisbon, Portugal. We thank Dr. C. Berry, SE Thames Regional Genetics Centre, Guy’s Hospital, London, and Dr. B. Kendall, Department of Neuroradiology, The Hospital for Sick Children, Great Ormond Street, London for the referral of patients with Joubert syndrome. REFERENCES Aicardi J , Castello-Branco ME, Roy CL (1983): Le syndrome de Joubert. A propos de cinq observations. Arch Fr P6diatr 40:625-629. AppletonRE, Chitayat D, J a n JE,KennedyR,Hall J G (1989):Joubert’s syndrome associated with congenital ocular fibrosis and histidinemia. Arch Neurol 46:579-582. Baraitser M (1986): The orofaciodigital (OFD)syndromes.J Med Genet 23: 116-1 19. Baraitser M (1990): “The Genetics of Neurological Disorders.” Oxford Oxford University Press, 2nd ed, pp 176-177. Beemer FA, Gooskens R (1985): Chorioretinal coloboma and Joubert syndrome (letter). J Pediatr 107:158-159. Boltshauser E, Isler W (1977): Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia, associated with dysplasia of the cerebellar vermis. Neuropediatrics 8:57-66. Boltshauser E, Herdan M, Dumermuth G, Isler W (1981): Joubert syndrome: Clinical and polygraphic observations in a further case. Neuropediatrics 12:181-191. Bordarier C, Aicardi J (1990): Dandy-Walker syndrome and agenesisof the cerebellar vermis: Diagnostic problems and genetic counselling. Dev Med Child Neurol 32:285-294. Brett EM (1991): Ataxia. In Brett EM (ed): “Paediatric Neurology.” Edinburgh: Churchill Livingstone, 2nd ed, pp 263-270.
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