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Cerebral, cerebellar, and colobomatous anomalies in three related males: Sex-linked inheritance in a newly recognized syndrome with features overlapping with Joubert syndrome

Cerebral, cerebellar, and colobomatous anomalies in three related males: Sex-linked inheritance in a newly recognized syndrome with features overlapping with Joubert syndrome
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   American Journal of Medical Genetics 135A:297–301 (2005) Clinical Report Cerebral, Cerebellar, and Colobomatous Anomalies inThree Related Males:  Sex-Linked Inheritance in a NewlyRecognized Syndrome With Features Overlapping With Joubert Syndrome Hester Y. Kroes, 1 * Rutger-Jan A.J. Nievelstein, 2 Peter G. Barth, 3 Peter G.J. Nikkels, 4 Carsten Bergmann, 5 Rob H.J.M. Gooskens, 6 Gepke Visser, 7 Hans-Kristian Ploos van Amstel, 1 and Frits A. Beemer 1 1  Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands  2  Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands 3  Department of Pediatric Neurology, Emma Children’s Hospital/University Medical Center, Amsterdam, The Netherlands 4  Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands 5   Department of Human Genetics, Aachen University of Technology, Aachen, Germany 6  Department of Child Neurology, University Medical Center Utrecht, Utrecht, The Netherlands 7   Department of Metabolic Diseases, University Medical Center Utrecht, Utrecht, The Netherlands  WepresentasofarunrecognizedX-linkedmentalretardation syndrome with features overlapping with Joubert syndrome (JBS). Two brothersshowed hypotonia, mental retardation, ocularabnormalities with impaired vision and colobo-masandabreathingpatterncompatiblewithJBS.Neuroimaging revealed cerebellar vermis hypo-plasia and ventriculomegaly. A tentative diagno-sis of JBS was made, and autosomal recessiveinheritance considered most likely. In a subse-quent pregnancy that occurred after artificialdonor insemination,ultrasound inthe22nd week revealed a Dandy–Walker malformation andhydrocephaly.Atautopsyat34weeksofgestation,the male infant showed cerebellar vermis aplasiaand abnormalities of the brainstem and cerebralcortex. He was considered to have the samedisorder as his two half-brothers. This rendersthepedigreehighlysuggestiveofX-linkedinheri-tance. The clinical symptoms of this syndromeresemble JBS. However, the absence of the molartooth sign and the X-linked inheritance do notsupport JBS. We propose the name X-linkedcerebral-cerebellar-colobomasyndrometodistin-guishthetwodisorders.Differentiationofthetwodisordersisespeciallyimportantingeneticcoun-seling, where artificial donor insemination may  be considered as a means of reducing the recur-rencerisk,orwhenfemalerelativesofthepatientare concerned.   2005 Wiley-Liss, Inc. KEY WORDS: coloboma; Joubert syndrome; X-linked inheritance; molar toothsign; vermis hypoplasiaINTRODUCTION ThephenotypeofJoubertsyndrome(JBS),firstdescribedby Joubert and colleagues in 1969 [Joubert et al., 1969], hasexpanded over the years with more and more associatedanomalies being reported. In the last decennium diagnosticcriteria were formulated [Saraiva and Baraitser, 1992;Steinlin et al., 1997; Maria et al., 1999a] in an attempt todefine the syndrome more precisely. On MRI of the brain, the‘‘molartoothsign’’wasrecognizedasanimportantdistinguish-ing feature of the syndrome [Maria et al., 1997].The association of colobomas and JBS was first suggestedby Lindhout et al. [1980], and later confirmed by several otherauthors [Pfeiffer, 1981; Laverda et al., 1984]. LindhoutpostulatedX-linkedinheritanceincasesofJBSwithcolobomason the basis of the excess of male patients with this phenotype[Lindhout and Barth, 1985]. However, convincing X-linkedpedigrees were never published. Wepresentafamilywiththreemalecaseswithaphenotypeoverlapping with JBS, including vermis hypoplasia, colobo-mas, and neurological features of JBS syndrome. Two of themale siblings were briefly described before by Van Royen-Kerkhof et al. [1998] as autosomal recessive JBS (with co-incidental coexistence of Gaucher disease in the same family).In 2001, however, the third male case in this family was bornafter artificial donor insemination. We believe this providesstrong evidence for X-linked recessive inheritance. CLINICAL REPORTSPatient 1 Thefirstchildinthisfamily(II.1inthepedigree,seeFig. 1),a boy, was born after a normal pregnancy with a birth weightof 3,840 g. The mother (I.2) was of Caucasian, the father(I.1) of Indonesian origin; they were healthy and non-consanguineous. The family history included a stillborn child(sexunknown)withaneuraltubedefectandhydrocephalusonthe mother’s side (a child of the sister of her mother).Postpartum the infant had episodes of cyanotic apnea alter-nating with tachypnea, for which he was intubated for 3 days.He suffered from convulsions that responded to anti-epileptictreatment. On neurologic examination he was severelyhypotonic and reflexes were absent. There were roving eyemovements and the ophthalmologist found bilateral retinalcolobomas.Dysmorphicfeaturesinthechildincludedapparenthypertelorism, a small nose with broad alae nasi, lowset ears, *Correspondence to: Hester Y. Kroes, Department of MedicalGenetics, University Medical Center Utrecht, Internal mailKC04.084.2, P.O. Box 85090, 3508 AB Utrecht, The Netherlands.E-mail: H.Y.Kroes@dmg.azu.nlReceived 16 June 2004; Accepted 24 January 2005DOI 10.1002/ajmg.a.30690   2005 Wiley-Liss, Inc.  and micrognathia. Head circumference was 38.5 cm at birth( > p98), ultrasound revealed hydrocephalus. The anteriorfontanelwaslarge.Duringthe firstyeartheabnormalbreath-ing pattern persisted. Convulsions and anti-epileptic drug treatment continued. The boy had severe psychomotor delayand hypotonia. There were feeding problems because of diffi-culties in swallowing, requiring occasional gastric tube feed-ing.Headcircumferenceattheageof1yearwas47cm(p25).Atage 2 his eyes still did not fixate. The boy died at home at age3 years. Autopsy was not allowed.BecauseoftheassociationofvermishypoplasiaseenonaCT-scan(seebelow),acharacteristicbreathingpatternandocularabnormalities, a diagnosis of JBS seemed likely at the time.The parents were referred for genetic counseling and given arecurrenceriskof25%inaccordancewithautosomalrecessiveinheritance.Two years after his death, a cell line of cultured skin fibro-blastsofthepatientwasusedasacontrolforabeta-glucosidaseassay in another laboratory. Although used as a control, thiscell line was shown to have reduced beta-glucosidase activityleadingtoapostmortemdiagnosisofGaucherdiseasetypeIinadditiontoJBS.DNAanalysisofthegeneforbeta-glucosidaserevealed that the patient was compound heterozygous for twopointmutations,confirmingthebiochemicaldiagnosis.Eachof theparents wasshowntobecarrier ofamutation.Thepatienthad no apparent symptoms of Gaucher disease during hisbrief life. Clinical Investigations  A CT-scan of the brain shortly after birth showed severehypoplasia of the vermis of the cerebellum resulting in anenlarged communication of the fourth ventricle with a rela-tively large arachnoid space surrounding possibly slightlyhypoplastic cerebellar hemispheres (Fig. 2). The brainstemappeared normal in size. The lateral ventricles were enlargedwith a normal sized third ventricle and a small posteriorinterhemispheric cyst, possibly associated with callosaldysgenesis.In the right cerebral hemisphere an abnormal irregularband of gray matter was observed extending from the cortexto the dilated right lateral ventricle, suggesting some type of malformation of cortical development. Both cerebral hemi-spheres showed open Sylvian fissures secondary to abnormalopercularization. Chromosomal analysis was normal (46,XY).Metabolic screening performed in the first month after birthwasnormal.Visualevokedresponsesatage1yeardidnotshowany responses. The results of a BERA test (brainstem evokedauditoryresponses)wereunequivocal.AnEEGshowedseverediffuse hypofunctional irritative abnormalities.The next pregnancy (II.2) in this family ended in a spon-taneous abortion early in pregnancy. The third pregnancy(II.3)wasunremarkableandababygirlwasbornattermwitha birth weight of 2,500 g and a length of 45 cm. There wasprolonged neonatal icterus. There were no dysmorphic fea-tures.Herheighthas alwaysbeenjustbelowthe thirdpercen-tile, head circumference was repeatedly normal (25 centile).Hervisualfunctionsandresultsofophthalmologicalexamina-tions were normal. Her development was slow, with unaidedsitting at 16 months, walking at 20 months, and only a fewwords at 2½ years. Her behavior was characterized by hyper-kinesia and poor interaction. At age 4 her cognitive devel-opment was severely retarded. Her motorfunctions wereapparently normal (she could run and climb stairs). Neurolo-gical examinations and investigations, including repeatedMRI scans of the brain, were normal. She had possibly onespontaneous tonic clonic convulsion, and a generalized tonicclonic convulsion after anesthesia. An EEG performed at age16 was normal. Chromosomal investigations showed a normalfemale karyotype (46,XX). DNA-analysis of the  MeCp2  generevealed no abnormalities. Metabolic investigations revealedshe had Gaucher type I like her older brother, resulting inhepatosplenomegaly and severe diffuse infiltration of bonemarrow at age 15. Patient 2 In the fourth pregnancy (II.4) hydrocephalus was detectedon ultrasound screening in week 17. A baby boy was born atterm with a birth weight of 3,220 g, length 51 cm, and headcircumference 39.3cm(  p98).Hewasseverelyhypotonic andhad an irregular breathing pattern with periodic tachypneaand apnea, described as typical for JBS. There were nodysmorphic features apart from retrognathia. Head circum-ferencewas41cm(p75)atage3months,and44cm(p50)atage6 months. Ophthalmological examination revealed bilateralchorioideal colobomata. He reacted to light and auditorystimuli. The patient developed seizures that persistedthroughout his life. Tube feeding was necessary due to poorsucking. A CT-scan of the brain (Fig. 3) revealed an abnormallyshapedposteriorfossaduetoahighinsertionofthetentorium,with severe hypoplasia of the vermis of the cerebellum andfolial atrophy. Consequently, there was an enlarged commu-nication between fourth ventricle and pericerebellar CSFspace surrounding the cerebellum. The cerebrum showeddilated lateral ventricles with a normal sized third ventricle,agenesis of the corpus callosum and open Sylvian fissuressecondary to abnormal opercularization. A posterior inter-hemisphericcystwasseenpossiblyassociatedwiththecallosalagenesis. Metabolic screening revealed no abnormalities(Gaucher disease was not investigated because the diagnosishad not been made yet in Patient 1). The kidneys were normalon ultrasound. Fig. 1. Pedigree of the family.Fig. 2.  A : CT-scan of the brain in Patient 1, shortly after birth, showshypoplasia of the vermis (arrow) and cerebellar hemispheres (arrowheads),resulting in a relatively large arachnoid space in the fossa posterior. Inaddition,wideningofthesylvianfissurescanbeseen(curvedarrows).In( B )theenlargedlateralventricles,interhemisphericcyst(arrow),andabnormalirregular band of cortical gray matter (arrowheads) are shown. 298 Kroes et al.  Thepatientdiedattheageof8monthsduetoaspirationafteran apneic spell or seizure. Autopsy was not allowed.Because of the presumed autosomal inheritance, for furtheroffspring the parents opted for artificial donor insemination(I.3). Vasectomy was performed in the father. The fifth preg-nancy resulted in the birth of a healthy baby girl (II.5). She is6 years old now and her development is normal. No clinicalinvestigationshavebeendone,apartfrommetabolicscreening for Gaucher disease, which was normal. Patient 3 The sixth pregnancy (II.6) was also the result of artificialdonor insemination. Ultrasound at 22 weeks showed hydro-cephalus and a Dandy–Walker malformation, with a headcircumference above the 98th centile. A prenatal MRI at30 weeks confirmed these findings and also revealed an ab-normally smooth cortical surface. Chromosomal analysis of amniocytes revealed a normal male karyotype. Because of furtherincreasingheadcircumferenceacaesariansectionwasperformedinweek34.Thechild,aboy,diedimmediatelyafterdelivery. Atautopsytheinfantweighed3,100g,hiscrownheellengthwas 51 cm, crown rump length was 38 cm, and his headcircumference was 41 cm. All measurements were above thep98forhisgestationalageof34weeksandinaccordancewithagestational age of 38 weeks except the head circumference,which was far above the p98 for 38 weeks of gestation. Therewasslightfrontalbossingandhisearswerelowsetandrotatedbackwards.Theeyeswerenotexamined.Internalexaminationrevealed an aberrant srcin of the right subclavian artery anda Meckels’ diverticulum. Renal weight was normal for thepregnancy duration of 34 weeks and the other organ weightswereinaccordancewithapregnancydurationof38–40weeks. Apartfromsignsofrecenthypoxiainthethymusandamnioticfluidaspirationinthelungsnoabnormalitieswereseen.AnX-ray revealed thirteen ribs on both sides.Brain weight was 450 g with a severe hydrocephalus and aDandy–Walker malformation. The cerebellar vermis wasabsent and a there was a cyst-like structure in the fossaposterior. The fourth ventricle was wide. There was no sepa-ration of the various brainstem structures as lateral colliculi.The medulla oblongata was abnormally shaped with dorso-ventral flattening. The posterior raphe of the medullaoblongata was missing. The inferior olivary complex couldnot be identified (Fig. 4A). The absence of a midline raphe wasalsofoundintheventralpons,butthepontinetegmentumwas Fig. 3.  A : CT-scan of the brain in Case 2 shows a small posterior fossawith severe hypoplasia or aplasia of the vermis of the cerebellum (arrow)resulting in opposition of the moderately hypoplastic cerebellar hemi-spheres. There are open sylvian fissures (curved arrows). In ( B ) the dilatedlateral ventricles and left occipital cyst are shown (arrow). The lateralconvexity of the dilated frontal horns (curved arrows) and mild interdigita-tion of the gyri in the midline (arrowheads, see also A) are suggestive of callosal agenesis.Fig. 4.  A : Transverse section through the medulla oblongata near thelateral foramina. Note the dorsoventral flattening, absence of olivarynucleus at this level and absence of a midline raphe in the ventral part.H&Estain. B :Transverse sectionofmesencephalon.Thereis noseparationofrightandlefthalvesofthemesencephalictectum.Kluever–Barrerastain. C : Cerebral cortex with extensive leptomenigeal heterotopia and focalcortical disorganization. H&E stain.  X-Linked Cerebral-Cerebellar-Coloboma Syndrome 299  recognizable.Alsotheseparationbetweenrightandlefthalvesof the mesencephalic tectum was missing (Fig. 4B). The cere-bellar hemispheres showed some loss of Purkinje cells andcerebellar cortical dysplasia. The cerebral cortex showed focaldisorganization of the upper cortical layers and extensiveleptomeningeal heterotopia (Fig. 4C). The corpus callosumcould not be identified, possibly due to the severe hydrocepha-lus and consequent fragility of the brain. Unfortunately,samples taken for histology did not represent the area of thecorpus callosum adequately.DNA-analysis of L1CAM was performed because of possible X-linked hydrocephalus and was negative. MOLECULAR ANALYSIS DNA-investigations were performed to establish paternityinthethirdmalepatient(II.6).DNAfromthefather(I.1)ofthefirst two male patients was extracted from peripheral blood,DNA from the third male patient (II.6) was extracted fromcultured fibroblasts, using established procedures. DNA fromthe anonymous sperm donor was not available. Paternity wastested using the AmpFlSTR Profiler Plus PCR Amplificationkit as described by the manufacturer (Perkin-Elmer AppliedBiosystems, Foster City, CA). X-inactivation status was anal- yzed in the mother (I.2) and the mentally retarded daughter(II.3) essentially as described by Allen et al. [1992]. RESULTS Paternity of the father (I.1) of the first two male patientscould be excluded in the third male patient (II.6). X-inactiva-tion in the mother (I.2) and mentally retarded daughter (II.3)followed a random pattern. DISCUSSION Comparing the clinical data of these three cases, we believethey represent the same disorder. Unfortunately, we didnot check for colobomas in case three. On the basis of thebrain anomalies alone, we cannot be absolutely certain thethree cases represent the same disorder. An autosomal reces-sive disease in case one and two, with an unrelated disorderin case three, is theoretically possible, especially as theDandy–Walker anomaly is reported often as a sporadic dis-order. However, the pedigree is very suggestive of X-linkedinheritance.The differential diagnosis includes, besides JBS, COACHsyndrome, an acronym for cerebellar vermis hypoplasia/ aplasia,oligophrenia,congenitalataxia,coloboma,andhepaticfibrosis, described by Verloes and Lambotte [1989]. Theabsence of liver involvement and the X-linked pedigree in ourcases render COACH syndrome unlikely. Muscle-eye-braindisease was also considered, but there was no musculardystrophy (no raised CK values) and the brain abnormalitiesseen on brain scans and especially on autopsy of patient threewere not compatible with this diagnosis either. Recently, amutation in  OPHN1 , a gene already implicated in X-linkednon-syndromic mental retardation [Billuart et al., 1998], wasshown to cause a phenotype with, besides mental retardation,epilepsy, cerebellar hypoplasia and ventricular enlargement,although no ocular anomalies [Bergmann et al., 2003]. DNA-analysis of   OPHN1  in case 1 was performed recently, butshowed normal results. An extensive search through OMIM( revealed no X-linkedphenotypes combining the typical ocular and cerebellaranomalies. Mutations in the ARX gene can cause several X-linked mental retardation phenotypes with agenesis of thecorpus callosum and cerebral abnormalities including lissen-cephaly and hydranencephaly. Distinct ocular and cerebellaranomalieshavenotbeendescribedinthepatientsinvestigatedsofar,whereasgenitalabnormalitiesareanimportantfeaturein male patients, making involvement of ARX in our patientslesslikely[Katoetal.,2004].Intwobrotherswithcolobomasof theopticnerveandiris,mentalretardationandagenesisofthecorpus callosum, Graham et al. [2003] detected a possiblypathogenicmutationintheIGBP1geneontheX-chromosome.However, MRI scans of these patients were otherwise normal,and they had several additional congenital malformations,differentiating this phenotype from the one seen in ourpatients.The simultaneous occurrence of Gaucher disease in two of the sibs, the eldest patient and his mentally retarded sister, isvery likely coincidental. Linkage of Gaucher disease with theneurological syndrome seems unlikely, since in that caseinheritance of the syndrome should be autosomal recessive,and the difference in phenotype between the two sibs (case 1(II.1)andthementallyretardedsister(II.3),inwhomGaucherdisease was diagnosed), as well as the reoccurrence of thesyndrome after artificial donor insemination in the third malecase (II.6), would be hard to explain (no investigations forGaucher disease were performed in II.6).Theseverementalretardationinoneofthetwodaughtersispuzzling. Carriership of an X-linked dominant disease withsevere expression in males is theoretically possible, but thenormal intelligence of the mother with a random pattern of  X-inactivation does not support this (although germinalmosaicism of an X-linked dominant disease in the motherremains an option).Evaluating the data in the light of today’s insights, webelievethedisorderinthisfamilyshouldberegardedasanovelsyndrome distinct from JBS with characteristic X-linkedinheritance. The main distinguishing clinical features com-pared to JBS are the absence of the molar tooth sign (that hadnot yet been reported in the literature at the time the first twocaseswereborn)andthepresenceofadditionalsupratentorialbrain malformations. An important difference from previous pathological reportson JBS [Friede and Boltshauser, 1978; Van Dorp et al., 1991; Yachnis and Rorke, 1999] is the presence of leptomeningealheterotopiaoverlying theneocortex.Neocortical dysplasiaofadifferent kind (cortical heterotopia) are reported in a singlepatient by Ten Donkelaar et al. [2000]. The presence of hydrocephalus and Dandy–Walker malformation has beenobserved in some previous reports. Dandy–Walker malforma-tion is related to hypoplasia of the vermis, and as such can beregardedasavariantwithintheJoubertcomplex,ratherthana separate abnormality. Abnormalities of the inferior olivarynucleihavebeendescribedpreviously.FriedeandBoltshauserreported dysplasia, while Yachnis and Rorke reported hypo-plasia of the inferior olivary nuclei. The apparent absence of these nuclei in the present case may constitute an (extreme)variation. Interesting also are the midline abnormalitiesaffecting the raphe of the pons and the dorsal raphe of themedullaoblongata.Absenceofthedorsalmidlineseparationof the medulla oblongata is mentioned in the report of Yachnisand Rorke. Absence of the normal division of the tectum hasbeen reported by Ten Donkelaar. The multiple midlineabnormalities found in the present autopsy report are there-fore in line with previous reports on JBS. They point to anembryonic organizing failure affecting the midline structuresof brainstem and cerebellum.The molar tooth sign is regarded as an obligatory feature in JBSbySteinlinetal.[1997]andMariaetal.[1999b].Thelatterevaluated the neuroradiological findings in 46 patientsdiagnosed previously as JBS, and found the molar tooth signin 85% of cases (n ¼ 38). They reported that the eight patients 300 Kroes et al.  without the molar tooth sign had other definable conditionsand called them ‘‘JBS mimics.’’ JBS is a genetically heterogeneous disease [Blair et al.,2002]. So far, two genes have been identified in autosomalrecessive JBS: the  AHI1  gene, that causes a JBS phenotype inwhich no ocular (or renal) anomalies have been described yet[Ferlandetal.,2004],andtheNPHP1gene,inwhichdeletionshave been found in two patients with juvenile nephronophthi-sis and a mild JBS phenotype [Parisi et al., 2004]. Of the twoloci JBTS1 on chromosome 9q34.3 and JBTS2 on chromosome11p11.2-q12.3 only the JBTS2 locus is associated with retinaldisease and colobomas [Keeler et al., 2003]. X-linked inheri-tance was postulated for the first time by Lindhout and Barthin 1985, on the basis of the absence (up to that point) of femalecaseswithcolobomasandthelowfrequencyofconsanguinityincases with JBS and colobomas compared to cases with JBSwithout colobomas. Although later on a few female cases with JBS and colobomas were described by Raynes et al. [1999], byDahlstrometal.[2000],andlesstypicalcasesbyVanDorpetal.[1991] and Kher et al. [1994], male cases are still much moreprevalent in the literature. Although some of these casesreported as ‘‘JBS with colobomas’’ may actually be cases of thesyndrome described in this report, many show the classical JBS symptoms, including the molar tooth sign withoutadditional supratentorial brain malformations. Considering the marked genetic heterogeneity of JBS, an X-linked form of ‘‘classical’’ JBS with coloboma remains feasible. Without further elucidation of the molecular biology of JBSand related syndromes genetic counseling will remain incon-clusive in families with a male patient with cerebellar vermisabnormalities and colobomatous malformations. In thosefamilies artificial donor insemination as a means of reducing the recurrence risk for sibs should not be propagated.To conclude, we feel the phenotype we describe should benamed separately to distinguish it from overlapping syn-dromes.Combiningthemostsalientfeaturesofthisphenotypewe propose the name X-linked cerebral-cerebellar-colobomasyndrome. REFERENCES  Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. 1992.Methylation of HpaII and HhaI sites near the polymorphic CAG repeatin the human androgen-receptor gene correlates with X chromosomeinactivation. 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