congenital malformations of the human brainstem
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Congenital Malformations of the Human Brainstem
Laurence Walsh
ongenital disorders of the brainstem often result in multiple severe neurodevelopmental problems. With thedvent of magnetic resonance imaging and discovery of genes directing brainstem formation, a more coherentlinical picture of these disorders is emerging. Proper evaluation, management, and counseling for these disordersests on the clinician having a framework through which to approach them.
2004 Elsevier Inc. All rights reserved.
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ISORDERED BRAINSTEM development rsults in complex clinical conditions. Seve
isorders have long-standing eponyms, and oarry more descriptive names. Managemenhildren with these disorders requires knowlef disturbances in brainstem development. Tlso leads to an understanding of clinical outcond when intervention is needed, as well as reence risk counseling.
GENERAL DEVELOPMENTALCONSIDERATIONS
The development of the brainstem occurs in cert with that of the head and neck. DeMyer’s adition that “the face predicts the brain” in holoprosephaly applies equally to some disordersrainstem genesis.1 Understanding the normal pr-ess facilitates discussion of the specific disordeDuring Carnegie stage 10 (postconception
2), circumferential constrictions in the still-opeural tube define the prosencephalon, mesenlon, and rhombencephalon.2 Near the end of th
ourth conceptual week, the mesencephalic–meephalic junction, or isthmus, is well recogniznd a more caudal constriction of the rhombephalon defines the metencephalon (pons)yelencephalon (medulla).2,3 As the pontine flex-re develops, the alar plates of the rhombenclon are forced laterally, partly resulting in the ladiamond” configuration of the fourth ventriclransverse segmentation from Carnegie stage
o 15 eventually results in the formation of tight rhombomeres (r1 to r8), which begin cau
o the isthmus. Isthmus formation may be esseor this later rhombomerization of the caudal bratem, or hindbrain, including the formation ofhe progenitor for the metencephalon and cerear cortex. The isthmus itself forms the cephaortion of the fourth ventricle, the superior ceellar peduncles, and the superior medullary
um. Several genes that play a crucial rolerainstem development have been identifi
nt1-mediated activation ofEn1 and En2 is re-eminars in Pediatric Neurology, Vol 10, No 4 (December), 2003: pp 241
uired for the formation of both the isthmus andn mice. Pax2, Pax5, Gbx2 (caudal),Otx1, Otx2rostral), andFgf8 (indirectly) are but a few of thther genes required for the formation of tritical region. Homeobox-containing (Hox) genesesponsible for patterning normal brainstem depment, display specificially organized expressatterns within the developing rhombomeres.Development of the brainstem and of the head
eck occur in concert. After segmentation, nerest cells from the dorsal margin of the neural thindbrain) migrate to ensheath unsegmented mhyme to form the branchial arches.4 These rhom-omere-specific neural crest cells direct the diffe
iation of previously undifferentiated somaesenchyme into specific branchial arch–der
tructures of the head and neck. Ultimate fatesther cell groups include the trigeminal ganglionandible (r1/r2), geniculate ganglion (r4), and cial nerve (CN) IX ganglion (r6). CNs V to
hemselves arise from r2 to r8, but althoughrganization is stereotypical, it also is complex.
nstance, although the cochlear nucleus originat2, some fibers that compose CN VIII begin in r4.5 r4lso gives rise to the facial branchial efferent neurut these migrate caudally to r5 and r6,6,7 resulting in
he internal genu of the facial nerve. r5 providesrigin for the abducens nerve.8 The superior saliva-
ory nucleus, supplying visceral efferents, also oates from r5. This tightly orchestrated developmeans that errors in patterning genes result inictable CN abnormalities.Recognizable CN structures appear beginninarnegie stage 12 to 13 in humans, with m
From the Riley Hospital for Children, Indianapolis, IN.Address reprint requests to Laurence Walsh, MD, Child
eurology Section, Riley Hospital for Children, RI 1757, 702arnhill Drive Indianapolis, IN 46202.© 2004 Elsevier Inc. All rights reserved.1071-9091/04/1004-0000$30.00/0
doi:10.1016/S1071-9091(03)00078-0241-251
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242 LAURENCE WALSH
bers preceeding sensory fibers.9 The hypoglossalerve (CN XII) first appears in stage 12 (days 26 to0), followed sequentially by CNs V, VII, VIII,X/X, and XI. CNs III and IV appear in stage 13days 28 to 32), whereas the abducens nerve (VI)ppears in stage 15 (days 35 to 38).10
While the cerebellar hemispheres arise from r1, theeep cerebellar nuclei originate in r2. Cerebellar de-elopment may be divided into four phases: (1) initialevelopmental gene expression along the neural tubehat defines the cerebellar region, (2) early formationf cerebellar granule cell and related brainstem nucleirom the rhombic lip, (3) formation of cerebellar cellayers, and (4) differentiation of cerebellar neurons.11
istological evidence of the cerebellar hemispheress seen by stage 13 to 14; visible paired cerebellarulges are present at stage 18 (conceptual day 44). Byhe end of the second month, these have fused withinhe midline to form the vermis. The outline of theerebellar hemispheres is present by the end of thehird month, with the dentate appearing in the secondonth and displaying a more mature configuration
uring the third month as well.12 The main fissuresnd lobules of the vermis form by the fourth month ofestation.2 Hemispheric growth lags by 1 to 2onths. Cerebellar growth, arborization, and cellularigration continue through the first 2 years of post-
atal life. This results in a long period of cerebellarevelopmental vulnerability.
Deficits in cerebellar development may be dividedimplistically into two broad categories. Cerebellarypoplasia implies a primary reduction in the numberr ultimate size of the cerebellar folia (or lobules),hereas cerebellar atrophy involves reduced volumef once-normally formed cerebellar structures. Cere-ellar hypoplasia may be further divided into truegenesis, or aplasia (partial or complete), and hyp-plasia. Cerebellar dysplasia, which implies abnor-al cellular migration with resultant heterotopia or
ther cerebellar malformations, occurs either withypoplasia or independently. Cerebellar dysplasiaay be divided into focal and diffuse forms as well as
yndromic and isolated forms.13 A few developmen-al cerebellar syndromes that relate to brainstem mor-hogenesis are discussed later in this article. Thenterested reader is directed to articles provding moreetails on this large group of disorders.13,14
DEVELOPMENTAL BRAINSTEM DISORDERS
Mobius Sequence
As first described in 1888, Mobius sequence is the
ongenital paralysis of the abducens and facial terves.15,16 Both the definition and the cause(s) haveeen debated over the subsequent 115 years. Familytudies threaten to render the eponym useless asidely variable findings come to light, includingarying core deficits within families. Keeping inind that Mobius is a sequence, not a syndrome,
rovides a framework by which to study the disorder.The core finding in Mobius sequence is bilateral
ongenital facial paralysis not obviously associatedith perinatal trauma. Although the specific cranialerve deficits are evident on examination, the iso-ated condition is discovered most often whilenvestigating feeding or breathing difficulties, fail-re to close the eyes completely while sleeping,econdary ocular changes, or hypotonia. Casesith nonneurologic involvement discussed later
re ascertained from other, more obvious abnor-alities. Autopsy cases demonstrate hypoplasia,
bsence, or necrosis of the facial nerves or nuclei.ncomplete cases usually spare the lower face andlatysma.17 As a practical matter, most (90% to5%) individuals with congenital facial diplegialso display bilateral abducens palsy, keeping withobius’ original description.17 Although the hy-
oglossal nucleus is the next most often affectedtructure, deficits may extend to multiple cranialerve nuclei.18 One autopsy case was reported withartial absence of CN nuclei III to XI and completebsence of roots comprising CNs V to XI.19
Mobius sequence usually presents with charac-eristic facies. Although part of the facial pheno-ype relates to a mask-like appearance, a smallownturned mouth and small jaw are also com-on. Cleft palate occurs in 12% to 25% of cases,
nd together with the facial features may suggestierre-Robin sequence.20,21 Theories advanced toxplain the oromandibular abnormalities includerowth failure due to decreased fetal jaw move-ent or diminished blood supply, absent trophic
nfluence usually provided by the developing facialerves, and a primary pleiotrophic effect of aausative Mobius sequence gene or genes. Many ofhese theories are consistent with the proposedore general link between brainstem dysfunction
nd Pierre-Robin sequence.22 Mobius sequencelso occurs as part of a more generalized malfor-ation sequence. Findings beyond the face include
ony abnormalities of the cervical spine (Klippel-eil sequence) and shoulder (Sprengel deformity),nilateral chest wall and limb defects (Polandnomaly), and various other malformations. Ar-
hrogryposis may be seen, and electrodiagnostic
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243BRAINSTEM MALFORMATIONS
tudies may demonstrate more widespread periph-ral neuropathy or myopathy. A so-called “myo-athic” form of Mobius sequence has been sug-ested but not proven. An alternative explanationould be a separate syndrome featuring both theobius sequence and congenital myopathy/mus-
ular dystrophy, similar to Carey-Fineman-Zeiteryndrome or pontocerebellar hypoplasia variantsiscussed later.23 Hypogonadism and peripheraleuropathy are infrequently reported nonskeletalndings and may also represent a distinct Mobiusequence–related syndrome.24 The boundaries ofobius sequence are not yet clearly established.Cognitive deficits in Mobius sequence have re-
eived much scrutiny. Nonspecific developmentalisabilities occur in up to 50% of affected individ-als; mental retardation is unusual. More intriguings a possible association with autism. Stromland etl21 described autistic features in 7 of 25 individ-als with Mobius sequence; others also have re-orted this association.20
Evaluation of children with Mobius sequenceegins with a magnetic resonance imaging (MRI)tudy of the brain, if the child’s clinical statusermits. MRI findings vary. MRI scan of the brains not diagnostic in Mobius sequence, but good-uality studies of the brainstem may show a lack ofrotuberances related to the involved CN nuclei.he fourth ventricular floor may be flattened orepressed, reflecting absence of the abducens nu-lei and genu of the facial nerve.25
Towfighi et al26 proposed four neuropathologicategories: CN hypoplasia/aplasia, CN necrosis,eripheral neuropathy, and myopathy. As dis-ussed earlier, the nature of the myopathic formemains unclear.
Proposed causes of Mobius sequence include pre-atal vascular events, genetic insults (both singleene and polygenic), exposure to teratogens, andultifactorial disorders. The vascular theory remains
ttractive in several cases with proven areas of ne-rosis or dystrophic calcification.27 Critical periods inhe development of the posterior circulation, such as
shift from rostral-caudal to caudal-rostral bloodow at 37 to 40 days of gestation, are nestled in aroader period of collective vulnerability for therainstem, branchial arch derivatives, and limbs.28
onetheless, ischemia may be the primary event oresult from other developmental derangements,hich could have many causes.Some cases of Mobius sequence are consistent
ith autosomal recessive inheritance, which im- c
lies a genetic component.29 Autosomal dominantonditions, both sporadic and familial, also muste considered. Depending on phenotype (isolatedulbar involvement versus bulbar and limb in-olvement), empirical evidence suggests that theffspring recurrence risk in dominant familial is5% to 30%. In mice, disruption of homeoboxenes Hoxb-1 or Hoxb-2 causes facial paralysis,efects in the somatic motor component of CN VII,nd, in Hoxb-2 disruption, cervical abnormali-ies.30,31 Linkage studies implicate chromosomeq21-22.32 In an interesting twist noted earlier,ice with null mutations of either Hoxa-1 oroxb-1 demonstrate not only brainstem changes,ut also apparent autistic behavior. These geneshus are now being examined for a possible role inoth brainstem and cognitive development in hu-ans.31,33 Other candidate genes examined so far
nclude PGT, GATA2, and EGR2, but no causativeutations have been found.34 Still, reports of fa-ilial occurrence, mapping results, and animal
tudies all provide evidence that Mobius sequences at least partially a genetic disorder.
Teratogens also are implicated in the develop-ent of Mobius sequence. One of those suggested
s misoprostol (an abortifacent).35-37
Although cognition may be affected in Mobiusequence, 25% to 70% of patients who survivenfancy have normal intelligence.38 Their pros-ects for education and gainful employment areood, although they may face aggressive earlyeasures to maintain nutrition and airway func-
ion, and later cosmetic intervention.39
Duane Anomaly
Duane anomlay (DS), also known as Duaneetraction syndrome, is the most well known dis-rder of extraocular motor neuron formation. Care-ul clinical observation and genetic studies haveelineated a group of genetically determined dis-rders manifesting as variable patterns of congen-tal extraocular muscle deficit. The core deficit inS is an inability to abduct the eyes, either unilat-
rally or bilaterally, with relative preservation ofdduction.40 The globes retract on attempted ad-uction, with resultant narrowing of the palpebralssure. It occurs more commonly in females. DSesults from partial agenesis of CN VI motor neu-ons with aberrent innervation of the lateral rectususcle by oculomotor nerve (CN III) fibers.DS usually occurs sporadically; about 5% of
ases are inherited in an autosomal dominant fash-
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244 LAURENCE WALSH
on. Two DS loci, DURS1 and DURS2, have beenapped. Okihiro syndrome is the eponym for the
riad of DS, sensorineural hearing loss, and radial rayefects (Duane-radial ray syndrome).41 Okihiro syn-rome results from mutations in the SALL4 gene,hich codes for a zinc-finger transcription factor.42
nly 12% of affected patients exhibit the full triad;ther associated anomalies include heart and renalnomalies, as well as cervical defects. Okihiro syn-rome superficially resembles a variant of Mobiusequence/Poland anomaly, but with different patternsf cranial nerve and limb involvement. Two relatedisorders are acro-renal ocular syndrome and cer-ico-oculo-acoustic (Wildervanck) syndrome.43
Congenital Fibrosis of the ExtraocularMuscles and Related Disorders
Congenital fibrosis of the extraocular musclesCFOEM) is a group of disorders involving, atinimum, the oculomotor nucleus.44 In CFOEM-1
here is abnormal development of the motor neu-ons subserving the superior division of the oculo-otor nerve. Because these neurons innervate the
evator palpebrae and superior rectus, bilateral pto-is and and failure of upgaze on abduction result.FOEM-2, caused by mutations in the ARIX gene,
esults in bilateral ptosis and exotropia. The mouseomolog of this gene is required for developmentf CN nuclei III and IV. CFOEM-2 has an auto-omal recessive inheritance, whereas the otherFEOM variants described to date are autosomalominant. CFEOM-3 affects the oculomotor nerveotor neurons globally. Isolated congenital ptosis
also autosomal dominant) has been mapped to twoifferent chromosomal locations. Finally, horizon-al gaze paralysis with kyphoscoliosis, associatedith loss of the facial colliculus as well as medul-
ary changes, has been mapped in one family tohromosome 11q23-q25.45
Pontocerebellar Hypoplasia
Pontocerebellar hypoplasia (PCH) goes by var-ous names. This heterogeneous group of disorderss defined neuropathologically by atrophy of hori-ontal pontine fibers and loss or absence of pontineeurons.46 There are two major clinical subgroups.CH-1 is evident usually at or before birth and
ncludes both central and peripheral motor deficits.he combination of anterior horn cell disease plus
ypical PCH features defines PCH-1.47 Prenatally,ecreased fetal movements and polyhydramnios
ay be discovered. Profound developmental delay, cystagmus, ataxia, and hypotonia occur postna-ally. Arthrogryposis may occur.48 Death usuallynsues in infancy. Thought to be quite rare, thisroup may include several phenotypes.49,50 In ninenfants ascertained through clinical diagnosis ofpinal muscular atrophy, Rudnik-Schoneborn etl46 found symmetric but variable pontocerebellarbnormalities. Seizures were reported in two pa-ients, and most of the patients survived to theirrst birthday with severe neurodevelopmental dis-bilities. A similar disorder that includes hepatic,enal, and gonadal involvement has been reported,s has the presence of peripheral neuropathy.48,51
he peripheral neuropathy may not imply a differ-nt disorder, because this may be seen in patientsith proven classic anterior horn cell disease.52
PCH-2, also congenital, lacks anterior horn cellnvolvement. Children with PCH-2 attain few, ifny, developmental milestones and display pro-ressive microcephaly. An extrapyramidal move-ent disorder and seizures coomplicate this severe
linical course.53-55 Grosso et al56 used two unre-ated patients to suggest distinct PCH-2 pheno-ypes. They described one girl with severe infra-entorial changes but relatively spared cerebralemispheres and dyskinesias and another girl withlobal brain involvement and a history of polyhy-ramnios and akinesia interrupted only by hy-erekplexia. Other reported PCH-2 patients sug-est that these patients represent two points in aontinuous PCH-2 clinical spectrum rather than dis-rete subgroups.57-59 Some reported cases of PCH doot fit neatly into either the PCH-1 or PCH-2 pheno-ypes. These include PCH with progressive micro-ephaly, ataxia, spasticity, and Marfanoid habitus,nd radiographic PCH in the setting of clinical andistological congenital muscular dystrophy (CMD),lthough the latter more aptly may be labeled CMDariants.60-62 These can be either merosin-positive orerosin-negative disorders.63
Broad PCH phenotypes exist with other brain-tem abnormalities and are instructive. One rareisorder, thought initally to be due to an in uteroascular event, is congenital absence of the mid-rain and upper pons with cerebellar hypoplasia.his lethal infantile lethal disorder in severe respi-
atory and feeding difficulties; MRI and autopsyeveal a cord-like midbrain and upper pons, withevere global cerebellar hypoplasia. Histologicalxamination showed findings inconsistent withascular insult. One reported child had stereotypi-
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al posturing and hyperekplexia. A similar murine
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245BRAINSTEM MALFORMATIONS
henotype is produced with homozygous mutationsf En2, coding engrailed-2, an organizer protein.arnat et al3 postulated that the human disorder mayesult from mutations in the the human homologN2, rather than from vascular interruption.Diagnosis of PCH is made on clinical and neu-
oimaging grounds. MRI scans should be reviewedy a pediatric neurologist, geneticist, or neuroradi-logist with experience with cases of children withrain malformations. Electromyography and mus-le biopsy may be needed. Besides congenitaluscular dystrophies, congenital disorders of gly-
osylation (CDG) require exclusion, especially inhildren with PCH and nonneurologic organ in-olvement. Specifically, associated retinal pigmen-ary degeneration raises the possibility of CDG-a.64 Mitochondrial cytopathies likewise should beonsidered, especially if there are findings beyondhe posterior fossa.65 Urine organic acids (to ex-lude 3-methylglutaconic aciduria) should be per-ormed. PEHO syndrome (progressive encephalop-thy, hypsarrhythmia, and optic atrophy) also has
66
Fig 1. Molar-tooth sign. T1-weighted axial MRI images thridened interpeduncular spaces ventrally (“cusps”), thickeypoplastic cerebellar vermis that give rise to the typical mo
een associated with PCH. Finally, RELN muta- c
ions may result in an autosomal recessive pheno-ype consisting of profound developmental delaynd seizures. MRI scan in these patients revealsoderate lissencephaly with severe cerebellar and
rainstem hypoplasia.67 Thus, overlapping disor-ers should be sought and excluded when makingdiagnosis of PCH-1 or PCH-2.Autosomal recessive inheritance is assumed inost cases. Genetic testing is not yet available,
ecause no causative genes have been identifiedor typical forms. The various PCH phenotypesay exhibit both genetic and allelic heterogeneity.rognosis is not encouraging and may be espe-ially poor if the brainstem is very thin or rudi-entary appearing. The corallary to this is thatajor medical decisions should be made after
areful expert review of the patient’s MRI scans.reatment is supportive, but dyskinesia/dystonia inCH-2 may be dopa-responsive.56
Joubert Syndrome
Joubert syndrome (JS) consists of congenital
ontomesencephalic junction shows cerebral peduncles withd elongated superior cerebellar peduncles (“roots”), and
h sign.
ough pned an
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246 LAURENCE WALSH
is associated with the characteristic brainstemnding of a “molar tooth sign” on MRI scan.68 It is
hought to be autosomal recessive, but occurs twices frequently in boys as in girls. MRI or patholog-cal study also often reveals other cerebral andosterior fossa dysgenesis. Concomitant clinicalanifestations include characteristic facies, devel-
pmental delay (in 100% of cases) and mentaletardation (70% to 90%), hypotonia (100%), eyeovement abnormalities (60% to 100%), ataxia
75%), and unusual infantile respiratory patterns40% to 75%).69-71
The typical facial features of JS include largeead, high rounded eyebrows, epicanthal folds,road nasal bridge with anteverted nares, tentedouth with protruding tongue, and low-set, mildly
ysplastic ears.71 This facial appearance becomesess evident with age. Cognitive disability may beevere and nonspecific, but autism and pervasiveevelopmental disorders, as well as lesser devel-pmental delays, have been associated with JS.yptonia is moderate to severe. Eye movement
bnormalities include decreased smooth pursuit,culomotor apraxia (with abnormal saccades ifncomplete), and nystagmus.72 Respiratory ab-omalities include both central apnea and parox-smal tachypnea.71
MRI shows the characteristic molar tooth sign in0% of patients with JS (Fig 1). This sign, ob-erved in a transverse or axial cut through theontomesencephalic junction, comprises widenednterpeduncular fossa; splayed, thickened, elon-ated, and horizontally oriented superior cerebellareduncles; and vermian atrophy, often with a ver-ical vermian cleft. Other reported brain abnormal-ties include cerebral and cerebellar gray mattereterotopia, callosal agenesis, dysplastic dentatend inferior olives, and lack of medullary pyrami-al decussation.73 These features may be uncom-on in typical, uncomplicated JS.74
Diagnosis of JS requires both clinical and neu-oimaging findings; diagnostic criteria are outlinedn Table 1.71 Although the molar tooth sign orermian abnormalities are required for diagnosis,n themselves they are not sufficient for diagnosis.able 2 lists other clinical disorders in which theolar tooth sign occurs. Verification of whether
here is a “Joubert spectrum” or whether theseisorders each represent genetically discrete syn-romes awaits further molecular studies. Linkageas been established to both chromosome 9q34 and
7p11.2, but other individuals with JS do not show cinkage to either site, suggesting significant geneticeterogeneity.75 To date, study of several attrac-ive candidate genes mapped ot 9q34.3 has notevealed any mutations.76 Mice heterozygous foric1 knockdown mutations (Zic1�/�) display an-
erior vermian hypoplasia, but there are at least 50nown attractive candidate genes in humans.77 Toate, WNT1 mutations have not been found ineople with JS.Disorders that share the molar tooth sign also
hare several other specific features. In addition toermian hypoplasia and characteristic brainstemndings, these disorders feature mental retardation,ye movement abnormalities, ataxia, breathing ab-ormalities, retinal dystrophy and colobomas, he-atic disease, and renal disease. The mental retar-ation is often severe; the retinal disease may be
Table 1. Diagnostic Criteria for Joubert Syndrome
Common Abnormalities:
Muscle tone Hypotonia (100%), mostsevere as neonate andinfant.
Balance- 75% of children learn to sit(by 18 months) 50%learn to walk withunstable gait (4 years)
Calcaneal eversionDevelopment- Global, often severe
developmental delay;Pleasant disposition
Neuroradiology- Molar tooth sign in axialplane
Vermis hypoplasia ordysplasia
Vertical cleft of vermisPathology- Vermis
hypoplasia/dysplasiaBrainstem dysplasia
Associated Abnormalities:Face- See textBreathing- Episodic hyperpnea and or
apnea, most evident inthe neonatal period andin infancy.
Eyes-. Retinal dysplasia,colobomas, nystagmus,strabismus, and ptosis.Retinal blindness israrely present
Ocular-motor- Apraxia and defectivesaccadis
Renal- Microcystic renal diseaseLimbs-. PolydactylyUncommon- Abnormal head size
onsistent with Leber congenital amaurosis or may
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247BRAINSTEM MALFORMATIONS
e less specific. Hepatic disease may be eitherbrotic or cystic, and renal disease may be con-enital or infantile cystic disease or a later-onsetclerofibrotic disease (nephronophthisis). Congen-tal cystic renal disease correlates with early death.atran et al found78 that individual patients usuallyid not display both retinal disease and colobomas,or did they have intermediate forms of renalisease. This again suggests that these disordersepresent discrete points on a clinical spectrum,ather than a single, variably expressed syndrome.
If this indeed is the case, then the clinicalpectrum is a very crowded one. Other casesecognized to date include those with typicalosterior fossa findings and either otherwise iso-ated retinal, renal, or hepatic disease.79 Thathese represent distinct syndromes is supportedy the finding of NPH1 mutations in some pa-ients with molar tooth sign and nephronophthi-is. The spectrum also is broad if one includesaciodigital syndromes (OFD II, or Mohr syn-rome; and OFD VI, or Varadi syndrome), orimply JS plus polydactyly.80,81 Finally, a sib-air case that we have reported raises the ques-ion of why the molar tooth sign develops.82 Ourubjects, two sisters with lifelong disabilities,
Table 2. Conditions Associated
Disorder InheritancePattern
Locus/Gene
Joubertsyndrome
AR
COACHsyndrome
AR
Senior-Lokensyndrome
AR 2q13/NPHP1
Arimasyndrome
AR
Mohrsyndrome
AR
Varadisyndrome
AR
ere found to have a phenotype intermediate f
etween Pelizaeus-Merzbacher disease (PMD)nd JS. Their MRIs revealed somewhat atypicalolar tooth signs (thinner superior cerebellar
eduncles, no rostral fastigial shift) and vermianypoplasia, but grossly undermyelinated cere-ral white matter consistent with that seen inoys with PMD. PLP1 mutation analysis, as wells extensive additional ancillary testing, has noteen fruitful to date. It may be that the molarooth sign has more to do with the developmen-al biology of posterior fossa development thanith its genetics.Given the marked variability in associated find-
ngs, evaluation of children with a molar tooth signn brain MRI includes ophthalmologic examina-ion and tests of both renal and hepatic structurend function. Additional testing is warranted basedn individual case findings.Some other disorders are often mentioned in
he same breath as JS. These include isolatedandy-Walker malformation, tectocerebellarysraphia, and rhombencephalosynapis, as wells other single case reports.83 Tectocerebellarysraphia comprises occipital encephalocele,entrolaterally displaced and hypoplastic cere-ellar hemispheres, and a thin extension of tissue
Molar Tooth Sign on Brain MRI
ther Neurologiceatures
Other Major Features
ee text
ental retardation,taxia
ocular colobomas, hepaticfibrosis, nephronophthisis
ild-severe mentaletardation
episodic hyperpnea,retinopathy,nephronophthisis
evere mentaletardation,ultiple brain
bnormalities
retinopathy, dysplastic(cystic) kidneys
ental retardation short stature, midline cleftlip, lingual clefts orhamartomas, preaxialpolydactyly, syndactyly,coloboma, conductivehearing loss
sually severeental retardation,
otary nystagmus,andy-Walkeralformation
hyperpnea and apnea, shortstature, multiple oralfrenulae, cleft lip/palate,polysyndactyly (usuallypostaxial), conductivehearing loss, cardiac defects
with a
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248 LAURENCE WALSH
ephalocele. Near or complete vermian aplasia iseen. Outcome is poor. Conversely, rhomben-ephalosynapsis is interesting, because affectedhildren may have significant neurodevelopmen-al preservation despite grossly abnormal braintructure that includes absent vermis and fusederebellar hemispheres and dentate nuclei (Fig). Cerebral peduncles, colliculi, and thalamiay be fused, and cerebral cortical involvement
s seen. Occipital or parieto-occipital encephalo-ele may occur. Rhombencephalosynapsis repre-ents a failure of normal midline formation (ie,f the fourth ventricle and vermis) before the endf the seventh conceptual week (stages 18 and
9), with subsequent secondary fusion of the cerebellar hemispheres. This is in contradistinc-ion to the failure in cleavage that leads tooloprosencephaly. The disorders in this lastroup usually lack the molar tooth sign andany of the neurologic and nonneurologic fea-
ures of the conditions described earlier. Asoted, the prognoses may vary widely.
CONCLUSION
This discussion represents only a primer ofisordered brainstem development in humans.ertebrate brainstem formation results from the
nteractions of multiple genes. Homeodomain-
Fig 2. Rhombencephalosynapsis. MRI images show neu-oradiographic features of rhombencephalosynapsis. (A)agittal T1-weighted image shows gross cerebral corticalisorganization and evidence of repaired parietal encephalo-ele. (B) Axial T1 image reveals absence of cerebellar vermisnd continuity of cerebellar hemispheres across the midline;ore rostral image shows fused thalami and again, diffuseigrational abnormalities. (C) Coronal T2-weighted image
gain shows cerebellar hemispheres contiguity across theidline.
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ontaining genes, and other related genes in-
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249BRAINSTEM MALFORMATIONS
olved in signal transduction, may control theate of multiple brainstem cell populations ornly a single discrete nucleus. For example,nimal studies have demonstrated that a singleene knockout (eg, Rnx in mice) disrupts theormation of first-order visceral sensory neuronsn the brainstem.84 The resultant phenotype iseonatally lethal due to respiratory failure.here already are numerous vertebrate models
or such specific brainstem deficits, many ofhich will likely find human homologs over theext few years.Disruption of brainstem development pro-
uces variable and often profound clinical ef- t
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ects. Likewise, gene mutations resulting in dis-rdered formation of the brainstem and its nucleiroduce myriad but very specific and predictablehenotypes. Some of these phenotypes allowtherwise normal development and lifespan,hereas others portend neurodevelopmentalevastation and early death. Understandingrognosis and management in individual patientsequires synthesis of the clinical picture, the
RI image, and, soon, results of genetic testing.his will give the clinician the best chance ofelping families of affected children make diffi-ult and often wrenching decisions regarding
heir children’ s care.ES
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