síndrome de moebius

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síndrome de moebius
HOSPITAL CLÍNICO SAN BORJA ARRIARÁN SERVICIO DE NEUROPSIQUIATRÍA INFANTIL SÍNDROME DE MOEBIUS Dr. Guillermo Fariña Kutz
Neurólogo Infan.l
Dra. Daniela CasHllo Villagrán Residente Neurología Infan.l Mayo 2014 SÍNDROME DE MOEBIUS DEFINICIÓN DEBILIDAD FACIAL CONGÉNITA ASOCIADA A ALTERACIÓN EN LA ABDUCCIÓN OCULAR Developmental facial paralysis
•  Se debe, en parte, a la pérdida de la función de nervios craneales motores •  La mayoría de los casos se diagnos.can durante la infancia Developmental facial paralysis
•  Es una enfermedad no progresiva 1321
Figure 2 Example of classical Möbius syndrome case. Preoperative picture of a 9-year old boy
palsy (Möbius syndrome), left side more involved than the right. Note the absence of expression
(Figure 2a). Neurological examination in addition to the bilateral seventh nerve involvement (
(III) bilaterally, (inability to gaze upward), bilateral sixth (VI) (paralysis of lateral gaze) and
undergone a left otoplasty for correction of prominent ear deformity and a static fascial slin
performed elsewhere at a younger age. He was treated with a two-stage free gracilis muscl
motor fibers from the contralateral facial nerve. Secondary revisional surgery took place tw
temporalis pedicle transfer to the left commissure. Appearance of the patient in his last follo
surgery (Figure 2b).
talipes equinovarus, syndactyly, hemimelia, Poland’s
anomaly, craniofacial deformities, etc. (Figures 3 and 4).
Hemifacial microsomia (HFM)
Figure 2
vascular disruption hypo
HFM risk and other patho
free radical generation,4
sure to teratogens39 an
technologies have been p
A common association is Hemifacial Microsomia (HFM), an
Neonatal asymmetric
umbrella term that covers a variety of developmental
defects. HFM involves first and second branchial arch
derivatives with a highly variable phenotype. Deformities
The clinical hallmark o
may include auricular defects, preauricular tags and
appearance at rest, but s
fistulae, microtia-atresia, mandibular, maxillary, and
the lower lip with crying
orbital hypoplasia, micropthalmia, epibulbar dermoid,
been used to characteriz
Example of classical Möbius syndrome
case. Preoperative
picture
of a 9-year oldhearing
boy withloss,
bilateral
facial
strabismus,
conductive
or sensoneural
and developmental
crying faces,
congenital h
SÍNDROME DE MOEBIUS HISTORIA 1880 Von Graefe describe un caso de diplejía facial congénita Leipzig, W Engelman. 1880;6:60. 1888 y 1892 El síndrome es descrito con más detalle por Paul Julius Möbius, neurólogo alemán Munchen Medizinische Wochenschri7. 1888;35:91-­‐4. Munchen Medizinische Wochenschri7. 1892;39:17-­‐21, 41-­‐3, 55-­‐8. Von Graefe y Möbius aceptaron sólo casos con DIPLEJÍA FACIAL CONGÉNITA Y PARÁLISIS DEL VI P.C. BILATERAL para consHtuir el síndrome de Moebius SÍNDROME DE MOEBIUS HISTORIA 381
1939 Henderson amplía la definición e incluye casos con parálisis facial congénita UNILATERAL THE CONGENITAL FACIAL DIPLEGIA SYNDROME: CLINICAL FEATURES, PATHOLOGY AND ETIOLOGY. 1
A REVIEW OF SIXTY-ONE CASES
(From the Department
• 
University of
Edinburgh.)
Brain. 1939;62:381-­‐403. paralysis of cranial nerves is sufficiently
rare to attract
special attention. The ocular and facial nerves are those most frequently
and thela anatomical
relationships
of thedlatter
render them
suscep- entre En la aaffected
ctualidad, definición y criterios iagnósHcos varían tible to paralysis from a greater variety of causes. Thus, there are several
autores types of congenital facial palsy. The intra-partum types predominate and,
with the extremely rare exception of bilateral peripheral trauma, they are
Algunos más restric.vos en su definición, requieren la presencia de all unilateral. Of the ante-partum types, however, the bilateral variety is
una anomalía congénita musculoesqueléHca para hnerve
acer el the commonest
and is usually
associated with other cranial
palsies.
This paper is solely concerned with the ante-partum bilateral type.
diagnós.co A child displaying many typical features of the condition was seen
recently at the Royal Edinburgh Hospital for Sick Children. Perusal of
the relevant literature showed that no adequate review of the published
CONGENITAL
• 
of Child Life and Health,
Downloaded from http://brain.oxfordjournals.org/ at Univers
BY J. L. HENDERSON
URRENT
C
OPINION
Congenital cranial dysinnervation disorders:
a concept in evolution
Thomas M. Bosley a, Khaled K. Abu-Amero a,b, and Darren T. Oystreck a,c
Curr Opin Ophthalmol. 2013 Sep;24(5):398-­‐406. Purpose of review
We review the congenital and genetic diagnoses that are currently included in the congenital cranial
dysinnervation disorders (CCDDs).
•  Hace más de 60 años à Ciertos niños nacen con alt. de la mo.lidad ocular aRecent
sociados findings a músculos extraoculares fibró.cos Recent literature contains new genotypic and phenotypic descriptions of Duane retraction syndrome,
Moebius syndrome, and other CCDDs. New genes which when mutated can result in CCDD have been
identified, permitting a better understanding of associated phenotypes. More information is available
regarding
neurodevelopmental
and clinicalceffects
of various gene
associated with individual
Concepto de “fibrosis ongénita de lmutations
os músculos CCDDs. For certain CCDDs, the phenotype of a particular individual may not completely predict the
genotype, and conversely,
the genotype may not always
predict the phenotype.
extraoculares” (CFEOM) Summary
The CCDD concept has focused attention on specific congenital disturbances of human ocular motility
and on the fact that these disorders are typically neurogenic in origin. The past decade has seen rapid
evolution within this field with the last 2 years yielding additional information about existing diagnoses,
genes, and phenotypes that may result in better classification of these disorders and new genotype–
phenotype correlations in the future.
•  Síndrome de retracción de Duane (DRS) y el síndrome de Moebius Keywords
(MBS) fbrainstem
ueron development,
reconocidos omo patologías únicas desde n strabismus
congenitalccranial
dysinnervation
disorders,
cranial nerves,
ocularumotility,
principio INTRODUCTION
Ophthalmologists recognized over 60 years ago that
certain children were born with congenital ocular
motility abnormalities associated with restricted
nerve development. It is likely that we have not yet
identified all syndromes that would fall under the
CCDD rubric, although presumably the ones not yet
identified are less common (or at least harder to
DESÓRDENES DE DESINERVACIÓN CRANEAL CONGÉNITA •  La evidencia acumulada muestra que la mayor parte de estos síndromes tendrían una causa neurogénica •  2002 à concepto alternaHvo de “DESÓRDENES DE DESINERVACIÓN CRANEAL CONGÉNITA” (CCDD) que cambió el enfoque del desarrollo muscular •  Los avances en la úl.ma década han apoyado el concepto de CCDD, con todos los genes iden.ficados hasta el momento afectarían el desarrollo del tronco cerebral y/o PC •  Es probable que aún no se hayan iden.ficado todos los síndromes que caigan bajo el concepto de CCDD Bosley TM, Abu-­‐Amero KK, Oystreck DT. Congenital cranial dysinnerva.on disorders: a concept in evolu.on. Curr Opin Ophthalmol. 2013 Sep;
24(5):398-­‐406. 400
Table 1. Genetic classification of currently recognized CCDDsa
www.co-ophthalmology.com
Main category
Gene
Locus
Phenotype
Duane retraction
syndrome
!!!
!!!
Isolated Duane retraction
syndrome
SALL4
20q13.2
Inheritance
Comments
DRS
!!!
Unknown
Prevalence "0.1%; acc
all cases of incomita
bilateral in 14–20%
Duane-radial ray syndrome
DRRS
607323
AD
Rare
Three unrelated patient
8q12–13
Duane retraction syndrome 1
DURS1
126800
AD
2q31.1
Duane retraction syndrome 2
DURS2
604356
AD
Rare; 10 recognized m
!!!
Possible X chrm
Wildervanck syndrome
Wildervanck
314600
Unknown
Females>>males
7p15.2
Bosley-Salih-Alorainy syndrome
BSAS
601536
AR
Rare
Athabascan brainstem dysgenesis
syndrome
ABDS
HOXA1
Volume 24 # Number 5 # September 20
Other horizontal
MIM
CHN1
!!!
Congential fibrosis
of the extraocular
muscles
Phenotype
abbreviation
!!!
Multiple chrm
locations
Chromosomal DRS
Chromosomal DRS
!!!
!!!
Unilateral or bilateral D
a wide spectrum of o
developmental abno
(excluding syndrome
KIF21A
12q12
Congenital fibrosis of the
extraocular muscles type 1A
CFEOM1A
135700
AD
13 recognized mutation
heterogeneity resultin
phenotypes (CFEOM
Congenital fibrosis of the
extraocular muscles type 3B
CFEOM 3B
PHOX2A
11q13
Congenital fibrosis of the
extraocular muscles type 2
CFEOM 2
602078
AR
Five currently recognize
TUBB3
16q24.3
Congenital fibrosis of the
extraocular muscles type 3A
CFEOM3A
600638
AD
TUBB3 mutations result
phenotypic heteroge
recognized mutation
either in isolation (C
as part of a larger sy
to as TUBB3 syndrom
Congenital fibrosis of the
extraocular muscles type 1B
CFEOM1B
TUBB3 syndrome
TUBB3-CFEOM
CFEOM1B or 3A assoc
neurological symptom
TUBB3-E410K-syndrome
TUBB3-E410KCFEOM
CFEOM associated with
features. Arises from
acid substitution
TUBB2B
6p25.2
TUBB2B-E421K-Congenital
fibrosis of the extraocular
muscles
TUBB2B-E421KCFEOM
!!!
AD
Three affected members
rare TUBB2B phenot
CFEOM only occurs
acid substitution
!!!
13q12.11
Congenital fibrosis of the
extraocular muscles type 3C
CFEOM3C
609384
AD
Four affected members
Tukel syndrome
CFEOM-U
609428
AR
Six affected members in
same family
Moebius syndrome
MBS
157900
Unknown
Prevalence of 0.0002%
births; rare chromoso
!!!
!!!
Bosley TM, gaze
Abu-­‐Amero KK, Oystreck DT. Congenital cranial dysinnerva.on disorders: a concept in evolu.on. Curr Opin Ophthalmol. 2013 Sep;
disorders
24(5):398-­‐406. ROBO3
11q24.2
Horizontal gaze palsy and
HGPPS
607313
AR
23 recognized mutation
me 24 # Number
5 # September
2013 1040-8738 ! 2013 Wolters Kluwer Health | Lippincott
400
www.co-ophthalmology.com
Volume 24 William
# Numb
TUBB2B
6p25.2
TUBB3-E410K-syndrome
TUBB3-E410KCFEOM
TUBB2B-E421K-Congenital
fibrosis of the extraocular
muscles
TUBB2B-E421KCFEOM
!!!
AD
Three affected memb
rare TUBB2B phen
CFEOM only occu
acid substitution
CFEOM3C
609384
AD
Four affected membe
609428
MIM
AR
Inheritance
Six
affected members
Comments
same family
a
Table 1. Genetic classification
of currently
CCDDs
!!!
13q12.11 recognized
Congenital
fibrosis of the
extraocular muscles type 3C
Phenotype
CFEOM associated w
features. Arises fro
acid substitution
Main category
Gene
Locus
Tukel syndrome
Phenotype
CFEOM-U
abbreviation
Duane retraction
Other
horizontal
syndrome
!!!
!!!
Isolated Duane retraction
Moebius
syndrome
syndrome
MBS
157900
!!!
Unknown
Prevalence
all casesofof0.0002
incom
bilateral
14–2
births;
rareinchromo
SALL4
20q13.2
Duane-radial ray syndrome
8q12–13
Duane
retraction
syndrome 1
progressive
scoliosis
DRRS
HGPPS
607323
607313
AD
AR
Rare
23
recognized mutat
!!!
CHN1
2q31.1
Duane retraction syndrome 2
DURS2
604356
AD
Rare; 10 recognized
!!!
Possible X chrm
Wildervanck syndrome
Wildervanck
314600
Unknown
Females>>males
7p15.2
Bosley-Salih-Alorainy syndrome
BSAS
601536
AR
Rare
Athabascan brainstem dysgenesis
Hereditary
syndrome congenital facial
ABDS
Multiple chrm
locations
paresis 1 DRS
Chromosomal
Chromosomal DRS
12q12
17q21.3
Congenital
of thefacial
Hereditaryfibrosis
congenital
extraocular muscles type 1A
gaze disorders
!!!
ROBO3
Other vertical gaze
disorders
Other facial motility
disorders
!!!
HOXA1
!!!
!!!
!!!
Congential fibrosis
of the extraocular
muscles
KIF21A
HOXB1
!!!
11q24.2
!!!
3q21-q22
10q21.3-q22.1
Horizontal gaze palsy and
Isolated superior oblique palsy
DRS
DURS1
Isolated SOP
HCFP1
126800
———
Unknown
AD
601471
Three unrelated pati
Unknown
AD
!!!
PHOX2A
1p34.1-p32
Xq24-q27.1
11q13
Several familial
Rare
!!!
!!!
Unilateral or bilatera
a wide spectrum
Rare
developmental ab
(excluding syndro
CFEOM1A
HCFP3
135700
614744
AD AR
13 recognized
muta
Four affected
in
heterogeneity res
unrelated
fam
phenotypes (CFEO
Hereditaryfibrosis
congenital
Congenital
of theptosis 1
extraocular muscles type 3B
PTOS13B
CFEOM
178300
AD
Congenital fibrosis of the
extraocular muscles type 2
CFEOM 2
Hereditary congenital facial
paresis 2
HCFP2
604185
AD
paresis 3
!!!
Prevalence "0.1%;
Hereditary congenital ptosis 2
PTOS2
300245
602078
AR
X-linked
TUBB3
16q24.3
fibrosis of the
CFEOM3A
600638
AD
AD, autosomal dominant; AR,
autosomal recessive;
chrm, chromosome;Congenital
HCFP, Hereditary
congenital facial paresis;
MIM, Online Mendelian
Inheritance of Man
number.
extraocular muscles type 3A
a
CCDD, congenital cranial dysinnervation disorder.
Rare
Linkage in one
Five currently recogn
TUBB3 mutations res
phenotypic hetero
recognized mutat
either in isolation
as part of a large
to as TUBB3 synd
Congenital fibrosis of the
extraocular muscles type 1B
CFEOM1B
TUBB3 syndrome
TUBB3-CFEOM
CFEOM1B or 3A as
neurological sym
TUBB3-E410K-syndrome
TUBB3-E410KCFEOM
CFEOM associated
features. Arises fr
acid substitution
TUBB2B-E421KAD
TUBB2B
6p25.2
TUBB2B-E421K-Congenital
Bosley TM, Abu-­‐Amero KK, O
ystreck DT. Congenital cranial dysinnerva.on disorders: a concept in evolu.on. Curr O!!!
pin Ophthalmol. 2013 Sep;
CFEOM
fibrosis of the extraocular
24(5):398-­‐406. muscles
Three affected memb
rare TUBB2B phe
CFEOM only occ
Síndrome de retracción de Duane •  Falta de abducción, con limitación de la aducción, retracción variable del globo ocular y estrechamiento de la hendidura palpebral en aducción •  Esporádico, unilateral o bilateral, aislado o sindromá.co •  Gen HOXA1 (creación o supervivencia de neuronas PC VI) o genes CHN1, SALL4 (crecimiento de axones al recto lateral) Fibrosis congénita de músc. extraoculares •  Alteración de movimientos oculares horizontales y/o ver.cales, y ptosis •  Unilateral o bilateral •  Estrabismo divergente y posición anormal de la cabeza, en especial la elevación del mentón Parálisis de la mirada horizontal y escoliosis progresiva •  Parálisis de la mirada horizontal completa o parcial congénita, sin compromiso mirada ver.cal, escoliosis progresiva de inicio precoz •  Gen ROBO3 (involucrado en la decusación de tractos neurales en tronco encefálico). Bosley TM, Abu-­‐Amero KK, Oystreck DT. Congenital cranial dysinnerva.on disorders: a concept in evolu.on. Curr Opin Ophthalmol. 2013 Sep;
24(5):398-­‐406. troch
both
SALL
ponti
abno
defec
locati
predi
moto
(CFE
Cong
Figure 5 Clinical syndromes in CCDDs and corresponding
Assaf AA. Congenital innerva.on dysgenesis syndrome (CID)/ congenital dysinnerva.on (CCDDs). (2011) 25, 1251–1261. cranial
nerves.
Responsible
genecranial names
aredisorders given
inEye italics.
The
To da
and t
CFEO
CF
SÍNDROME DE MOEBIUS EPIDEMIOLOGÍA •  Aprox. 300 casos descritos en la literatura inglesa •  Prevalencia en EEUU: 0,002-­‐0,0002% de los nacimientos, o 1 caso por cada 50.000 RN Neurology. Aug 12 2003;61(3):327-­‐33. •  En una encuesta a nivel nacional holandés en 2003, la prevalencia fue al menos el 0,002% de los nacimientos (4 casos por cada 189.000 RN) para los años 1996-­‐1998 •  En 2007, la Fundación Síndrome de Moebius es.mó que 2.000 personas de todo el mundo .enen la condición Am J Matern Child Nurs. Sept/Oct, 2008;33(5):272-­‐278. SÍNDROME DE MOEBIUS CLASIFICACIÓN •  En 1979, Towfighi et al propuso un sistema de clasificación en base a diferencias patológicas observadas en estudios de pacientes con el síndrome Acta Neuropathol (Berl). Oct 1979;48(1):11-­‐7. Grupo I Hipoplasia simple o atrofia de los núcleos PC Grupo II Lesiones primarias a nivel periférico de los PC Grupo III Necrosis focal, gliosos y calcificación en núcleos PC Grupo IV Miopaqa primaria sin lesiones en PC o SNC SIN CORRELACIÓN CLÍNICA SIGNIFICATIVA SÍNDROME DE MOEBIUS PATOGENIA •  No se ha podido establecer el evento primario: Aplasia del nervio, a nivel de tronco cerebral, o muscular •  Los PC que pueden estar involucrados à VI al XII, con preservación general del VIII •  VII en todos los casos •  VI 75% •  XII minoría •  PC III y IV en raras ocasiones SÍNDROME DE MOEBIUS PATOGENIA MÚLTIPLES TEORÍAS: •  Moebius creía que la condición era de origen degeneraHva o tóxica y que involucraba a los núcleos de los nervios afectados •  Algunos autores sugieren que se debe a una hipoplasia o agenesia congénita hereditaria de los núcleos PC •  Displasia mesodérmica que involucra la musculatura derivada de los 1er y 2º arcos branquiales •  Esta teoría sos.ene que los cambios del tronco cerebral son secundarios a la atrofia retrógrada de los PC SÍNDROME DE MOEBIUS PATOGENIA •  Malformaciones de las extremidades asociadas a la disfunción de los PC sugieren una interrupción de la morfogénesis normal, con mayor probabilidad en las semanas 4-­‐7 de gestación SÍNDROME DE MOEBIUS ETIOLOGÍA •  Controversial à MulHfactorial •  Por definición, las lesiones traumá.cas no son parte del síndrome Gené.ca Aprox. 2% Mayoría esporádicos Neurology. Aug 12 2003;61(3):327-­‐33. Daño hipóxico/
isquémico Exposición prenatal a tóxicos SÍNDROME DE MOEBIUS ETIOLOGÍA: TEORÍA VASCULAR 1.  Interrupción del flujo a nivel de la arteria basilar o regresión prematura de las arterias trigeminales primi.vas 2.  Interrupción del flujo de la arteria subclavia que implica la interrupción del flujo de sangre embrionario Findings that shed new light on the possible pathogenesis of a disease or
an adverse effect
Maternal homocystinuria and Moebius syndrome? Vascular
aetiology
N Gupta, M Y Anthony
Neonatal Unit, John Radcliffe Hospital, Oxford, UK
Correspondence to N Gupta, [email protected]
BMJ Case Reports 2011; doi:10.1136/bcr.09.2010.3331 Summary
A case of Moebius syndrome is reported in an infant of a mother known to have pyridoxine-unresponsive homocystinuria. The authors
SÍNDROME DE MOEBIUS ETIOLOGÍA: GENÉTICA •  Síndrome listado en OMIM con gen locus 13q12.2-­‐q13 •  Uzumcu et al. no encontró microdeleciones en esta región críHca en 9 pacientes y excluyó varios genes candidatos (FGF9, GSH1 y CDX2) Eur J Med Genet. Sep-­‐Oct 2009;52(5):315-­‐20. 1977 Variante de SM con una translocación recíproca t(1p34; 13q13), en al menos 7 miembros de una familia afectada de más de 3 generaciones Ziter FA, et al. Arch Neurol. Jul 1977;34(7):437-­‐42. 1991 Niña de 2 años con SM con una deleción de la banda q12.2 del cr 13 Cario.po de la madre normal Slee JJ, et al. J Med Genet. Jun 1991;28(6):413-­‐4. •  Ambos informes sugieren que un gen responsable se encuentra en la región 13q12.2-­‐q13 -­‐Online Mendelian Inheritance in Man. %157900 -­‐ MOEBIUS SYNDROME; MBS. OMIM -­‐ Online Mendelian Inheritance in Man. SÍNDROME DE MOEBIUS ETIOLOGÍA: GENÉTICA 1996 Gran árbol genealógico con SM AD consistente en gran parte de paresia facial bilateral asimétrica Después de la exclusión de la región 13q12.2-­‐13, localizaron un gen en 3q21-­‐22 Kremer H, et al. Hum Mol Genet. Sep 1996;5(9):1367-­‐71. 1997 Niño con sd. Möbius-­‐like (diplejía facial y ptosis pero con mov. extraoculares normales y sin anomalías esquelé.cas) con una translocación recíproca entre los cromosomas 1 y 2 (p22.3, q21.1) Nishikawa M, et al. Clin Genet. 1997;51(2):122-­‐3. •  También se han reportado casos familiares SÍNDROME DE MOEBIUS GENÉTICA? HERENCIA? •  Debido a la inconsistencia en la definición de la patología, el rol de la herencia en el síndrome de Moebius sigue siendo poco claro •  Se han descrito genealogías con herencia AD, AR, y ligada al X recesiva 102
C. Vauzelle et al. / Reproductive Toxicology 36 (2013) 98–103
Table 5
Published studies on misoprostol malformative risk.
SÍNDROME DE MOEBIUS ETIOLOGÍA: TÓXICOS Author
Location
Methodology
Reason for misoprostol use
Number of women or infants
use of other abortifacients
Results
U S EProspective
O F M I S O study
P R O STO L D U R I N G P R EG N A N86
CYmisoprostol-exposed
A N D M Ö B I U S’ SYpregnancies
N D R O M E I N I N FA N T SMajor birth defects among life births:
vs. 86 pregnancies exposed to
Mostly self-attempted
2/67 vs. 2/81
non-teratogens
abortions (95%)
RR = 1.21 (95% CI = 0.17–8.35)
31.4% in the exposed group used
Birth defects in the misoprostol group:
another abortifacient
- constriction rings of the arms
USE OF MISOPROSTOL DURING PREGNANCY
AND MÖBIUS’ SYNDROME
- hepatosplenomegaly, pulmonary
IN INFANTS
hypertension, persistent fetal
circulation
ARLOS E.
PASTUSZAK
, M.SC., LAVINIA SCHÜLER, 120
M.D.,
PH.D., Cexposed
SPECK-MARTINS, M.D.,
Birth defects: 5/118 vs. 81/4575
misoprostol
pregnancies
Prospective
cohort:
Dal Pizzol Tda et al. [16], ANNE L.
YNTHIA M. CORDELLO, M.D.,
KATIA-EDNI F.A. COELHO
, M.D.,
FERNANDO
VARGAS
, M.D.,
DECIO BRUNONI
, M.D.,OR
PH=.D.,
pregnancies
without
exposure
2.64 (95% CI = 1.03–6.75)
vs. 4575
Adjusted
Study S
on
Brazil
Brazilian
IDA V.D. SCHWARZ
, M.D.,Diabetes.
MARIELA LARRANDABURU, M.D.,
HELOISA SAFATTLE, M.D., VERA F.A. MELONI
M.D., in the misoprostol group:
to misoprostol
Birth,defects
Gestational
- myelomeningocele
Misoprostol used to
AND GIDEON KOREN, M.D.
- clubfoot
induce menstruation
N Engl J Med. 1998 Jun 25;338(26):1881-­‐5. - syndactyly
- fingernailitdefect
mended for use during pregnancy, because
may
ABSTRACT
- microcephaly
stimulate
uterine
contractions
and
cause
vaginal
Background Patients with upper gastrointestinal No information on other abortifacients
No information on time of exposure
Schüler et al. [15],
Brazil
ulceration may be treated with misoprostol, but it is
bleeding, which may endanger fetal survival. The
Major birth defects
study women because it 94 combination
misoprostol-exposed
Prospective
[17],
Barbero et al.
of pregnancies
misoprostol and mifepristone
or among life births:
not
recommended
for pregnant
self-attempted and cause vagi- vs. methotrexate
401 pregnancies exposed
to
vs.
8/372
Mostly contractions
5/77
Argentina may stimulate uterine
has been used for the elective induc(81%) Recent data from Bra- non-teratogens
= 3.80 (95%
nal bleeding and abortions
miscarriage.
electiveRRabortion of abortion.1,2 In Brazil, whereAdjusted
CI = 1.05–14.61)
zil, where misoprostol is used orally and vaginally as
tions are prohibited, 57 to 75 percent
of women
Birth defects in the misoprostol group:
an abortifacient, have suggested a relation between
who attempt abortion use misoprostol,
which can
transverse limb
- encephalocele,
the use of misoprostol by women in an unsuccessful
misoprosbe obtained over the counter.3-5 However,
constriction
ring
defects,
attempt to terminate pregnancy and Möbius’ syntol
often
fails
to
induce
abortion
during
the
first
triporencephaly
drome (congenital facial paralysis) in their infants.
pulmonary adenomatous
cystic
in
mester,6 and up to 80 percent of the -pregnancies
Methods We compared the frequency of misomalformation
women who use this agent continue to term.
prostol use during the first trimester by mothers of
encephalocele
- occipitalactions
Although misoprostol has no teratogenic
infants in whom Möbius’ syndrome was diagnosed
- intestinal malrotation
7-9
10
in pregnant rats and mice, there are reports of
and mothers of infants with neural-tube defects in
35.2% in the exposed group used
Brazil. All diagnoses in infants were made between another
Möbius’
syndrome (congenital facial paralysis, with
abortifacient
•  Estudio de niños en Brasil de 1998 à Fuerte asociación entre SM y uso prenatal de misoprostol •  Se cree que causa un evento isquémico en el tronco cerebral embrionario temprano en la gestación January 16, 1990, and May 31, 1996, by clinical genetCase-control
study
seven hospitals
who
also interviewed the
self-attemptedabout
abortions
Mostlyinformation
and recorded
the admin(98%)
istration of misoprostol,
among other data.
Results We identified 96 infants with Möbius’
Case-control
study
nested
a
Brasil et al. [14],
syndrome and matched
them
with
96ininfants
with
of mean
very low
birth
Brazil
cohort
neural-tube defects.
The
age
atweight
the time of the
infants. syndrome was 16 months
diagnosis of Möbius’
abortions of neural-tube
(range, 0.5 to 78),Self-attempted
and the diagnosis
[10],
Case-control
study
Orioli and Castilla
defects was made within 1 week of birth in most
al. [11],at
Pastuszak eticists
Brazil
mothers
or without limb defects) in infants whose mothers
Misoprostol
exposure among
attempt
at aborMoebius’syndrome vs. neural tube
In one study, in a small cohort of 20 women
tion.
defects:
who used misoprostol unsuccessfully OR
as =an
abortifa29.7 (95% CI = 11.6–76.0)
cient
during
the
first
trimester,
3
had
a
second-triMisoprostol exposure among birth
37 infants with birth defects vs. 387
mester
abortion,
and 17 gave birth to infants
without
without
birth defects
controls:
controls
defects vs.
study
was to
malformations.15 The purpose of our6/37
vs. 28/387
= 2.4
(95% CIthe
= 1.0–6.2)
compare the frequency of misoprostolOR
use
during
4673
infants
with birth
vs.
exposure
first
trimester
of defects
pregnancy
between Misoprostol
mothers of
in- among birth
96 took
infantsmisoprostol
with Moebius’syndrome
vs.
in an unsuccessful
with neural-tube defects
96 infants
11-14
First case of Moebius-Poland syndrome in child
prenatally exposed to misoprostol
Sr. Editor:
SÍNDROME DE MOEBIUS -
El síndrome de Moebius (OMIM 157900) se caracteriza por
descargado de http://zl.elsevier.es el 14/05/2014. Copia
para facial
uso personal,
se prohíbe
la transmisión
de El
este
documento por cualquier medio o formato.
con alteración
de la abducción
ocular.
nerRev. Med. FCM-UCSG, Año 2011, vol.17 Nº1. Pparálisis
áGS. 65-69
vio facial (VII nervio craneal) y nervio abducens (VI nervio
ISSN - 1390-0218
craneal) son más frecuentemente involucrados, pero otros
nervios craneales pueden estar involucrados también. El
fenotipo es variable y puede incluir defectos congénitos oro502
CARTA
faciales y de las extremidades1 .
La secuencia de Poland (OMIM 173800) se caracteriza por
la presencia de braquisindactilia unilateral y aplasia ipso∗
b
lateral dea lay porción
esternocostal
del músculo pectoral
Autor correspondencia.
G. Salazar a,∗ , D. Cuello a , M. Fragoso
L. Benlloc
mayor. Algunas veces se denomina síndrome de Poland por
Correo electrónico: [email protected] (G. Sal
ser inicialmente descrito por Poland2 .
a
Servei de Neurologia, Hospital
Consorci
Sanitari
de
La combinación del síndrome de Moebius y Poland
Terrassa, Barcelona, España se presenta raramente y se ha estimado una prevalendoi:10.1016/j.nrl.2011.01.020
cia de 1 en 500.000; en la literatura revisada no se
b
Serveicase
dereport:
Psiquiatría,
Consorci
Sanitari
de
Clinical
Moebius Hospital
syndrome
associated
with
the
use
of
misoprostol
in
pregnancy
encontró esta asociación en expuestos prenatalmente
a
3
Terrassa, Barcelona, España misoprostol .
Figura
comisura
labial
desviada
hacia el lado
Figura
1 1.
Nótese
fenotipo
típico
de síndrome
de MoebiusSe presenta un reporte de síndrome de Moebius y Poland
Poland,
hipoplasia
del
pectoral
con
atelia
y
pie
equinovaro.
en un neonato expuesto prenatalmente a misoprostol.
1
Paciente
de madre
de 18
años, quien
consultó
por2
Callehijo
Morillo
, Javier
Aquiles
Hidalgo
Acosta
María Fernanda Calderón León1, Lennys Viviana
dismorfismo facial, encontrándose al examen físico parálisis
facial bilateral,
cara redondeada,
fisuras palpebrales delga1
Universidad Católica de Santiago de Guayaquil, Facultad de Ciencias
Médicas, Guayaquil,
Ecuador
das, labios en arco de cupido, paladar ojival, micrognatia,
2
Hospital IESS, Portoviejo, Ecuador
hipoplasia de pectoral mayor con ausencia de tetilla (ateel desarrollo de los vasos sanguíneos cambiando
lia), además se encuentra sindactilia proximal del segundo
y tercer dedo, y pie equinovaro bilateral (figs. 1 y 2).
Comola estructura6,7 . Las anormalidades vascu
y/o
antecedente de importancia se encuentra que la madre utisubclavia derecha observada en síndrom
lizo por vía oral y vaginal a las 5 semanas de gestaciónarteria
400 !g
de misoprostol con fines abortivos, presentando sangrado
pueden relacionarse con una disrupción vascular
RESUMEN
escaso.
durante un período crítico5,8 .
El misoprostol es un análogo sintético de la misoprostol
prostaEl síndrome de Moebius conocido también como diplejia
facial congénita
o agenesia
nuclear,
una enfermedad
neurológica
glandina
E1 aprobado
según
las es
entidades
reguladoras
de congénita poco frecuente en la que se ven afectados los núcleos
de origen de de
los pares
craneales
y VII, impidiendo
su total
desarrollo.
medicamentos
muchos
paísesVIpara
la prevención
y el
tratamiento de úlceras gástricas asociadas con el uso de
describe el caso clínico de un paciente de 11 meses de
edad cuya madreno
usó
tabletas de misoprostol
porantisecretor
vía vaginal (400 mcg),
antiinflamatorios
esteroideos,
por su efecto
de ácidos gástricos. La exposición prenatal a misoprostol
doi:10.1016/j.nrl.2011.01.019 se ha asociado
a la ocurrencia de defectos por disrupción
Figura 2. se observa lagoftalmia en ojo derecho
vascular, principalmente la secuencia de Moebius y defectos
no siendo así en el primer trimestre de gestación, donde los efectos son devastadores provocando un aborto,
o en su defecto,
de las extremidades de tipo terminal y transversal4,5 .
Las anormalidades
en la estructura vascular
ser
El síndrome
Moebius
(OMIM
se caracteriza
por pueden
legal,
el misoprostol sede
emplea
para la interrupción
del 157900)
embarazo, sin embargo
la infrecuente supervisión
profesional, llevan a
Figura 2 Nótese la parálisis facial bilateral, característica
secundarias a efectos teratógenos. Los teratógenos pueden
típica del síndrome de Moebius.
parálisis
facial
con
alteración
de
la
abducción
ocular.
El
actuar
directamente
disminuyendo
el nerflujo sanguíneo o en
de anomalías congénitas. El presente trabajo demuestra la injerencia del misoprostol como agente teratógeno durante el primer
trimestre
de embarazo
inductor
al desarrolloydel
síndrome abducens
de Moebius.
vio facial
(VIIy posible
nervio
craneal)
nervio
(VI nervio
Palabras clave
Reporte de caso clínico: síndrome de Moebius asociado al
uso de misoprostol en el embarazo
Primer caso de síndrome de
Moebius-Poland en niño expuesto
prenatalmente a misoprostol
First case of Moebius-Poland syndrome in child
prenatally exposed to misoprostol
Sr. Editor:
SÍNDROME DE MOEBIUS ETIOLOGÍA: TÓXICOS •  Otros tóxicos descritos asociados: •  Ergotamina •  Cocaína •  Fármaco: Zonisamida -­‐Smets K, at al. Ergotamine as a possible cause of Möbius sequence: addi.onal clinical observa.on. J Child Neurol. May 2004;19(5):398. -­‐Puvabanditsin S, et al. Poland-­‐Möbius syndrome and cocaine abuse: a relook at vascular e.ology. Pediatr Neurol. Apr 2005;32(4):285-­‐7. -­‐Kanemoto N, et al. A case of Moebius syndrome presen.ng with congenital bilateral vocal cord paralysis. Eur J Pediatr. Aug 2007;166(8):831-­‐3. SÍNDROME DE MOEBIUS CUADRO CLÍNICO Figura 1. Paresia de la musculatura frontal izquierda
Parálisis Facial Espectro au.sta Discapacidad Intelectual Hipogonadismo? Figuras 2. Sonrisa asimétrica, por la paresia facial
SÍNDROME DE MOEBIUS PARÁLISIS FACIAL •  La diplejía facial es el síntoma más notable •  Puede ser observado poco después del nacimiento •  Cierre incompleto del párpado durante el sueño •  Babeo y dificultad para la succión •  Incapacidad para cerrar los labios, prominencia del labio superior •  En adultos à Labio inferior generalmente ever.do y prominente TRASTORNOS DEL HABLA à 76-­‐90% • 
• 
• 
• 
Comp. funcional de labios, lengua, paladar, laringe Malformaciones orofaciales: paladar hendido, microgna.a y microglosia DI o pérdida de la audición Disartria flácida Briegel W. Neuropsychiatric findings of Mobius sequence -­‐-­‐ a review. Clin Genet. Aug 2006;70(2):91-­‐7. SÍNDROME DE MOEBIUS ESPECTRO AUTISTA •  En 1989, Gillberg y Steffenburg à Síntomas auHstas presentes en el 30-­‐40% de niños y adultos jóvenes con SM Acta Paediatr Scand. Mar 1989;78(2):314-­‐6 •  Confirmado en otras series: Neuropsychiatry of Möbius sequence
Table 1. The occurrence of autistic disorders in recent studies on Möbius sequence
Studies
Gillberg and
Steffenburg (47)
Johansson et al. (48)
Bandim et al. (12)
Verzijl et al. (2)
Autistic
patients
5/17
6/22
5/23
2/37
Mental retardation
among autistic
patients (%)
80
100
100
No information
Patients’
age (years)
Autism-specific
instruments
Classification
systems
2–34
Check-list for autism (11)
DSM-III-R
1–22
1–11
0.5–53
ABC, CARS, ADI-R
CARS
No information
DSM-III-R, ICD-10
DSM-IV
No information
ABC, Autism Behaviour Check-List (66); ADI-R, Autism Diagnostic Interview Revised (68); CARS, Childhood Autism-Rating
Scale (67).
be extensively reduced or even impossible due to
and in-time treatment of deficits. For many pacranial nerve palsies. Other diagnostic difficulties
tients, contact to and support by the Möbius
result from developmental delays, especially
foundation could be very helpful.
and language
delays,
and
– most
all –Clin Genet. Aug 2006;70(2):91-­‐7. Briegel speech
W. Neuropsychiatric findings of Mobius sequence -­‐-­‐ a of
review. Möbius
SÍNDROME DE MOEBIUS •  Johansson et al. à 45% Research in Developmental Disabili.es 31 (2010) 9–24 •  Briegel et al. à Sin asociación en pacientes sin DI Research in Developmental Disabili.es 31 (2010) 1462–1466 Total group
Diagnosed re ASC
Total group
Age range, yrs
Mean age (S.D.), yrs
CI, yrs
Diagnosed
Age range, yrs
Mean age (S.D.), yrs
CI, yrs
ASCd,e
AD
ALC
AT
AT?
No suspicion of ASCs
DB
Too young
Cognitive levelh
A
NA
MMR
SMR
PMR
Too young
Visual impairmenti
VI
n = 25
(Male:female)
n = 25
n = 21a
(18:7)
(16:5)
1 month–55
12:4 (11:7)
7:6-17:1
1:11–55
13:11 (11:5)
8:10–19:0
10
6 (MMR 2, SMR 4)
1 (MMR)
3 (NA 3)
3 (A 2, NA 1)
8 (A 6, NA 2)
4 (A 1, SMR 1)f
9
6
3
5
2
No subjects with PSVI/SVI.
Data on number of subjects with VI not available.
PSVI
SVI
Hearing impairmentj
Bilateral
5/19
Data on severity of hearing impairment not available.
SÍNDROME DE MOEBIUS DISCAPACIDAD INTELECTUAL •  La inteligencia suele ser normal •  DI LEVE à Aprox. el 10-­‐15% de los pacientes •  Muchos autores señalan que sin pruebas formales, la inteligencia puede estar subes.mada debido a la apariencia facial del paciente •  Verzijl et al no encontró ninguna disminución en el CI, capacidad de concentración o de memoria en 12 adultos con SM, en comparación con la población sana J Neurol. 2005 Feb;252(2):202-­‐7. Briegel W. Neuropsychiatric findings of Mobius sequence -­‐-­‐ a review. Clin Genet. Aug 2006;70(2):91-­‐7. for Möbius
patients.
conclusion
was also
Compared
with
the children
German normative
sample,
ourtostudy
dailymore
livingappropriate
skills domain:
standard
score –This
below
20, age equivaeducation or
university.
Seven
or adolescents
went
thesocialization
finding that GIT
scoresstandard
were more
in accorpopulation
hadto significantly
resultswho
for Full
Scale and
lent –supported
2 years, by
1 m;
domain:
score
– 40,
‘Gymnasium’
, and two
‘Realschule’. lower
All subjects
attended
dance
with
education
levels
than
the
WAIS-III
scores.
Performance
IQ,
Perceptual
Organization
Index
and
Processing
‘Gymnasium’ made good grades, and none of them received age equivalent – 2 years, 0 m; adaptive behaviour composite:
Taking
account
these– results
Speed Index.
In contrast,
their Verbal
Comprehension
standard
scoreinto
– 26,
percentile
<<0.1. by Verzijl and colleagues
special assistance
at school.
Additionally,
two subjects
attendedIndex
was significantly higher. Results for all performance subtests (2005) and our own study findings, we argue that the WISC-III
All other probands were assessed with the WISC-III. Results
a school specialized in providing education for students with
were significantly worse whereas verbal subtests were, at least, is not an adequate predictor for academic success in Möbius
special needs with one of them attending a school for mentally are shown in Table 1. Only one boy had a Full Scale IQ below 70,
patients, and that intelligence tests should be employed that are
not significantly different.
thus
meetingand
ICD-10
retarded students.
W. Briegel, M. Schimek, D. Knapp, R. Holderbach,
P. Wenzel
E.-M.criteria
Knappfor mental retardation.
As we did not include a matched control group in our study, less dependant on time constraints.
No significant differences for any of the WISC-III subtests or
Four subjects
hadargue
already
been
seen
by a child
and and
adolescent
Department
ofthat
Child
and
Adolescent
Psychotherapy,
one might
our
data
reflect Psychiatry
a bias from
the
composi-Leopoldina Hospital, Schweinfurt, Germany
scales could be found between males and females, subjects with
psychiatrist.
children
had being
attention
deficit/hyperactivity
Accepted
for publication
7 December
2008to the German norm
tion Two
of
our
group
not
matched
Journal c
ompila.on ©
2
009 B
lackwell P
ublishing L
td, C
hild: care, himpairment
ealth and development, 35, 5, 650–655 or
without
of ocular adduction,
and children with
disorder and
were
with
methylphenidate,
subject that
group
of medicated
the WISC-III;
however,
we have oneone
indication
Key
messages
or without congenital malformations of the upper extremities.
suffered from
social phobia
medication),
one subject
this explanation
is less(no
likely:
The standardand
deviations
of the Full
had no ICD-10
Another
child was
treated with
lamScale IQdiagnosis.
(SD = 14.837),
theAbstract
Verbal
IQ (15.313)
and the
Perfor- Significant differences could be found between Verbal IQ and
• Standardized
intelligence
testing
with
the WISC-III reveals
Background
Möbius
sequence
is a rare
condition
usually
as unior
bilateral
congenital
Performance
IQ (Pdefined
= 0.002),
Verbal
Comprehension
Index and
otrigine because
of(15.835)
seizures.are almost identical to that of the German
mance IQ
mentalMental
retardation
in 9%isofestimated
childrentoand
adolescents
with
facial weakness with impairment of ocular abduction.
retardation
occur
in
norm group (SD = 15.0).
Perceptual Organization Index (P = 0.005), and Freedom from
Möbius
sequence.
10–15% of cases, but at present there have been no studies focusing on the intellectual capacities
Another remarkable result of this study is that Full Scale IQ of
Distractibility Index and Processing Speed Index (P = 0.024).
• Compared with the general population, subjects with
of children and adolescents with Möbius sequence.
Intellectual
performance
Möbius
patients does not seem to predict academic success of
According
to
thesequence
WISC-III
manual
(Tewes etlower
al. 2000),
18/21
Möbius
Methods Twenty-three children and adolescents
aged 6–16
years achieve
could be significantly
recruited following
a results for
Möbius
patients.
All
probands
who
attended
‘Gymnasium’
subjects
had
a
significantly
higher
(P
<
0.05)
Verbal
than
PerIntelligence assessment took aboutrequest
2 h and
was
performed
of the
German
Möbius in
foundation. TheFull
primary
of all subjects
out a special
Scalecaregivers
IQ, Performance
IQ,filled
Perceptual
Organization
made
good
grades,
even
though
their
average
Full
Scale
IQ
was
formance
IQ, and
andProcessing
20/21
showed
significantly
higher scores
for
the morning.
questionnaire to compile personal, somatic
andIndex
psychosocial
history
ofSpeed
the probands.
All significantly
subjects
Index, but
higher
about 92, and their mean Performance
IQ
was
below
average.
In
examination.
assessthe
intellectual
capacities,
the German
version
the
Wechsler
Verbal
Comprehension
Index
thanoffor
the
Perceptual OrgaOne boy, aged 11 years, could had
nota physical
be examined
withTothe
results
for Verbal
Comprehension
Index.
• contrast,
En caso de students
DI severa à
E
scala d
e usually
pursuing
the
highest
educational
Intelligence
Test-III
(WISC-III)
was administered.
In
case
of aIQ
severe
mental
retardation,
the seem
Vineland
nization
Index.
WISC-III as he was both mentally and
physically
severely
handi• Full
Scale
of the
WISC-III
does not
to be a good
Cognitive evaluation in children and adolescents
with Möbius sequence
•  23 pacientes, 6-­‐16 años •  Se aplicó la versión alemana del WISC-­‐III route,
‘Gymnasium’, are expected
toBehavior
have at Rating
least high
Vineland Adaptive
Formaverage
was used as anpredictor
alternative.
for academic success in Möbius patients.
Keywords
Full
Scale
IQ.
Table 1. IQ
scales,
indices
and
subtests
of
the
Wechsler
Intelligence
Test-III:
minimum
and
maximum
values,
means,years]
standard
deviations
and
children and adolescents,
Results Twenty-two subjects [12 males, 10 females;
mean age:
11.3 (6–16)
could
be
intelligence,
mental
comparison with
the
normative
sample
There are several hypothetical
explanations
the discrepincluded;
21 could be for
examined
with the WISC-III. Compared with the normative sample, Full Scale
retardation, Möbius
ancy between
going
to
‘Gymnasium’
with
a
low
average
IQ (mean: 92.05; standard deviation:Full
14.84) was significantly lower (P = 0.023) which was the Comparison with
sequence
IQ scale/index
Minimum
Maximum
Mean 80.48; standard
Standard
deviation
normative
sample
Scale IQ and doing well there.
For one,ofparents
may
strongly IQ (mean:
consequence
a very low
Performance
deviation:
15.84). Compared
with
Acknowledgements
Correspondence:
the76
normative
sample, the
results of all performance
were significantly lower
the prestigious
‘Gymnasium’
Verbal IQ advocate for their child to attend
144
106.24 subtests 15.313
n.s.
Dr Wolfgang Briegel,
(P
=
0.033–0.000),
whereas
verbal
subtest
scores
did
not
differ
or were
eventohigher
[‘Similarities’
which
might
be
as
well
an
explanation
as
a
school
placement
Performance IQ Klinik für Kinder- und
56
127
15.835
LowerDeutschland
(P = 0.000)
The80.48
authors are very
grateful
Moebius
Syndrom
Full Scale IQwith some
65
92.05
14.837
Lower
(P = 0.023) of
Jugendpsychiatrie
und While
(P =
0.026)
and have
‘Vocabulary’
(P = 0.019)]. Verbal
IQ
(mean:
106.24;
standard
deviation:
15.31)
was
not
assistance.
we
do not
any135
information
e.V., the German Möbius foundation, and to all participants
Psychotherapie,
Verbal Comprehension
Index
77
143the normative sample.
108.33
15.078
Higher (P = 0.020)
significantly
different
from
Two
boys
met
ICD-10
criteria
for
mental
aboutLeopoldina
the firstKrankenhaus,
aspect, to our knowledge, none of the children this study. They also want to thank Prof Regina Bussing, GainesPerceptual Organization
Index
53
15.609
Lower (P = 0.000)
Full Scale
IQ124
was not
predictive for81.14
academic success.
Gustav-Adolf-Straße
4,
received special Index
assistance
atretardation.
the
‘Gymnasium’
. Another
possible
ville,
Florida, for help
with the manuscript. n.s.
Freedom from Distractibility
57
130
99.19
16.857
97422 Schweinfurt,
Conclusions
The WISC-III
is notisanthat
adequate predictor for academic success in Möbius patients;
mentioned
above
Processing explanation
SpeedGermany
Index for the discrepancies
60
103
83.14
11.829
Lower (P = 0.000)
intelligence tests which are less dependant on time constraints should be preferred for subjects
E-mail: is not really appropriate for subjects with Möbius
the WISC
Comparison with
[email protected]
with Möbius sequence.
References
sequence.
Verbal subtests
Minimum
Maximum
Mean
Standard deviation
normative sample
Up to date, only one study with a primary focus on cognitive
Amaya,
J. & Taylor, D. (1990) Möbius
Information
3
16
10.57L. G., Walker,2.731
n.s.syndrome: a
reported, an
Similarities capacities of adults with Möbius7sequence has been18
11.48and report of2.804
Higher (P5,= 0.026)
study
18 cases. Binocular Vision Quarterly,
SÍNDROME DE MOEBIUS EXAMEN FÍSICO •  Los hallazgos {sicos dependen de la definición de caso del SM •  Al u.lizar la definición más comúnmente aceptada, la apariencia qpica fenoqpica es un aspecto de cara hipomímica con diversas parálisis de la mirada FACIE DE MÁSCARA Dificultades para relacionarse con otras personas • 
• 
• 
• 
Parálisis de oculares externos, incluyendo ptosis à 80% de los pacientes ConjunHviHs recurrente o crónica Opacidades corneales inusuales Disfagia común SÍNDROME DE MOEBIUS EXAMEN FÍSICO Anomalías menos frecuentes: •  Dextrocardia, artrogriposis múlHple congénita •  Alt. de la piel: Pigmentación café-­‐au-­‐lait, ausencia de tejido subcutáneo •  Un caso con parálisis cordal bilateral congénita fue reportado por Kanemoto en 2007 Eur J Pediatr. Aug 2007;166(8):831-­‐3. SÍNDROME DE MOEBIUS PARÁLISIS DEL NERVIO ABDUCENS •  Parálisis del VI PC se presenta en aprox. el 75% de los pacientes •  La mayoría bilateral y generalmente completa •  Es la única parálisis ocular en aprox. el 50% de los pacientes •  Los niños afectados pueden nacer con un estrabismo convergente marcado SÍNDROME DE MOEBIUS Carta et al ! Möbius Syndrome: An Italian Case Series
Figure 1. A, Möbius syndrome pattern A: eyes are fixed in straight position with a complete Ophthalmology deficit of both abduction
adduction;
Volume 1and
18, N
umber 8, objects
August moving
2011 laterally are followed by large head movements. AI, Bilateral injury of the entire VIth and VIIth cranial nerves, other than superior lacrimal nuclei
(outlined area), may be responsible for a balanced but opposite muscles palsy. B, Möbius syndrome pattern B: large angle esotropia with crossed fixation
and incomplete deficit of both abduction and adduction. BI, Bilateral lesion of the ventral portion of the VIth cranial nerve nucleus sparing its dorsal
portion (outlined area) can allow overaction of the medial rectus, thus producing esotropia. C, Möbius syndrome pattern C: large-angle exotropia with
vertical misalignment. CI, Bilateral injury affecting the lower brainstem with another one located in proximity of the mesencephalic center for vertical
SÍNDROME DE MOEBIUS COMPROMISO DEL NERVIO HIPOGLOSO •  Es el 3er PC más frecuentemente afectado y está implicado en aprox. el 25% de los casos reportados •  Atrofia de la lengua •  Incapacidad para protuirla •  Fasciculaciones •  Los músculos oculares están siempre involucrados cuando la lengua se ve afectada ORIGINAL
Manifestaciones oculares y sistémicas del síndrome de
Möebius!
A.M. Borbolla Pertierra ∗ , P. Acevedo González, V. Bosch Canto, J.C. Ordaz Favila
y J.C. Juárez Echenique
Servicio de Oftalmología Pediátrica, Instituto Nacional de Pediatría, México Distrito Federal, México
ediatr (Barc). 014. h}p://dx.doi.org/10.1016/j.anpedi.2013.10.023 10 Pde
octubre
de 22013
Recibido el 23 de junio de 2013; aceptado elAn • 
• 
Documento descargado
de http://zl.elsevier.es el 11/05/2014. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
64 expedientes clínicos +Model Resumen
PALABRAS CLAVE
Limitación a la abducción (100%), parálisis facial (100%), endotropia (54%), ANPEDI-1436;
No. of Pages
6
IN
PRESS
Introducción:
El síndrome
de Möebius ARTICLE
es una enfermedad caracterizada
por
en los núcleos
Síndrome de Möebius;
epicanto (
51,5%), e
ntropión (
22%) y
a
ntec. d
e u
so d
e a
bor.vos e
n la lesión
madre del sexto y séptimo nervios craneales, produciendo parálisis facial y limitación
a la abducción
Endotropia;
A.M
principalmente.
El objetivo es (describir
los hallazgos oftalmológicos del síndrome de Möebius
Parálisis facial;
durante el primer 4 trimestre d
e e
mbarazo 28%). en niños mexicanos.
Agentes abortivos;
Epicanto;
Entropión
Pacientes y métodos: Estudio retrospectivo, transversal, observacional y descriptivo. Se revi-
En nuestro estudio predominó el
Tabla 2saron
Hallazgos
en los párpados y los anexos
expedientes clínicos de los pacientes con síndrome de Möebius del Instituto Nacional de
sin embargo en otras series se ha e
ción muy similar entre sexos39,40 .
Resultados: Se revisaron 64 expedientes clínicos. Los hallazgos más importantes fueron limitaLa etiología
de este síndrome aú
Epicanto
33 endotropia (54%), epicanto
ción a la abducción (100%), parálisis facial (100%)
(51,5%), entropión
propuesto
una
causa genética y una
(22%) y antecedente de uso de abortivos en la
trimestre
de embarazo
Lagoftalmos
21madre durante el primer
seexotropia
ha descrito
la aparición del síndr
(28%). Sin embargo, también se presentaron 14
hallazgos atípicos como
e hipertropia.
Entropión
Conclusiones:
El
síndrome
de
Möebius
tiene
una
amplia
gama
de
manifestaciones
oftalmológicas
uso
del
misoprostol
durante el em
Telecanto
12
que se deben detectar temprano para mejorar su función y estética.
luar nuestros resultados observam
Epibléfaron
11
© 2013 Asociación Española de Pediatría. Publicado por Elsevier España,
S.L.
los derechos
parte
deTodos
las madres
de nuestros pa
Hendiduras
antimongoloides
10
reservados.
como
antecedente
el
uso de algún
Ptosis
7
las primeras etapas de la gestación
Hendiduras mongoloides
4
gatorio dirigido a establecer su uso
Eye and systemic manifestations of Mobius
Euribléfaron
1 syndrome
(17,1%) que reconocieron la ingest
Estenosis vía lagrimal
1
Abstract
casos (9,3%) la utilización de té co
Hemangioma
1 by damage in the
Introduction: Mobius syndrome is characterized
nucleus of the sixth and
nicas.
Tomando en cuenta que es
seventh cranial nerves, with subsequent facial palsy and abduction limitation of the eyes. The
ser más elevados si se realizara u
Pediatría de México atendidos entre los añosN.
2000
y 2010.
o
Hallazgo
pacientes
KEYWORDS
Mobius Syndrome;
Facial palsy;
Esotropia;
Abortion inducing
B) Right brachysyndactyly.
SÍNDROME DE MOEBIUS Table 3. Horizontal ocular alignment in primary gaze position of patients with
Möbius sequence from Brazil and Italy
ALTERACIONES MÚSCULO-­‐ESQUELÉTICAS Groups
Ocular Motility
Brazilian
(n=46)
Italian
(n=20)
P value*
Orthotropia
13 (28.3%)
8 (40.0%)
0.3959
Esotropia
18 (39.1%)
8 (40.0%)
1.0000
08 (17.4%)
3 (15.0%)
1.0000
•  Se producen en un 1/3 o más de lExotropia
os pacientes *= Fisher’s exact test
• 
• 
• 
• 
• 
• 
Pie bot Braquidac.lia, sindac.lia Amputaciones congénitas Artrogriposis Extremidades más pequeñas Anomalía de Poland J. C. Rucker et al.
Table 4. Systemic anomalies in Möbius sequence patients from Brazil
and Italy
Groups
Anomalies
Brazilian
(n=46)
Italian
(n=20)
P value*
Limb
27 (58.7%)
12 (60.0%)
1.0000
Club foot
26 (56.5%)
10 (50.0%)
0.7886
Incomplete closure of the
eyelid
23 (50.0%)
15 (75.0%)
0.1027
Tongue
20 (43.5%)
11 (55.0%)
0.4310
*= Fisher’s exact test
A
B
Figure 2. Brazilian patient with Möbius sequence presenting upper and lower limb
defects. A) Amputation defect in left upper limb. B) Bilateral feet deformity with amputation defects on the left foot.
204
Arq Bras Oftalmol. 2012;75(3):202-6
arteries, and/o
potentially be
teratogenic ag
factors, low p
fectious and c
with easy acce
of birth defec
Misoprost
for legal and i
and Central A
ses in which m
unstable fami
sent study, the
stable relation
majority of th
with a signific
Various ca
defects and a
with the use o
of Möbius seq
gestational we
of misoprosto
the current st
The reality
is a delicate
religious, and
dividuals with
of more than
An increased
the Italian po
tically signific
group. Memo
bias might be
to the fact tha
when the mo
of contracept
contributing t
Some ca
of significant
series, there is
first trimester
terminal trans
SÍNDROME DE MOEBIUS ANOMALÍA DE POLAND Documento descargado de http://zl.elsevier.es el 14/05/2014. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
502
G. Salazar a,∗ , D. Cuello a , M. Fragoso a y L. Benlloc b
CARTA AL EDITOR
Autor correspondencia.
Correo electrónico: [email protected] (G. Salazar)
∗
de Neurologia,
Consorci Sanitari
de SM .ene aplasia o •  Se es.ma que eTerrassa,
l Servei
15% de los Hospital
pacientes con Barcelona, España
Servei de Psiquiatría, Hospital Consorci Sanitari de
hipoplasia de grupos musculares a nivel del tronco Terrassa, Barcelona, España
a
b
doi:10.1016/j.nrl.2011.01.020
•  Músculos pectorales, trapecio, laqsimo del dorso, músculos abdominales externos, serrato anterior, y músculos intercostales Primer caso de síndrome de
Moebius-Poland en niño expuesto
prenatalmente a misoprostol
el desarrollo de los vasos sanguíneos cambiando la anatomía
y/o la estructura6,7 . Las anormalidades vasculares de la
arteria subclavia derecha observada en síndrome de Poland
pueden relacionarse con una disrupción vascular causada por
misoprostol durante un período crítico5,8 .
•  Primera vez asociada con el síndrome de Moebius en 1973 •  Generalmente uFirst
nilateral y está asociada on hipoplasia mamaria case of Moebius-Poland
syndrome incchild
prenatally exposed to misoprostol
Sr. Editor:
A neonate with poland-mobius syndrome
El síndrome de Moebius (OMIM 157900) se caracteriza por
parálisis facial con alteración de la abducción ocular. El nervio facial (VII nervio craneal) y nervio abducens (VI nervio
craneal) son más frecuentemente involucrados, pero otros
nervios craneales pueden estar involucrados también. El
fenotipo es variable y puede incluir defectos congénitos orofaciales y de las extremidades1 .
La secuencia de Poland (OMIM 173800) se caracteriza por
la presencia de braquisindactilia unilateral y aplasia ipsolateral de la porción esternocostal del músculo pectoral
mayor. Algunas veces se denomina síndrome de Poland por
ser inicialmente descrito por Poland2 .
Figure 1: Bilateral VI nerve palsy, resulting in
Figure 2:La
Picture
showing left facial del
palsy. síndrome
Figure
deformityyandPoland
abnormalities of the
combinación
de3: Chest
Moebius
complete loss of abduction.
right hand.
se presenta raramente y se ha estimado una prevalencia de 1 en 500.000;
en la literatura
revisada
no se
cosmetic purposes.
If the infant
has feeding
difficulties,
recessive and x-linked recessive modes of inheritances.
encontró
esta physical
asociación
expuestostherapy
prenatalmente
a Surgery
anden
occupational
is required.
In addition to the involvement of chromosome
13, other
loci map to 3q21-q22 and 10q21.3-q22.1.2 misoprostol3 . can correct ophthalmological problems and smile
Figura 1 Nótese fenotipo típico de síndrome de Moebiuscandebesíndrome
done which
includesy muscle
presenta surgery
un reporte
de Moebius
Poland transfer
Clinical features of Mobius syndrome includes Se
complete
Poland,
hipoplasia del pectoral con atelia y pie equinovaro.
from
the
thigh
to
the
corner
of
the
mouth.
Surgery
is
enpalsy
un neonato
or partial unilateral or bilateral facial nerve
with expuesto prenatalmente a misoprostol.
SÍNDROME DE MOEBIUS ALTERACIONES OROFACIALES •  La base de la nariz ha sido descrita como amplia y más bien plana •  Epicanto bilateral, hipertelorismo •  Malformaciones del oído (generalmente bilateral y confinado al lóbulo) •  Paladar ojival y úvula bífida Figure
3: Thickend lower lipm
andicrogna.a, nose deviation to rightmalformaciones de dientes y •  Microglosia, m
icrostomia, Figure 1:
mandíbula bduction and partially absent
adduction
Figure
2: Absent right foot
Figure 3: Thickend lower lip and nose deviation to right
Figure 5: Thickened lower lip and Bell’s phenomena
SÍNDROME DE MOEBIUS DIAGNÓSTICO DIFERENCIAL •  Primero excluir trauma del parto PARÁLISIS FACIAL CONGÉNITA HEREDITARIA •  Síndrome poco frecuente de disfunción aislada del nervio facial que causa debilidad facial o parálisis •  La mayor parte de los casos reportados con herencia AD •  Considerada inicialmente dentro de un espectro de Sd. de Moebius (MBS2) , en la actualidad se considera una enHdad aparte •  Clínica: Asimetría facial, ptosis y movimientos faciales disminuidos •  Compromiso asimétrico, bilateral, par.cipación desigual de las tres ramas del nervio facial Alrashdi et al. A family with hereditary congenital facial paresis and a brief review of the literature. Clinical Dysmorphology 2010, 19:198–201 (a)
Fig. 1
(a)
(c)
Fig. 2
(b)
(b)
(d)
(c)
(d)
200 Clinical Dysmorphology 2010, Vol 19 No 4
T2-weighted volume sequence. Axial image through the internal
auditory canals (IAC) show markedly hypoplastic facial nerves in the
T2-weighted
volume
Axial aimage
through the internal
anterosuperior quadrants
of both IACs
(longsequence.
arrows). Note
normal
canals
(IAC)
markedly
hypoplastic facial nerves in the
calibre vestibular nerveauditory
posteriorly
in the
leftshow
IAC (short
arrow).
Fig.
4
anterosuperior
quadrants of both IACs (long arrows). Note a normal
calibre vestibular nerve posteriorly in the left IAC (short arrow).
Fig. 3
Fig. 3
was normal. They
in several relative
and neurological i
neurological disord
in their family res
of a Spanish family
in 1943 by Carme
Spanish family sho
nucleus.
Verzijl et al. (2005c
hereditary congeni
family. The brainst
Sagittal oblique reformat image through the left IAC (internal auditory
canal) (cerebellum to right of image) shows normal calibre cochlea
(e)
(f)
family with autoso
reformatwith
image
left IAC (internal auditory
nerve anteroinferiorly inSagittal
the IACoblique
(short arrow),
the through
vestibularthe
nerve
was compared wit
(cerebellum
to right
image)
shows
normal calibre cochlea
lying behind, before itscanal)
division
into superior
and of
inferior
nerves.
The
(e)
(f)
nerve isanteroinferiorly
in the IACjust
(short
arrow),
hypoplastic left facial nerve
visible in cross-section
above
andwith the vestibular nerve
and with that of p
lying behind,
its division into superior and inferior nerves. The
slightly in front of the cochlea
nervebefore
(long arrow).
authors observed
hypoplastic left facial nerve is visible in cross-section just above and
neurons in the fac
slightly in front of the cochlea nerve (long arrow).
small facial nerve
He had excessive tearing from the left eye, which
genital facial palsy
improved with ageHe
but had
his eyelids
remained
during
ranged between 28
excessive
tearingopen
from
the left eye, which
sleep. His right palpebral
fissure
the left.
8700 for controls.
improved
with was
age larger
but histhan
eyelids
remained open during
He had normal eyesleep.
movements
and
examination
of was
other
or necrosis, neuro
His right
palpebral
fissure
larger than the left.
sagittal T1-weighted
scan
shows
the brainstem to have a
cranial nerves wasMidline
unremarkable.
Hismovements
ears
were
promipresent. There we
He
had
normal
eye
and
examination
of
other
normal configuration without flattening of the pons.
nent bilaterally and
mild nerves
plagiocephaly
was noticed. His
He ears were promiencephalon and
cranial
was unremarkable.
had normal development
and
there
was
no
concern
about
cospinal tracts wer
nent bilaterally and mild plagiocephaly was noticed. He
his hearing nor speech.
His
peripheral
blood
karyotype
syndrome is part o
had normal development and there was no concern about
diagnosis
congenital facial
weakness
FISH
for ao22q11
deletionnor
were
normal.
Alrashdi et al. A family with hereditary congenital facial paresis and aand
brief review f tdifferential
he lhearing
iterature. Clinical Dof
ysmorphology 010, 1karyotype
9:198–201 of the posterior
his
speech.
His peripheral 2blood
PARÁLISIS FACIAL CONGÉNITA HEREDITARIA •  Se propone que sería resultado de una alteración en el desarrollo del núcleo facial y/o del nervio •  Con mayor frecuencia se asocia con ausencia total o parcial del nervio facial, ya sea unilateral o bilateral •  Van der Wiel (1957) à Describe a una familia con la condición manifiesta en seis generaciones con 14 padres afectados y 32 niños afectados de un total de 70 •  Ninguno de los hermanos afectados mostraba otros síntomas neurológicos •  El autor sugiere que la enfermedad debe ser considerada como una forma monosintomá.ca del síndrome de Moebius Van der Wiel HJ (1957). Hereditary congenital facial paralysis. Acta Genet Sta.st Med 7:348. The neuropathology of hereditary
congenital facial palsy vs
Möbius syndrome
H.T.F.M. Verzijl, MD; B. van der Zwaag; M. Lammens, MD, PhD; H.J. ten Donkelaar, MD, PhD;
and G.W. Padberg, MD, PhD
NEUROLOGY 64 February (2 of 2) 2005 Abstract—Objective: To characterize the neuropathology of hereditary congenital facial palsy. Methods: The authors
compared n
brainstem
pathology of three members
of one family f
with
autosomal
dominant congenital
facial palsy to e
that
•  Estudio europatológico de parálisis acial congénita hereditaria n in
three age-matched controls. The neuropathologic findings of the familial patients were compared with those of patients
with Möbius
syndrome.
The
authorsfobserved
a marked decrease in the number of neurons in the facial motor
varios casos de uResults:
na m
isma amilia nucleus with corresponding small facial nerve remnants. In the patients with congenital facial palsy the number of facial
motoneurons ranged between 280 and 1,680 as compared to 5,030 and 8,700 for controls. No signs of neuronal degenera•  3 m
iembros con parálisis facial congénita con There
herencia AD se comparó tion
or necrosis with
neuronal
loss, gliosis,
or calcifications
were present.
were no other
abnormalities
of the
rhombencephalon and its associated structures. The corticospinal tracts were fully developed. In contrast, Möbius syncon la d
3 ofcaontroles e la manomaly
isma ofethe
dad y con a dhypoplasia
e los pofacientes con SM drome
is e part
more complexd
congenital
posterior
fossa lwith
the entire brainstem,
including the traversing long tracts, with signs of neuronal degeneration and other congenital brain abnormalities.
Neuropathologic
findings
confirm
observations
hereditary congenital
facial fpalsy
and Möbius
•  En Conclusion:
los pacientes con PFC, el nclinical
úmero de nthat
euronas motoras aciales osciló syndrome are two different entities with a different pathogenesis.
entre 280 y 1.680 en comparación con 5.030 y 8.700 para los controles. •  Sin Insignos de dreported
egeneración euronal patients
o necrosis, érdida neuronal, congenital p
unilateral
facial
nerve palsy has
1888, Möbius
patients with n
congenital
been described as part of a wider syndrome on chrononprogressive bilateral facial and abducens nerve
gliosis alcificaciones. Sin osyndrome
tras anomalías del The
rombencéfalo. mosome 22q11.
palsy. o
A c
clear
delineation of the Möbius
pathogenesis of Möbius synNEUROLOGY 2005;64:649 –653
1
has been hampered by varying definitions. Isolated
congenital facial palsy and the extended phenotype
of congenital facial palsy with ocular muscle weakness, with or without craniofacial dysmorphisms and
congenital abnormalities of the extremities, were criteria for the diagnosis of Möbius syndrome.2 Recently, we suggested facial palsy with impairment of
ocular abduction as the primary criterion for Möbius
syndrome.3 While dysfunction of other cranial
nerves, orofacial malformations, limb malformations,
and musculoskeletal system defects are associated
features, we did not consider them.3 By restricting
the definition, we excluded congenital facial palsy,
and ascertained on clinical grounds that congenital
facial palsy is a separate entity.
6
drome is unclear as hereditary cases are rare and
most cases are sporadic.3 Two explanations have
been proposed: a primary genetic7,8 and a primary
ischemic cause.9-11 Teratogenicity has been suggested
as an important environmental possibly secondary
factor in both explanations.12 The postulated pathogenetic mechanisms in Möbius syndrome are based
on limited pathologic observations.13 Previously, we
suggested, on clinical grounds, that Möbius syndrome is more than a cranial nerve or nuclear developmental disorder and that it could be viewed as a
rhombencephalic developmental disorder with variable severity, involving motor nuclei and axons, as
well as traversing long tracts.3
To investigate the hypothesis that hereditary con-
•  En contraste, el síndrome de Moebius es parte de una anomalía congénita más compleja de la fosa posterior con hipoplasia del tronco cerebral. Se asocia con degeneración neuronal y otras anomalías cerebrales congénitas PARÁLISIS FACIAL CONGÉNITA HEREDITARIA GenéHca: •  En una gran familia holandesa con parálisis facial congénita, Kremer et al. (1996) iden.ficaron un locus candidato en el cromosoma 3q21-­‐q22 •  Michielse et al. (2006): análisis en una familia paquistaní con parálisis facial congénita dominante •  Una región cosegregante con el trastorno fue iden.ficada en el brazo largo del cromosoma 3q21-­‐q22 •  Mediante el uso de ARN de hibridación in situ, Van der Zwaag et al. (2005) iden.ficaron varios genes candidatos dentro de la región crí.ca •  Estudio de mutaciones en siete genes (KLF15, CCDC37, PODXL2, TMCC1, PLXNA1, PLXND1 y GATA2), no detectadas Alrashdi et al. A family with hereditary congenital facial paresis and a brief review of the literature. Clinical Dysmorphology 2010, 19:198–201 Volume 24 # Number
5 # September
2013 1040-8738 ! 2013 Wolters Kluwer Health | Lippincott
400
www.co-ophthalmology.com
Volume 24 W
#
TUBB3 syndrome
TUBB3-CFEOM
CFEOM1B or 3A ass
neurological symp
TUBB3-E410K-syndrome
TUBB3-E410KCFEOM
CFEOM associated w
features. Arises fro
acid substitution
PARÁLISIS FACIAL CONGÉNITA HEREDITARIA TUBB2B
6p25.2
TUBB2B-E421K-Congenital
fibrosis of the extraocular
muscles
a
Table 1. Genetic classification
of currently
CCDDs
!!!
13q12.11 recognized
Congenital
fibrosis of the
extraocular muscles type 3C
TUBB2B-E421KCFEOM
!!!
AD
Three affected memb
rare TUBB2B phen
CFEOM only occu
acid substitution
CFEOM3C
609384
AD
Four affected membe
609428
MIM
AR
Inheritance
Six
affected members
Comments
same family
Phenotype
Main category
Gene
Locus
Tukel syndrome
Phenotype
CFEOM-U
abbreviation
Duane retraction
Other
horizontal
syndrome
!!!
!!!
Isolated Duane retraction
Moebius
syndrome
syndrome
MBS
157900
!!!
Unknown
Prevalence
all casesofof0.0002
incom
bilateral
14–2
births;
rareinchromo
SALL4
20q13.2
Duane-radial ray syndrome
Rare
23
recognized mutat
gaze disorders
!!!
Prevalence "0.1%;
8q12–13
DRRS
HGPPS
607323
607313
AD
AR
CHN1
2q31.1
Duane retraction syndrome 2
DURS2
604356
AD
Rare; 10 recognized
!!!
Possible X chrm
Wildervanck syndrome
Wildervanck
314600
Unknown
Females>>males
7p15.2
Bosley-Salih-Alorainy syndrome
BSAS
601536
AR
Rare
Athabascan brainstem dysgenesis
Hereditary
syndrome congenital facial
ABDS
Multiple chrm
locations
paresis 1 DRS
Chromosomal
Chromosomal DRS
12q12
17q21.3
Congenital
of thefacial
Hereditaryfibrosis
congenital
extraocular muscles type 1A
!!!
HOXA1
!!!
!!!
!!!
Congential fibrosis
of the extraocular
muscles
Unknown
Horizontal gaze palsy and
Duane
retraction
syndrome 1
progressive
scoliosis
!!!
Other facial motility
disorders
DRS
11q24.2
ROBO3
Other vertical gaze
disorders
!!!
KIF21A
HOXB1
!!!
3q21-q22
10q21.3-q22.1
Isolated superior oblique palsy
DURS1
Isolated SOP
HCFP1
126800
———
AD
601471
Three unrelated pati
Unknown
AD
!!!
PHOX2A
1p34.1-p32
Xq24-q27.1
11q13
Rare
!!!
!!!
Unilateral or bilatera
a wide spectrum
Rare
developmental ab
(excluding syndro
CFEOM1A
HCFP3
135700
614744
AD AR
13 recognized
muta
Four affected
in
heterogeneity res
unrelated
fam
phenotypes (CFEO
Hereditaryfibrosis
congenital
Congenital
of theptosis 1
extraocular muscles type 3B
PTOS13B
CFEOM
178300
AD
Congenital fibrosis of the
extraocular muscles type 2
CFEOM 2
Hereditary congenital facial
paresis 2
HCFP2
604185
AD
paresis 3
!!!
Several familial
Hereditary congenital ptosis 2
PTOS2
300245
602078
AR
X-linked
TUBB3
16q24.3
fibrosis of the
CFEOM3A
600638
AD
AD, autosomal dominant; AR,
autosomal recessive;
chrm, chromosome;Congenital
HCFP, Hereditary
congenital facial paresis;
MIM, Online Mendelian
Inheritance of Man
number.
extraocular muscles type 3A
a
CCDD, congenital cranial dysinnervation disorder.
Rare
Linkage in one
Five currently recogn
TUBB3 mutations res
phenotypic hetero
recognized mutat
either in isolation
as part of a large
to as TUBB3 synd
Congenital fibrosis of the
extraocular muscles type 1B
CFEOM1B
TUBB3 syndrome
TUBB3-CFEOM
CFEOM1B or 3A as
neurological sym
TUBB3-E410K-syndrome
TUBB3-E410K-
CFEOM associated
features. Arises fr
acid substitution
Bosley TM, Abu-­‐Amero KK, Oystreck DT. Congenital cranial dysinnerva.on disorders: a concept CFEOM
in evolu.on. Curr Opin Ophthalmol. 2013 Sep;
24(5):398-­‐406. SÍNDROME DE MOEBIUS ESTUDIO •  No hay estudios de laboratorio con hallazgos específicos para el síndrome de Moebius •  Neuroimágenes recomendadas •  EMG se puede u.lizar para ayudar a determinar si los síntomas del paciente se derivan de trauma del nacimiento •  Hallazgos histológicos gruesos incluyen la asimetría de la médula, pero la apariencia externa del cerebro generalmente es normal (Figs 1A, 1B).
Discussion
drome [6-19]. Although the pathogenesis of Möbius syndrome is incompletely understood, four mechanisms have
been proposed: (1) hypoplasia of cranial nerve nuclei, (2)
necrosis of brainstem nuclei, (3) peripheral neuropathies,
and (4) myopathies [18].
During the first trimester, the developing brainstem
typically responds to injury with malformative changes,
such as cranial nerve hypoplasia. Reactive necrosis and
SÍNDROME DE MOEBIUS Our patients demonstrated typical features of Möbius
syndrome. All manifested bilateral incomplete facial
palsy, and all had involvement of the sixth cranial nerve
[4]. Two of the seven manifested talipes equinovarus,
NEUROIMÁGENES •  TC o RM cerebral pueden demostrar calcificaciones bilaterales en las regiones de los núcleos PC VI •  Sin embargo, estas calcificaciones no son específicas para la enfermedad •  El tronco encefálico puede aparecer hipoplásico, con aplanamiento del piso del 4º ventrículo Figure 1. (A) Computed tomographic scans illustrating the typical appearance of brainstem calcification at the level of the pons in 5/7 children with
Möbius syndrome. (B) The scans from the same patient indicating no evolution over a 4-year interval.
40 PEDIATRIC NEUROLOGY Vol. 30 No. 1
Dooley JM, Stewart WA, Hayden JD, Therrien A. Brainstem calcifica.on in Möbius syndrome. Pediatr Neurol. Jan 2004;30(1):39-­‐41. SÍNDROME DE MOEBIUS Ferreira et al
Topic in Magnetic Resonance Imaging
&
Volume 22, Number 6, December 2011
FIGURE 4. Midsagittal T1-weighted MRI scan shows flattening of the ventral pons and a dorsal vault projection from the pontine
tegmentum into the fourth ventricle. The vermis is hypoplastic. Axial T2-weighted MRI scan demonstrates hypoplasia of middle cerebellar
peduncles. Axial 3D-CISS MRI scan with normal abducens nerves, but lacking seventh and eighth right cranial nerves. Courtesy of Ronnie
Peterson Alves, MD, Porto Alegre, Brazil.
In a group of 37 Dutch Möbius patients of different age
Further analysis by diffusion tensor imaging (DTI) with
16,21
groups,22 the majority of patients presented a homogeneous
color coding and fiber tracking
demonstrates also striking
findings: an abnormal bundle of transversely oriented fibers
clinical picture characterized by facial diplegia of the upper and
forming the typical pontine tegmental cap as well as absence of
lower facial muscles, bilateral abduction impairment, hypoglossia,
decussation of the superior cerebellar peduncles and of the
and craniofacial and limb malformations. The distribution of
usual
transverse
fibers
in
the
ventral
pons.
the facial
in the RMbS
casesImaging, contrasts
considerably
with6, that
Mar.ns R, et al. Imaging Findings in Congenital Cranial Dysinnerva.on Disorders. Topic palsy
in Magne.c esonance Volume 22, Number Although
found in the common supranuclear and infranuclear types of
December 2011. cases of MbS may present with abnormalities in
Topic in Magnetic Resonance Imaging
&
S
M
Volume 22,
Number 6,D
December
2011
ÍNDROME
E OEBIUS
Congenital Cranial Dysinnervation Disorders
FIGURE 5. A 5-year-old with congenital right facial palsy and impairment of ocular abduction. Sagittal and axial 3D-CISS MRI scans
demonstrate straightening of the floor of fourth ventricle because of lacking right facial colliculi (arrowhead). Abducens nerves (arrows)
and right seventh and eighth cranial nerves are absent.
Summary Imaging Findings MbS
B. Unilateral or bilateral absence of facial nerve
A.
Straightening
of
the
floor
of
fourth
ventricle
due
to
absence
Absence
of hypoglossal
Mar.ns R, et al. Imaging Findings in Congenital Cranial Dysinnerva.on Disorders. TC.
opic in Magne.c Resonance Ieminence
maging, Volume 22, Number 6, facial colliculi ventricle
D. Variable lacking sixth, eighth, ninth, and 12th cranial nerves
December 2of
011. SÍNDROME DE MOEBIUS MANEJO •  No hay un tratamiento definiHvo disponible •  Manejo sintomáHco de complicaciones, enfoque mul.disciplinario: • 
• 
• 
• 
• 
• 
Úlceras o abrasiones corneales Férulas, prótesis O..s media Vigilancia de infecciones respiratorias Alteraciones de la deglución Apoyo psicológico familiar •  Tratamiento ortopédico y/o quirúrgico del pie bot •  Se recomienda postergar la cirugía para el estrabismo porque la condición a menudo mejora con la edad SÍNDROME DE MOEBIUS INJERTO Y PROCEDIMIENTOS DE REINERVACIÓN •  Las regiones afectadas no .enen un sistema neuromuscular funcional à El injerto de nervio y las técnicas de susHtución de los NC han tenido poco éxito •  Sin embargo, los procedimientos que implicarían la integración de un nuevo sistema neuromuscular podrían tener éxito •  La restauración de la función puede ser más exitosa si la cirugía se lleva a cabo antes de los 7 años de edad •  Técnicas u.lizadas: •  Uso del nervio accesorio no afectado o la rama mesentérica del PC V como donantes para los procedimientos de reinervación •  Disposi.vos compuestos de trasplantes musculares y tendinosos, junto con procedimientos de reinervación •  Transferencia muscular de Gracilis con la inervación del nervio masetero HOSPITAL CLÍNICO SAN BORJA ARRIARÁN SERVICIO DE NEUROPSIQUIATRÍA INFANTIL SÍNDROME DE MOEBIUS Dr. Guillermo Fariña Kutz
Neurólogo Infan.l
Dra. Daniela CasHllo Villagrán Residente Neurología Infan.l Mayo 2014 

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