This document discusses congenital cranial dysinnervation disorders (CCDDs), which are a group of congenital neuromuscular diseases resulting from developmental errors in cranial nerve innervation. The document focuses on congenital fibrosis of the extraocular muscles (CFEOM), providing details on the classification, clinical features, genetics, and pathogenesis of different types of CFEOM. It also briefly discusses other CCDDs such as Duane syndrome and Möbius syndrome.

1. DATE OF PRESENATION-:16-12-2014
PRESENTOR- DR. ANJU NAGAR

2. Normal extraocular muscle (EOM) innervation
depends on-
◦ normal cranial nuclear motoneuron formation from
neuronal precursors,
◦ normal axonal path finding from the cranial nuclei
to developing EOMs, and
◦ the establishment and maintenance of normal
connections between mature neurons and their
target cells.

3. A number of well-defined syndromes
characterized by congenital limitation of eye
movements from abnormal innervation or
miswiring of EOMs have recently been grouped
as the “congenital
cranial dysinnervation disorders,” a term coined
for
congenital disorders resulting from aberrant
innervation of the ocular and facial
musculature.

4. Assaf proposed the term of ‘CID syndrome’.
Features of this syndrome include:
_ Congenital defect in the innervation EOMs.
_ Present since birth, and non-progressive.
_ Unilateral or bilateral
_ Findings are not explained by purely isolated
oculomotor nerve palsy/palsies.
_ Anatomical muscle changes, including tight muscle
_ can be associated with synkinesis phenomena
and/or co-contraction
_ abnormal head posture common

5. The term ‘congenital cranial dysinnervation disorders’ or CCDDs
was derived in 2002 at a European Neuromuscular Centre (ENMC)
international workshop by Gutowski et al for a group of congenital
neuromuscular diseases reflecting the belief that these disorders
resulted from developmental errors in innervation.
They define these disorders include-
CFEOM,
Congenital ptosis,
Duane’s syndrome,
Duane radial ray syndrome,
Horizontal gaze palsy with progressive scoliosis (HGPPS),
Mo¨bius syndrome.
The CCDDs also encompass developmental disorders of non-ocular
cranial nerves, such as congenital familial facial weakness.

6. They summarized the features of the CCDDs as
follows:
_ Congenital, non-progressive abnormalities of cranial
musculature that result from developmental abnormalities
of one or more cranial nerves with primary or secondary
muscle dysinnervation
_ Primary may result from absence of normal muscle
innervation. Secondary may occur from aberrant muscle
innervation during development by branches of other
nerves.
_ May be associated with secondary muscle pathology
and/or other orbital and bony structural abnormalities.

7. _ Predominantly, vertical ocular motility defects are likely to result
from abnormalities in development of oculomotor and trochlear
nerves and/or nuclei (CFEOM variants and congenital ptosis).
_ Predominantly horizontal ocular motility defects are likely to result
from abnormalities in the development of the abducens nerve
and/or nucleus (Duane’s syndrome and HGPPS).
_ Predominately facial weakness is likely to result from abnormal
development of facial nerve and/or nucleus, sometimes with
associated ocular motor abnormalities
(congenital facial weakness and Mo¨bius syndrome).
Recently, Kolling et al indicated congenital Brown’s syndrome is
caused by missing fourth cranial nerve in some cases, which put it
in the category of congenital dysinnervation.

8. The main CCDDs currently recognised and subdivided
1.Predominantly vertical disorder of ocular motility
• Congenital fibrosis of the extraocular muscles (CFEOM)
• Congenital ptosis
2.Predominantly horizontal disorder of ocular motility
• Duane syndrome (DS)
• DS + radial ray (DRRS)
• Horizontal gaze palsy with progressive scoliosis (HGPPS)
3.Disorder of facial motility
• Congenital facial palsy
4.Disorder of facial motility and ocular abduction
deficit
• Möbius syndrome

9. Congenital fibrosis of the extraocular muscles (CFEOM)
describes a group of rare congenital eye movement
disorders that result from the dysfunction of all or part of
the oculomotor (CN 3) and the trochlear (CN 4) nerves,
and/or the muscles these nerves innervate.
 CFEOMs are characterized by –
◦ Variable impairment of horizontal and/or vertical eye
movements and ptosis.
◦ It can be unilateral or bilateral, with the bilateral form
being more common.
◦ Additional features include divergent strabismus and
abnormal head position, especially chin elevation

10. Congenital fibrosis syndrome has traditionally
been considered a primary muscle disorder
Ocular motility restrictions correlate with-
muscle hypoplasia
displaced scleral insertions
abnormal muscle substructure
Histopathologically, this condition is
characterized by degenerative muscle changes
and replacement of muscle fibres with fibrous
tissue.

11. Recently, CFEOM has been accepted to be of neurogenic
origin rather than primary muscle pathology.
α motoneurons of sup. division of III are present very
early in development, but disappear early-?apoptosis,
?necrosis
• Pulleys are normal-Demer
Engle EC., Leigh RJ.Genes, brainstem development and eye movements. Neurology
2002;59:304-305

12. 1. Histopathology-
◦ unreliable in distinguishing neurogenic from
myopathic ocular muscle weakness.
2. Co- contraction phenomenon-
◦ Co-contraction phenomenon resulting in globe
retraction has also been described in patients with
CFEOM.

13. 4. Electro-myographic studies:
Patients with CFEOM commonly have variable angle
strabismus.
Purely mechanical factors appear insufficient to explain this
variability, which more likely reflects innervational
disturbances.
Also, the degree of limitation of ocular movements in some
patients do not always correlate with the degree of tightness
of the agonist or antagonist muscle, as indicated by the
intraoperative forced duction test.
Nystagmus is another indicator of central ocular motor
disturbance in cases of CFEOM.

14. 4. Neuro-imaging
Abnormalities such as cerebellar hypoplasia and
asymmetrical ventricular size further hint at the
possibility of brain malformation.
Hence, cases of CFEOM have neurogenic aetiology
similar to that of DRS but involving the III cranial nerve
complex.

15.  CFEOM refers to at least seven genetically
defined strabismus syndromes:
◦ CFEOM1A,
◦ CFEOM1B,
◦ CFEOM2,
◦ CFEOM3A,
◦ CFEOM3B,
◦ CFEOM3C, and
◦ Tukel syndrome

16. Affected individuals exhibit the following:
 Congenital non-progressive bilateral external
ophthalmoplegia
 Congenital non-progressive bilateral ptosis
 Primary vertical position of each eye: infraducted
(downward)
 Vertical eye movements: inability to elevate the eyes above
the horizontal midline
 Primary horizontal position of each eye: normal
(orthotropic), inward (esotropic), or outward (exotropic)
 Horizontal eye movements: normal to severely restricted
 Aberrant eye movements: common, especially both eyes
turning inward on attempted upgaze

17.  Forced duction test positive for restriction
 Binocular vision: usually absent
 Refractive errors: frequently high astigmatism
 Amblyopia: may be strabismic or refractive in
nature
 Pupils: normal
 Family history: consistent with autosomal
dominant inheritance; simplex cases (i.e., a
single occurrence in a family) are observed.
Parental germline mosaicism can mimic
autosomal recessive inheritance.

18. CFEOM1 phenotype. A. Primary position showing marked bilateral
ptosis. B. Primary position with lids held showing resting globe
position. Both eyes remain infraducted below midline. C.
Attempted up gaze showing inability to reach midline with
convergence of the visual axis (synergistic convergence).

19.  CFEOM- autosomal dominant inheritance with
full penetrance and minimal variation in
expression
 CFEOM1 is divided into CFEOM1A and
CFEOM1B based on genetic findings.
◦ CFEOM1A is associated with mutations in KIF21A
gene; chr 12(centromeric region),
◦ CFEOM1B is associated with mutations in TUBB3
gene.

20. Affected individuals exhibit the following:
 Congenital non-progressive bilateral external
ophthalmoplegia
 Congenital non-progressive bilateral ptosis
 Primary vertical position of each eye: normal or
positioned slightly above or below the midline
 Vertical eye movements: severely restricted
 Primary horizontal position of each eye: typically
fixed outward (exotropic) or rarely fixed in a
normal straight-ahead position (orthotropic)
 Horizontal eye movements: severely restricted

21.  Aberrant eye movements: small amplitude, if
present
 Forced duction test: positive for restriction
 Binocular vision: absent
 Refractive errors: frequent
 Amblyopia: frequent
 Pupils: often small and sluggishly reactive to light
 Genetics:
◦ autosomal recessive disorder
◦ mapped to chromosome 11g13.1.711
◦ result from mutations in the PHOX2A gene

22. CFEOM2
phenotype. A.
Primary position
showing bilateral
ptosis and
exotropia. B.
Primary
position with lids
held showing
resting globe
position. C.
Patient with right
face turn and
holding left upper
lid to clear
pupillary axis. D.
Miotic irregular
pupil.

23. Affected individuals may exhibit the following:
 Lid position and movement: normal or congenital
non-progressive bilateral or unilateral ptosis
 Primary vertical position of each eye: downward
(infraducted) or normal (primary position)
 Vertical eye movements: variable restriction with
presence or absence of upgaze above the midline
 Primary horizontal position of each eye: normal
(orthotropic) or outward (exotropic) may be more
common than inward (esotropic)
 Horizontal eye movements: normal to severely
restricted

24.  Aberrant eye movements: absent or present
 Forced duction test: positive for restriction at
least in attempted upgaze
 Refractive errors: absent or present
 Binocular vision: absent or present
 Pupils: normal
 Magnetic resonance imaging of cranial nerves
and orbits: hypoplasia of the oculomotor
nerve and levator/superior rectus muscles

25.  CFEOM3 is divided into CFEOM3A, CFEOM3B,
and CFEOM3C based on a combination of
clinical and genetic findings.

26.  CFEOM3A refers to the CFEOM3 phenotype that
results from mutations in TUBB3.
 a subset of individuals may have associated
findings, including:
◦ Intellectual disabilities
◦ Social disabilities
◦ Facial weakness
◦ Progressive sensorimotor axonal polyneuropathy
◦ Magnetic resonance imaging of the brain that reveals
dysgenesis of the corpus callosum, anterior commissure,
corticospinal tracts, and basal ganglia
◦ Family history consistent with autosomal dominant
inheritance

27.  CFEOM3B refers to CFEOM3 when it results from
mutations in KIF21A.
◦ Affected individuals exhibit CFEOM3 as described above.
◦ Family history is consistent with autosomal dominant
inheritance.
 CFEOM3C refers to a single family that co-segregates
CFEOM3 with a translocation.
◦ Affected family members harboring a balanced
translocation have the CFEOM3 phenotype.
◦ One affected member with an unbalanced translocation also
had facial dysmorphisms, kyphosis, pectus excavatum,
developmental delay, and motor regression.
◦ Family history is consistent with autosomal dominant
inheritance

28. CFEOM3A phenotype. A. Primary position. B. Right gaze with
absent adduction and slight down shoot OS. C. Left gaze with
absent adduction, slight down shoot OD, and limited abduction
OS. D. Attempted upgaze showing limitation OU with OS unable to
reach midline and with development of an esotropia. E. Down
gaze fixing OD with slight downward movement OD and only
outward movement of non-fixing OS. F. Down gaze fixing OS with
slight downward movement OS and only outward movement of
non-fixing OD

29. CFEOM3B phenotype. All images are in primary position. A.
Patient has unilateral ptosis and esotropia. B. Patient has severe
bilateral ptosis in primary position despite with marked frontalis
effort. C. Same patient as B in primary position with lids held
showing resting globe position marked by exotropia and
bilateral infraduction

30.  Tukel syndrome. Affected individuals exhibit
the following:
◦ CFEOM3 phenotype
◦ Postaxial oligodactyly or oligosyndactyly of the
hands
◦ Family history: consistent with autosomal recessive
inheritance

31.  Systemic associations
◦ Mental retardation
◦ Facial palsy
◦ Craniofacial dimorphism
◦ Dental anomalies
◦ Syringomyelia
◦ Spina bifida
◦ Joubert syndrome
◦ Prader-willi syndrome

32.  Congenital non progressive ocular motility defect.
 It was first described by Stilling and Turk.
 The syndrome is characterized by limitation or absence of
abduction and/or adduction of the eyes.
 There is also retraction of the globe and narrowing of the
palpebral fissure on adduction, which is often associated with
elevation or depression of the globes.
 When abduction is attempted, one often finds widening of the
palpebral fissure

33.  Pathological studies of DRS have provided clear evidence that
innervational deficiencies can cause fibrotic muscle changes.
 Most cases are due to innervational defects, which correlate
with aplasia of the sixth nerve nucleus and the VI cranial nerve
itself

34.  As shown by electrophysiological studies, innervation of the
lateral rectus is provided by the oculomotor nerve causing the
pathognomonic co-contraction of the medial and lateral recti
with globe retraction on adduction. (Synkinesis phenomenon)
 Additionally, an association of DRS is seen with synkinesis
phenomena such as Marcus Gunn jaw-winking (due to
aberrant trigeminal nerve innervation of levator palpebrae
superioris)

35.  autosomal dominant DRS- CHN1 gene mutation
 human CHN1 mutations alter the development of
abducens and, to a lesser extent, oculomotor
axons.
DRS without systemic associations:
The DURS2 locus- on chromosome 2q31 l
(dominant DRS pedigree)
The DURS1 locus- on chromosome 8q12.2-8q21.2
(isolated DRS)

36. DRS with systemic associations
Of the various malformation syndromes, associated with DRS,
Duane radial ray syndrome has been genetically mapped.
inherited as dominant and with incomplete penetrance
mapped to chromosome 20
results from heterozygous nonsense frame shift, and deletion
mutations in SALL4
The SALL4 gene has also been implicated in DRS associated
with Holt–Oram and acro-renal-ocular syndromes.

37.  Absence or hypoplasia of CN6 in the orbit or
brainstem regions, often with mild hypoplasia
and apparent misdirection of CN3 to the
lateral rectus muscle. (The LR muscle in
abducens palsy exhibits profound atrophy).

38.  Type I
◦ Limitation / absence of abduction
◦ Norma/slightly defective adduction
◦ Narrowing of palpebral fissure & retraction of globe on
adduction
◦ Widening of fissure on abduction.
 Type II
◦ Limitation / absence of adduction
◦ N/ slightly defective abduction
◦ Narrowing of PF & retraction of globe on adduction
 Type III
◦ Limitation /absence of both abduction & adduction of
affected eye
◦ Retraction of globe & narrowing of PF on attempted
adduction.

39.  Modification to Huber classification based on
primary position of gaze-
◦ Subgroup A- affected eye esotropic
◦ Subgroup B- exo
◦ Subgroup C- eyes straight in primary position.

40.  Globe retraction
 Narrowing of palpebral fissure on attempted
adduction
 Abduction deficiency
 Upshoot/downshoot on adduction
 Small angle strabismus (usually <30 PD)
 Face turn
 Pattern: V more common than A.

41.  Associated ocular anomalies-
◦ Nystagmus, anisocoria, aniridia, epibulbar dermoid,
ptosis, optic nerve coloboma, marcus gunn jaw
wink.
 Non ocular anomalies-
◦ Skeletal- limb hypoplasia, polydactyly,
hypoplastic/absent radius.
◦ Vertebral –scoliosis, spina bifida
◦ Genito-urinary defects- renal agenesis,VUR,
◦ Cardiac anomalies- PDA, Auricular septal defect.

42.  heterogeneous clinical disorder, which includes congenital facial
palsy with impairment of ocular abduction
 developmental disorder of the brainstem rather than an isolated
cranial nerve developmental disorder
 The ocular motility disturbances in Mo¨bius syndrome are
frequently bizarre and asymmetrical, resembling more of a
congenital fibrosis pattern than cranial nerve palsies.
In a study of 37 patients with facial paresis by Verzijl et al, 97%
had bilateral and 3% had unilateral ocular abduction weakness.

43.  Most cases are sporadic
 Three Mo¨bius syndrome loci have been
mapped:
◦ MBS1 to 13q12.2-q13,
◦ MBS2 to 3q21-q22
◦ MBS 3 to 10q21.3-q22.1

44.  Neural Imaging:
◦ Brain stem hypoplasia in the region of the sixth and
the seventh nerve complexes with or without other
posterior fossa abnormalities
◦ Hypoplasia of extraocular muscles and intraorbital
motor nerves

45. Some forms of congenital ptosis may result from aberrant
development of the unpaired caudal central oculomotor sub-
nucleus.
Two congenital ptosis loci are reported.
a. PTOS1 (1p32-p34.1)
Variable degree congenital unilateral or bilateral ptosis.
Inheritance is autosomal dominant with incomplete penetrance of
90%.
b. PTOS2 (Xp24-27.1)
Congenital bilateral symmetrical and severe ptosis almost impinging
on the visual axis in the primary position of gaze, with chin-up head
posture.
Inheritance is X-linked dominant (male and females are equally
affected).

46. Horizontal gaze palsy is suggested to result from hypoplasia of the abducens
nucleus with interneuron dysinnervation (medial longitudinal fasciculus and
pontine paramedian reticular formation).
ROBO3 [HGPPS (Horizontal gaze palsy with progressive scoliosis), 11q23-25.
The ROBO3 gene encodes a transmembrane receptor required for hindbrain axon
midline crossing.
HGPPS phenotype. There is congenital complete absence of conjugate horizontal
gaze and childhood onset progressive scoliosis.
Inheritance is autosomal recessive.
The uncrossed corticospinal and dorsal column pathways are not associated
with an obvious neurological deficit.

47.  Treatment difficulties:
◦ Varied genetic predisposition, penetrance &
expressivity
◦ Recalcitrant response to therapy
◦ Associated abnormal innervation & mechanical
anomalies

48.  1. Non surgical management-
◦ A. correction of refractive error & anisometropia
◦ Treatment of amblyopia.
 2.surgical management-
◦ Indications of surgery-
 Noticeable ocular deviation in primary position
 Marked abnormal head posture
 Marked globe retraction
 Cosmetically unacceptaable upshoot or downshoot

49.  Principles of surgery-
 No resection procedure should be attempted ( worsens
movement limitation, retraction & upshoot & downshoot)
 Recession of overacting muscle is safest & most effective
 Adjustable sutures may be used when indicated.
 Surgical options-
◦ For esotropia & face turn
 Recession of I/L or B/L MR
 Faden operation
 Transposition of vertical recti to LR- risk of over &
under correction, of inducing vertical tropias & anterior
segement ischaemia.

50. ◦ For exotropia
 I/L or B/L LR resection.
◦ For retraction & upshoot & downshoot:
 I/L MR & LR recession. Posterior fixation suture may be
added.
 Y- splitting with LR recession.

51.  Non surgical management-
◦ Detection & treatment of amblyopia, corneal
exposure & refractive errors
 Surgical management-
◦ No single surgery useful
◦ Transposition of vertical recti to insertion of LR
described

52.  Non surgical management
◦ Correction of refractive error
◦ Treatment of amblyopia,
 Surgical management-
◦ Correction of hypotropia, exotropia followed by
ptosis correction