Congenital cranial dysinnervation disorders: a

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REVIEW 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

Purpose of review We review the congenital and genetic diagnoses that are currently included in the congenital cranial dysinnervation disorders (CCDDs). Recent findings 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 clinical effects of various gene mutations associated with individual 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. 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. Keywords brainstem development, congenital cranial dysinnervation disorders, cranial nerves, ocular motility, strabismus

INTRODUCTION Ophthalmologists recognized over 60 years ago that certain children were born with congenital ocular motility abnormalities associated with restricted eye movements and fibrotic extraocular muscles [1]. This observation led to the assumption that the primary problem was a congenital abnormality of muscle development and thus to the concept of ‘congenital fibrosis of the extraocular muscles’ (CFEOM) [2]. Duane retraction syndrome (DRS) [3] and Moebius syndrome (MBS) [4] were recognized early on, and a number of other sporadic and familial congenital ocular motility syndromes were added as time passed. Evidence accumulated over time that most or all of these syndromes had a neurogenic cause. Therefore, in 2002 an alternative concept of ‘congenital cranial dysinnervation disorders (CCDD)’ was proposed that shifted the focus away from muscle development [5]. Developments in the last decade have supported the CCDD concept, with all currently identified genes that cause CCDDs when mutated affecting brainstem and/or cranial www.co-ophthalmology.com

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 characterize) than those already recognized.

THE CONGENITAL CRANIAL DYSINNERVATION DISORDERS CONCEPT The CCDD concept encompasses most congenital, static abnormalities of ocular motility and some additional abnormalities primarily involving lid

a

Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia, bDepartment of Ophthalmology, College of Medicine, University of Florida, Jacksonville, Florida, USA and cDivision of Ophthalmology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa Correspondence to Dr Thomas M. Bosley, MD, King Abdulaziz University Hospital, PO Box 245, Riyadh 11411, Saudi Arabia. Tel: +966 567869479; fax: +966 1 4775724; e-mail: [email protected] Curr Opin Ophthalmol 2013, 24:398–406 DOI:10.1097/ICU.0b013e3283645ad6 Volume 24  Number 5  September 2013

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Congenital cranial dysinnervation disorders Bosley et al.

KEY POINTS

atrophy, even if recognized to have a genetic cause.

 The CCDDs represent static congenital abnormalities of eye movement with or without associated systemic abnormalities which are caused by innervational abnormalities of extraocular muscles originating anywhere from brainstem to orbit.

Duane retraction syndrome

 Numerous causative genetic abnormalities have been identified which may involve exclusively the brainstem (ROBO3), the brainstem with both local and remote sequela (HOXA1), the brainstem with predominantly lower motor neuron sequela (PHOX2A), and lower motor neuron axonal guidance (KIF21A, TUBB3), sometimes with syndromic features (SALL4, CHN1, TUBB2B, and TUBB3).  The genes which cause CCDD phenotypes when mutated are neither the only genes involved in development of the oculomotor apparatus nor the only genes that will be identified in the future to affect ocular motility when mutated.  Our understanding of the CCDD phenotypes is broadening, but it has now become clear that a patient’s phenotype does not completely predict the genotype for certain CCDD categories, and the genotype does not completely predict the phenotype.

and facial muscle innervation. Our understanding of this field is in such rapid flux that a description today of the CCDDs is necessarily different from one created 2 years ago, and likely different from one(s) that will be created 2 years from now. Tables 1 and 2 organize the major types of CCDDs, including those that were part of the original CCDD concept (e.g., DRS and horizontal gaze palsy and progressive scoliosis), some that have been identified more recently (e.g., hereditary congenital facial palsy due to mutations in the HOXB1 gene and congenital fibrosis of the extraocular muscles due to mutations in the TUBB2B gene), and others that now seem to potentially make conceptual sense in this context (e.g., congenital isolated superior oblique palsies). Table 1 categorizes CCDDs by a combination of genetic and clinical criteria, whereas Table 2 details the clinical and radiologic characteristics of specific CCDD types. Not included within the CCDD concept at this time are ocular myopathies, orbital restrictive processes such as Brown syndrome, abnormalities that cause a substantial distortion of skull and orbit anatomy such as craniofacial anomalies and neurofibromatosis type 1 with orbitofacial involvement, congenital myasthenic syndrome, or progressive and/or degenerative ocular motility and neurologic problems such as chronic progressive external ophthalmoplegia or spinocerebellar

DRS is characterized most commonly by congenital absence of abduction, possibly with some limitation of adduction, with variable retraction of the globe and narrowing of the palpebral fissure on adduction [6]. This is the most common CCDD. It is usually sporadic and can occur as a unilateral or bilateral condition, either in isolation or as part of a more complex syndrome. Identified genetic variants have involved autosomal dominant and autosomal recessive inheritance, and recent reports have highlighted chromosomal abnormalities as well [7–9]. These genetic abnormalities presumably affect either the creation or survival of cranial nerve 6 neurons (HOXA1) or guidance of growing cranial nerve 6 axons to the lateral rectus (CHN1, SALL4).

Congenital fibrosis of the extraocular muscles Before the term CCDD came into use, some novel variants of congenital fibrosis of the extraocular muscles involving predominantly ptosis and limitation of vertical gaze with variable involvement of horizontal ocular motility were numbered sequentially (CFEOM1, 2, and 3). This classification is evolving rapidly with elucidation of underlying genetic mechanisms, including genes essential for the survival of certain developing neuronal populations (PHOX2A) and genes that are important for guidance of developing axons (KIF21A, TUBB3, TUBB2B). Table 1 reflects an on-going transition from pure phenotype categories to recognition of expanding genetic subtypes. One such example is CFEOM3 that is now known to be caused by mutations in either of two different genes (KIF21A or TUBB3). As a result CFEOM3 was modified into CFEOM3A (when due to TUBB3 mutation) or CFEOM3B (when due to KIF21A mutation). Additional classification elements are arising to address variants now known to cause even more specific genotype–phenotype correlations. For example, a specific amino acid substitution (E410K) in TUBB3 results in a disorder referred to as TUBB3-E410K-syndrome that has distinct nonophthalmological features not found in other known TUBB3 mutations with CFEOM [10].

Other horizontal gaze disorders MBS is defined as congenital, nonprogressive, unilateral or bilateral lower motor neuron facial

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Other horizontal gaze disorders  11q24.2

ROBO3

Horizontal gaze palsy and progressive scoliosis

Moebius syndrome

HGPPS

MBS

CFEOM-U

Tukel syndrome



CFEOM3C

Congenital fibrosis of the extraocular muscles type 3C

13q12.11



TUBB3-E410KCFEOM

TUBB3-E410K-syndrome

TUBB2B-E421KCFEOM

TUBB3-CFEOM

TUBB3 syndrome

TUBB2B-E421K-Congenital fibrosis of the extraocular muscles

CFEOM1B

Congenital fibrosis of the extraocular muscles type 1B

6p25.2

CFEOM3A

Congenital fibrosis of the extraocular muscles type 3A

CFEOM 2

CFEOM 3B

Congenital fibrosis of the extraocular muscles type 3B Congenital fibrosis of the extraocular muscles type 2

CFEOM1A

Chromosomal DRS

Congenital fibrosis of the extraocular muscles type 1A

Chromosomal DRS

BSAS ABDS

Bosley-Salih-Alorainy syndrome Athabascan brainstem dysgenesis syndrome

Wildervanck

DURS2

DURS1

DRRS

DRS

Phenotype abbreviation

TUBB2B

16q24.3

TUBB3

Multiple chrm locations



11q13

7p15.2

HOXA1

PHOX2A

Possible X chrm



12q12

Wildervanck syndrome

2q31.1

CHN1

KIF21A

Duane retraction syndrome 2

8q12–13



Congential fibrosis of the extraocular muscles

Duane-radial ray syndrome Duane retraction syndrome 1

20q13.2

SALL4

Isolated Duane retraction syndrome





Phenotype

Duane retraction syndrome

Locus

Gene

Main category

Table 1. Genetic classification of currently recognized CCDDsa

607313

157900

609428

609384



600638

602078

135700



601536

314600

604356

126800

607323



MIM

AR

Unknown

AR

AD

AD

AD

AR

AD



AR

Unknown

AD

AD

AD

Unknown

Inheritance

23 recognized mutations

Prevalence of 0.0002% to 0.002% of births; rare chromosomal etiology

Six affected members in three sibships of same family

Four affected members in same family

Three affected members in same family; rare TUBB2B phenotype where CFEOM only occurs with E421K amino acid substitution

CFEOM associated with neurological features. Arises from an E410K amino acid substitution

CFEOM1B or 3A associated with neurological symptoms

TUBB3 mutations result in allelic phenotypic heterogeneity; 8/14 recognized mutations result in CFEOM either in isolation (CFEOM1B or 3A) or as part of a larger syndrome referred to as TUBB3 syndrome

Five currently recognized mutations

13 recognized mutations; clinical heterogeneity resulting in different phenotypes (CFEOM1A>CFEOM3B)

Unilateral or bilateral DRS associated with a wide spectrum of other developmental abnormalities (excluding syndromes above)

Rare

Females>>males

Rare; 10 recognized mutations

Three unrelated patients

Rare

Prevalence 0.1%; accounts for 1–5% of all cases of incomitant strabismus; bilateral in 14–20%

Comments

Ocular genetics

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Linkage in one family

1p34.1-p32

Xq24-q27.1





AD, autosomal dominant; AR, autosomal recessive; chrm, chromosome; HCFP, Hereditary congenital facial paresis; MIM, Online Mendelian Inheritance of Man number. a CCDD, congenital cranial dysinnervation disorder.

Rare

X-linked 300245

AD 178300

PTOS2

17q21.3 HOXB1

Hereditary congenital ptosis 2

Hereditary congenital facial paresis 2 10q21.3-q22.1 

Hereditary congenital ptosis 1

PTOS1

Four affected individuals from two unrelated families AR 614744

Hereditary congenital facial paresis 1 3q21-q22  Other facial motility disorders

Hereditary congenital facial paresis 3

HCFP3

Rare AD 604185 HCFP2

Rare AD 601471 HCFP1

Several familial reports ———   Other vertical gaze disorders

Isolated superior oblique palsy

Isolated SOP

Unknown

Congenital cranial dysinnervation disorders Bosley et al.

weakness with limited abduction. Patients with MBS frequently have other associated cranial neuropathies, somatic anomalies, and/or neurological problems, but these features are not mandatory for the diagnosis. The cause is sometimes chromosomal [11] but often unknown [12]. Horizontal gaze palsy and progressive scoliosis (HGPPS) involves congenital partial or complete horizontal gaze palsy, full vertical eye movements, and progressive scoliosis of early onset with increasing severity after the child begins to walk. ROBO3, the responsible gene, is involved in decussation of certain developing neural tracts in the brainstem [13].

Other vertical gaze disorders Recent radiological reports of trochlear nerve aplasia with ipsilateral superior oblique hypoplasia in both sporadic [14] and familial forms [15] of congenital isolated superior oblique palsy has brought attention to this entity as a distinct CCDD phenotype. To date, no genetic locus has been identified, although mutations in PHOX2A and PHOX2B may be risk factors for some [16,17] but not all families.

Other facial motility disorders This group of disorders includes congenital nontraumatic facial weakness in isolation or occasionally in association with comitant strabismus. Isolated bilateral congenital ptosis is also included. Thus far, mutations in only one gene, HOXB1, have been reported as a cause of autosomal recessive facial palsy in a subset of patients [18 ]. &&

Congenital cranial dysinnervation disorders genetic mechanisms Some CCDDs involve primary abnormalities of brainstem development in which the nuclei of ocular motor nerves do not develop correctly (e.g., the HOXA1 spectrum and CFEOM2). Others involve abnormalities of axonal guidance resulting in abnormal lower motor neuron innervation of orbital muscles (e.g., CFEOM1 and CFEOM3), and at times syndromic features (e.g., CFEOM due to TUBB3 mutations or Duane-radial ray syndrome (DRRS) due to SALL4 mutations). At least one CCDD (HGPPS) involves an anatomically profound miswiring of neuronal pathways in the brainstem with no true lower motor neuron dysinnervation of orbital muscles.

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Ocular genetics Table 2. Primary phenotypic features of currently recognized congenital cranial dysinnervation disordersa Phenotype abbreviationb

Ophthalmological

Medical/neurological

Radiological

DRS

Limitation of abduction with variable limitation of adduction; retraction of the globe with palpebral fissure narrowing on attempted adduction

Medically and neurological normal

Small or absent CN6 on involved side

DRRS

DRS, unilateral or bilateral

Radial forearm and hand malformations, typically ipsilateral to DRS side; variable cardiac, renal, hearing, and vertebral anomalies

Variable bony malformations of forearm and hand

DURS1

DRS, unilateral or bilateral

Multiple associated anomalies; most consistent features involve developmental delay, facial dysmorphism, and variable heart, kidney, and hearing anomalies

Single patient with hypoplastic cochlea (Mondini malformation); single patient with hypoplasia of ribs on left

DURS2

Horizontal and/or vertical incomitant strabismus, including DRS (bilateral > unilateral); CN4 palsy, or unilateral or bilateral elevation deficit; unilateral ptosis rare

Rare occurrence of deafness or seizures

Small or absent CN6 with abnormal appearing lateral rectus at times; superior rectus, superior oblique, levator muscle, and optic nerve may be small

Wildervanck

DRS

Deafness and Klippel–Feil anomaly (fused cervical vertebrae)

Bony malformations of inner ear; cervical fusion

BSAS

Bilateral DRS or, in some patients, absence of horizontal gaze; vertical gaze intact

Bilateral deafness, variable cerebrovascular and cardiovascular anomalies, and sometimes autism

Absence of CN6 bilaterally; petrous bone maldevelopment

ABDS

Horizontal gaze palsy; vertical gaze intact

Similar to BSAS but also commonly have central hypoventilation syndrome, facial paresis, cardiac anomalies, and developmental delay; seizure disorder and vocal cord paralysis uncommon

———

Chromosomal DRS

Unilateral or bilateral DRS

Variable

Variable

CFEOM1A

Bilateral ptosis, eyes fixed in down gaze with severely limited upward eye movement; horizontal movement variably affected; chin up AHP; jerky convergent movements with attempted up gaze

Medically and neurologically normal

Variable hypoplasia of extraocular muscles and levator palpebrae muscle; hypoplasia or absence of ocular motor nerves; reduction in optic nerve diameter

CFEOM3B

Similar ocular motility and lid findings to CFEOM1 but more variable; ptosis may be mild or unilateral; one or both eyes may be able to elevate above the midline

Medically and neurologically normal

See CFEOM1A

CFEOM2

Bilateral ptosis with both eyes fixed in abduction; absence of adduction, elevation, and depression; AHP with head turn away from fixing eye with minimal chin up; irregular miotic pupils

Medically and neurological normal

Absence of both CN3 and likely CN4

CFEOM3A

Same phenotype as CFEOM3B but due to mutations in TUBB3

Medically and neurologically normal. Can be associated with neurological features – when these are present, becomes known as TUBB3 syndrome (see TUBB3-CFEOM)

Small orbital nerves (CN2, 3, 6) and EOM hypoplasia

CFEOM1B

Same phenotype as CFEOM1A but due to specific mutations in TUBB3 or TUBB2

Medically and neurologically normal unless part of another syndrome (e.g., TUBB3-E410K-CFEOM or TUBB2-E421K-CFEOM)

See CFEOM3A

TUBB3-CFEOMc (TUBB3 syndrome)

See CFEOM3A

CFEOM associated with neurological features (e.g., facial weakness, progressive peripheral sensorimotor axonal polyneuropathy, and intellectual and social disabilities)

See CFEOM3A, but varies with specific mutationsd; can include dysgenesis of corpus callosum, anterior commissure, and internal capsule; white matter loss and basal ganglia abnormalities

TUBB3-E410K-CFEOM (TUBB3 E410K syndrome)

See CFEOM1B

Bilateral facial weakness, facial dysmorphism, developmental delay, Kallmann syndrome, tracheomalacia, vocal cord paralysis, and later onset cyclic vomiting and progressive peripheral neuropathy

Hypoplastic or absent olfactory sulcus, olfactory bulb, and oculomotor and facial nerves; variable thinning of corpus callosum and anterior commissure

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Congenital cranial dysinnervation disorders Bosley et al. Table 2 (Continued) Phenotype abbreviationb

Ophthalmological

Medical/neurological

Radiological

TUBB2B-E421K-CFEOM

See CFEOM1B

Intellectual disability

Variable hypoplasia of EOMs; abnormal cerebral cortex, corpus callosum, cerebellum, and basal ganglia with grossly normal brainstem; abnormal tractography of commissural neurons

CFEOM3C

Bilateral ptosis and limitation of elevation; two individuals had bilateral excyclotorsion

Mental retardation, facial dysmorphism, kyphosis, and (one individual) pectus excavatum

Normal EOMs on CT

CFEOM-U

Unilateral elevation deficit; rare unilateral restriction all directions and unilateral ptosis

Ulnar hand anomalies with bilateral postaxial oligodactyly/ oligosyndactyly

Superior rectus hypoplasia

MBS

Abduction deficit, commonly bilateral with variable involvement of adduction; vertical eye movement limitations are not part of this diagnosis

Facial weakness, frequently bilateral and asymmetric and commonly associated with orofacial, limb, and musculoskeletal anomalies; variably associated with mental retardation, autism-spectrum conditions, and social problems

Varied reports including hypoplasia of posterior fossa and brainstem; CN hypoplasia; neuronal degeneration þ/ focal necrosis with gliosis and calcification of the tegmentum

HGPPS

Complete or almost complete horizontal gaze palsy with intact vertical gaze

Scoliosis, typically early childhood onset and severe; neurologically normal despite profound brainstem anomaly

Intact CN6 bilaterally; characteristic hypoplasia of pons and medulla with anterior and posterior clefts; absence of decussation in at least corticospinal tract, medial lemniscus, and superior cerebellar peduncle

ISOLATED SOP

Underaction of superior oblique muscle, usually unilateral

Medically and neurological normal

Absence of ipsilateral CN4 and/or variable hypoplasia of superior oblique muscle

HCFP1

Full ocular movements

Isolated, nonprogressive unilateral or bilateral facial weakness

On neuropathology, reduced number of neurons in CN7 with normalappearing brain and brainstem

HCFP2

Full ocular movements

Isolated, nonprogressive unilateral or bilateral facial weakness; some patients with congenital deafness or progressive hearing loss

———

HCFP3

Comitant strabismus (accommodative esotropia) – 4 individuals from 2 families

Bilateral facial weakness; bilateral hearing deficit; mild dysmorphism including mid-face hypoplasia; low-set, posteriorly rotated ears; upturned nasal tip; and smooth philtrum

Bilateral absence of CN7 and abnormal tapering of the basal turn of the cochlea

PTO1

Bilateral ptosis, severe or asymmetric

Medically and neurological normal

———

PTO2

Bilateral symmetric ptosis

Medically and neurological normal

———

AHP, anomalous head position; BSAS, Bosley-Salih_Alorainy Syndrome; CN, cranial nerve; CT, computed tomography; EOM, extraocular muscles; HCFP, Hereditary congenital facial paresis. a CCDD, congenital cranial dysinnervation disorder. b See Table 1. c CFEOM is only present with certain TUBB3 mutations (R262C, R62Q, R262H, R380C, D417H [at times], D417N, A302T). d Radiological features show correlation to specific mutations e.g., severe involvement associated with A320T, R262H, and R380C mutations; less severe involvement can occur with R62Q, R262C, or D417H mutations.

RECENT CONGENITAL CRANIAL DYSINNERVATION DISORDERS CLINICAL AND GENETIC OBSERVATIONS The last 2 years have seen expansion of the CCDD phenotypes and our understanding of the genes that cause them when mutated. Additional mutations have been documented in known genes that resulted in expected phenotypic features (e.g., HGPPS [19]) or expanded the phenotype (e.g., DURS2 [20]). Certain phenotypes are also now recognized to result from mutations in additional genes (e.g., CFEOM1 from specific mutations in

&&

TUBB2 and TUBB3 as well as KIF21A) [21,22 ] or from either gene mutations or chromosomal anomalies (e.g., bilateral DRS and deafness from HOXA1 mutations or partial chromosome 7 duplication [9]). Certain genes closely related to genes already identified also have potential ocular motility implications. For example, mutations in TUBB3 are known to be a cause of ocular motility and other congenital brain developmental abnormalities [21], but a specific TUBB2B mutation (E421K) can cause an ocular motility disturbance in addition to polymicrogyria [22 ]. Similarly,

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Ocular genetics

HOXA1 mutations may cause DRS, deafness, and vascular anomalies [23], whereas HOXB1 has now been shown to cause bilateral facial palsy, hearing loss, and strabismus without ductional abnormalities [18 ]. Recent reports have described additional information about the developmental actions of tubulin genes [24], Phox2A [25], Hoxa1 [26], Chimaerin-1 [27], PHOX2A [28], and KIF21A [29]. Large series of isolated unilateral or bilateral DRS continue to be reported [30]. These have not changed our understanding of the disorder, and in general, the cause of most cases of sporadic DRS remains unknown [31–33]. DRS occurs at times in combination with other congenital abnormalities [34], for example, rare posterior microphthalmos [35] and Marfan syndrome [36]. This may simply be coincidence. DRS has also been associated with a variety of syndromes with known genetic causes, including dominant mutations of SALL4 [31] and CHN1 [37] and certain chromosomal anomalies [38 ,39]. CHN1 mutations may cause DRS in isolation [37] or in association with vertical ocular motility disturbances [40]. Vertical motility disturbance has also been reported without DRS despite radiological evidence of small abducens nerves [20]. Our knowledge regarding the CFEOMs has also expanded. Associated developmental abnormalities in CFEOM1 extend beyond extraocular muscles to include, for example, the optic nerve [41–45]. The isolated CFEOM1 phenotype is caused most commonly by dominant KIF21A mutations [46], which may be less common in certain ethnic populations [47]. Specific mutations in TUBB2B and TUBB3 can rarely result in this phenotype, but generally are also associated with neurological problems [21,22 ]. Knowledge of the MBS phenotype is now more complete, but a comprehensive phenotypic and genotypic description has yet to appear. It typically occurs sporadically [12], and no specific causative gene is currently known [48]. Recent literature has reported the rare association of MBS with DRS [49] or hydrosyringomyelia [50]. The presence of MBS following certain environmental factors [51] or drug exposure, such as misoprostol [52,53] or thalidomide [54], may offer clues regarding pathogenesis and timing of brainstem maldevelopment. Some CCDDs are more common than others, although all the reasons for these differences in frequency are not yet completely known. When sporadic, DRS and, to some extent, MBS, almost certainly have a nongenetic (or at least nongermline) cause as a result of events during brainstem development that we do not yet understand. Autosomal dominant disorders such as CFEOM1 and &&

&

&&

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CFEOM3 are uncommon, but are nevertheless likely more common than autosomal recessive disorders such as CFEOM2 or HGPPS. The number of families reported with HGPPS far exceeds that of families with the HOXA1 spectrum, another autosomal recessive disorder, and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/ index.php) currently identifies 27 mutations in ROBO3 and only five in HOXA1. The reasons for this type of difference in mutation prevalence are not completely clear but could relate in part to simple chance, the size of a gene (ROBO3 is larger than HOXA1), better survivability of a fetus with homozygous or compound heterozygous ROBO3 mutations, increased severity of the phenotype (possibly causing HGPPS patients to seek medical attention with ophthalmologists or neurologists more often), or a variety of other factors related to specific genes and their expression [55]. The phenotype of CCDD patients does not completely predict genotype. For example, DRS has now been reported as an isolated phenomenon and as a cardinal feature of certain syndromes caused by autosomal dominant mutations in CHN1 and SALL4 and autosomal recessive mutations of HOXA1. However, the main features of DRS (limited abduction with ipsilateral globe retraction on adduction) have also been recognized in some individuals with ocular motility disturbances caused by KIF21A [56,57], and we have seen one patient with horizontal gaze restriction due to HGPPS with ROBO3 mutations who had absent abduction bilaterally and unequivocally had retraction on adduction of either globe. Therefore, the presence of DRS-like features by themselves may be of limited assistance in genetically classifying a patient. Even DRS in association with deafness can also be a somewhat ambiguous phenotype because DRS is linked to hearing impairment in a number of distinct syndromes including at least: the HOXA1 spectrum caused by autosomal recessive mutations in HOXA1 that also has cerebrovascular anomalies; DRRS caused by autosomal dominant mutations in SALL4 that is associated with upper limb and renal anomalies; DURS2 caused by autosomal dominant mutations in CHN1 that can include vertical ocular motility deficits and unilateral congenital ptosis; and Wildervanck syndrome in which bilateral DRS and bilateral deafness is associated with Klippel–Feil anomaly that currently has no known genetic cause. A male individual has been identified recently with Wildervanck syndrome due to an Xq26.3 microdeletion [8], and another patient with deafness and DRS was found to have a partial chromosome 7 duplication [9]. Of course, additional features of ocular motility, the entire phenotype (beyond Volume 24  Number 5  September 2013

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Congenital cranial dysinnervation disorders Bosley et al.

ocular motility), and the pedigree help in reaching a clinical diagnosis. Conversely, the genotype of a patient with a CCDD may not completely predict the phenotype. As in other genetic disorders, some monogenic CCDDs have a modest amount of phenotypic variability. For example, scoliosis in HGPPS is typically severe, but on occasion it is relatively mild [58]. Some patients have a moderate restriction of horizontal gaze, whereas others have no horizontal gaze at all [59]. Approximately one-third of patients with HGPPS have modest amplitude horizontal pendular nystagmus, looking most like benign infantile idiopathic motor nystagmus, for unclear reasons. Phenotypic variability is even more striking in patients with the HOXA1 spectrum disorders. Two brothers with congenital heart disease have now been identified who lack the cardinal features of DRS, deafness, and inner ear malformation despite homozygous HOXA1 mutations and who have cousins with the full Bosley-Salih-Alorainy syndrome [60]. It is unclear why some of these syndromes do not cause a more clinically severe phenotype. For example, HOXA1 is expressed very early in development and probably has a role in coordinating the expression of other genes in the HOX cascade in the hindbrain [61], and yet, homozygous mutations in this gene cause ‘only’ the recognized human HOXA1 phenotype. Perhaps this genetic defect is commonly lethal in utero, which would also explain the increased frequency of spontaneous abortions noted in affected consanguineous families. Robo3 and Phox2a mutations typically cause stillbirths in other species, but mutations of these genes in humans result in CCDD syndromes. TUBB genes affect microtubule structure and function, presumably in all cells of the body [21,22 ,45]. The fact that some mutations in these genes cause a relatively minor abnormality of peripheral neuronal guidance affecting predominantly ocular motility rather than a gross failure of neuronal development or obvious multiorgan disease implies restricted expression of the genetically programmed defect by mechanisms not currently understood. &&

CONCLUSION The CCDDs are a group of congenital ocular motility disorders that may or may not be inherited. The genetic causes are diverse. Multiple affected genes have been identified in patients, which act at different times in different places during development. Some disturb the development of brainstem nuclei, whereas others affect the growth of brainstem white matter tracks or peripheral neuronal

guidance. More phenotypes and genes are bound to be identified in the future as our understanding of these disorders increases. Acknowledgements None. Conflicts of interest All three authors are partially supported by a grant from the King Abdulaziz City for Science and Technology [Project AT-30-20]. No author has a conflict of interest.

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