SPECIAL ARTICLE Genetic Basis of Congenital

Elizabeth C. Engle, MD

trabismus is misalignment of one eye in relation to the other, resulting in failure of the 2 eyes to simultaneously focus on the same image and loss of . Strabis- mus affects 2% to 4% of the population and can result in , which is often not discovered in time to initiate effective treatment. Thus, an understanding of the genetic underpinningsS of strabismus may help identify patients at risk early enough to prevent disability and may lead to new preventive or therapeutic approaches. Arch Ophthalmol. 2007;125:189-195

Strabismus has both concomitant and in- quency and type in various ethnic popula- comitant forms. Concomitant strabis- tions. The prevalence of strabismus is 2% mus occurs when the angle of deviation to 4% among the white population1-4 and of the eyes remains constant, independent 0.6% among African1,5 and Asian popula- of the direction of gaze, and includes the tions.6,7 is more common than common forms of strabismus, such as eso- in the white population of the tropia, exotropia, hyperopia, microstrabis- United States and Europe,2,8 whereas exo- mus, and monofixation syndrome. The tropia is more frequent in the Asian popu- pathogenesis of concomitant strabismus in lation and among black populations of the the absence of obvious structural abnor- United States and Africa.6-8 In Hawaii, eso- malities of the eye or brain remains poorly tropia is more common in white popula- understood. Concomitant strabismus can tions, exotropia is more common in Asian be inherited as a complex genetic trait, populations, and the 2 forms are relatively however, and it is likely that both genes equal in the mixed ethnic population.6 and the environment contribute to its oc- currence. Incomitant strabismus, also re- Twin Studies ferred to as paralytic or complex strabis- mus, occurs when the misalignment or the The heritability of concomitant strabis- angle of deviation varies with gaze direc- mus is supported by twin studies, which tion. Incomitant strabismus accounts for reveal a concordance rate of 73% to 82% approximately 5% of strabismus cases and among monozygotic twins and 35% to 47% includes the various forms of Duane re- among dizygotic twins.8,9 The higher con- traction syndrome (DRS), horizontal gaze cordance between dizygotic twins than sib- palsy, and congenital fibrosis of the ex- lings likely reflects the influence of envi- traocular muscles (CFEOM). These rare ronmental risk factors. forms of complex strabismus can be in- herited as mendelian traits, and the ge- Family Studies netic bases of several forms of incomitant strabismus have been defined. Family studies support the heritability of concomitant strabismus. Examination of CONCOMITANT STRABISMUS: a cohort of 7100 strabismic patients from A COMPLEX GENETIC TRAIT 12 published family studies revealed that 2171 strabismic probands (30.6%) had a Population Studies close relative with strabismus.8 Families are usually concordant for either esotro- The heritability of concomitant strabis- pia or exotropia, but families with both mus is supported by differences in its fre- forms have been reported. This finding Author Affiliations: Program in Genomics and Department of Neurology, may reflect the presence of 2 relatively Children’s Hospital Boston, and Department of Neurology and Neurobiology common genes or 1 gene with variable ex- Program, Harvard Medical School, Boston, Mass. pressivity.10,11 In addition, the same geno-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 type may have different expressiv- lyzed by linkage and/or association lar motoneurons and their axonal ity. For example, among biological studies. Two approximately 10- connections and led to their renam- parents of children with congenital centimorgan (cM) genome-wide link- ing as the congenital cranial dysin- esotropia, the prevalence of primary age studies of concomitant strabis- nervation disorders (CCDDs).23 monofixation was found to be at least mus have been published.16,18 The first 12 7.8%, whereas the prevalence in the analyzed 7 large pedigrees cosegre- CONGENITAL FIBROSIS OF 12,13 general population is less than 1%. gating strabismus and obtained a sig- THE The incidence of strabismus was nificant lod score to markers on chro- determined among the 39 227 chil- mosome 7p22.1 in 1 family (STBMS1, Congenital fibrosis of the extraocu- dren of mothers enrolled in the Col- Online Mendelian Inheritance in Man lar muscles has been referred to by laborative Perinatal Project.14,15 Stra- [OMIM]: 185100).16 Although this more than 20 different names in the bismus subclassification was limited pedigree appears to segregate strabis- English literature alone, reflecting, to to esotropia and exotropia, and stra- mus as a dominant trait, analysis as- some degree, the varying opinions as bismus was diagnosed by pediatri- sumes recessive inheritance with in- to its pathogenesis.24 It is now most cians and neurologists using the complete penetrance and a high commonly referred to as CFEOM, Hirschberg test of corneal light re- carrier frequency. It remains pos- which remains a misnomer. Congen- flexes, a relatively imprecise esti- sible that the observed segregation re- ital fibrosis of the extraocular muscles mate of strabismus that may inac- sulted from complex interactions of has been reported in families of many curately segregate populations. several genes. The remaining 6 fami- different ethnic backgrounds. Al- Therefore, the reported 3% inci- lies were smaller and none mapped though most families demonstrate au- dence of esotropia and 1.2% inci- to this locus. In the second study, 30 tosomal dominant inheritance with dence of exotropia, with an overall sibpairs concordant for strabismus full penetrance, partial penetrance or odds ratio for concordant siblings of were analyzed, combining both eso- recessive inheritance are also re- 3.0 and 2.8, respectively, may have tropic and exotropic probands.18 This ported; genetic analysis of CFEOM been erroneously low. This finding study was underpowered and yielded pedigrees has led to the identifica- is supported by the finding of a much an insignificant lod score. There- tion of several different syndromes higher odds ratio from a smaller fore, although disease or susceptibil- that account for this variability. An in- study performed by pediatric oph- ity genes for common strabismus have dividual is now diagnosed as having thalmologists who tested for subtle yet to be identified, myriad popula- CFEOM based on the presence of forms of strabismus.12 Overall, the tion, twin, and family studies sup- congenital restrictive ophthalmople- relative risk for first-degree rela- port concomitant strabismus as a gia that primarily affects extraocular tives of an affected proband with complex genetic trait. muscles in the oculomotor distribu- common strabismus is currently es- tion. He or she is diagnosed as hav- timated to be between 3 and 5.12,14-16 INCOMITANT STRABISMUS: ing a specific form of CFEOM based CONGENITAL CRANIAL on both phenotype and genotype. Environmental Risk Factors DYSINNERVATION DISORDERS

Studies of the children of mothers The various forms of incomitant stra- CFEOM1 (OMIM: 135700) enrolled in the Collaborative Peri- bismus share a common presenta- as a Result of KIF21A Mutations natal Project also revealed that ad- tion as congenital, nonprogressive vanced maternal age, cigarette smok- restrictive ophthalmoplegias.19 Posi- An individual with CFEOM1 has (1) ing during pregnancy, and low birth tive forced duction testing, a tight congenital nonprogressive bilat- weight (Ͻ1500 g) each contribute feel to the extraocular muscles at the eral external ophthalmoplegia and to the risk of strabismus.14 When time of , and con- congenital bilateral , (2) an in- corrected for these environmental nective tissue apparent on extraocu- fraducted primary position of each risk factors, however, the odds ra- lar muscle biopsy specimens led to eye, and (3) inability to raise either tios for heritability of concomitant the hypothesis that these disorders eye above the horizontal midline. strabismus remained significant, de- result from primary fibrosis of the The horizontal position of each eye creasing to 2.2 for esotropia and 2.0 extraocular muscles and to the name can be midline, esotropic, or exo- for exotropia.17 congenital fibrosis syndromes. Au- tropic, and horizontal movements topsies of patients with DRS20,21 and can be full to none. Residual eye Linkage Analysis CFEOM,22 however, revealed ab- movements can be remarkably ab- sence of the abducens nerve and su- normal, including synergistic con- Large families that segregate concomi- perior branch of the oculomotor vergence and divergence, Marcus tant strabismus as a mendelian trait nerve, respectively, supporting the Gunn jaw-winking phenomenon,25 would provide the greatest power to hypothesis that these disorders re- or lid elevation while tooth brush- identify strabismus disease genes, but sult instead from aberrant innerva- ing.26 Misinnervation is also sup- such families are rare. Data from tion. Studies of mendelian forms of ported by electromyographic stud- smaller families with sibpairs or from incomitant strabismus have now ies that show aberrant extraocular trios (parents and affected child) who demonstrated that these disorders muscle firing and co-contraction27,28 are concordant or discordant for stra- can result from mutations in genes in individuals later determined to bismus can also be pooled and ana- critical to the development of ocu- harbor KIF21A mutations.29,30

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Autopsy findings of an affected growth cone and cytoskeleton dy- The disorder CFEOM2 maps to member of a CFEOM1 pedigree sub- namics,39-41 supporting the hypoth- the FEOM2 locus on chromosome sequently found to harbor the most esis that CFEOM1 results from a de- 11q1348 and results from recessive common KIF21A mutation30 sup- fect in neuronal differentiation. mutations in the homeodomain tran- port a neurogenic origin for Remarkably, mutations that affect scription factor PHOX2A (ARIX).49,50 CFEOM1. The autopsy revealed ab- only 5 KIF21A amino acid residues One nonsense, 1 missense, and 2 sence of the superior division of the have been reported among the more splice site homozygous mutations oculomotor nerve and profound hy- than 50 unrelated CFEOM1 pro- have been reported, suggesting that poplasia of the 2 muscles normally bands harboring KIF21A muta- CFEOM2 results from complete loss innervated by this nerve, the leva- tions.25,30,42-45 Three of these altered of function of PHOX2A. tor palpebrae superioris and supe- residues, including the most com- Phox2a encodes a pairedlike tran- rior rectus. In addition, the caudal mon, R954W (c2860C→T), which scription factor homeodomain pro- central motoneurons that normally is found in more than 80% of pro- tein with expression restricted to innervate the levator were absent. bands, are located in the a position, several classes of differentiating There was a qualitative decrease in whereas a fourth is located in the ad- neurons in the central and periph- the number of motoneurons in all jacent e position of heptad repeats eral nervous system.51,52 Mouse oculomotor subnuclei and the ab- within the same coiled-coil region Phox2a−/− null mutants53 and ze- ducens nucleus, a decreased diam- of the KIF21A stalk. The ␣-helical brafish with homozygous point mu- eter of inferior division of the ocu- heptad coiled-coil regions are criti- tations in the Phox2a homeodo- lomotor nerve, and an increase in cal for the association and stability main54 die soon after birth. In both central nuclei within myofibers of all of kinesin interactions, with the in- mutants, the oculomotor and troch- extraocular muscles examined.22 tertwined molecules touching at the lear nuclei are absent, consistent The disorder CFEOM1 is inher- a and d positions. Therefore, these with Phox2a expression in the pro- ited as an autosomal dominant trait, mutations may interfere with liferating oculomotor and troch- and if all affected members of a KIF21A’s interaction with its uni- lear motoneuron precursors.52 These CFEOM family meet CFEOM1 cri- dentified partner(s) and/or its uni- animals also have absence of the lo- teria, the family is classified as a dentified cargo. The fifth altered cus coeruleus, atrophy of cranial sen- CFEOM1 pedigree. In most pedi- amino acid residue is located at the sory ganglia, and absence of para- grees, CFEOM1 maps to the FEOM1 end of the motor domain. sympathetic ganglia of the head, locus at the centromeric region of Magnetic resonance imaging of phenotypes not detected in pa- chromosome 1231 and results from the and brainstem of partici- tients with CFEOM2. heterozygous mutations in KIF21A.30 pants from 6 unrelated CFEOM1 Magnetic resonance imaging In addition, rare CFEOM1 pro- pedigrees revealed no imaging fea- studies of brain and brainstem of bands likely harbor mutations in the tures that distinguished among the 9 individuals with CFEOM2 have FEOM3 gene.32 KIF21A has 3 do- 3 amino acid substitutions repre- revealed the anatomical absence of mains and is a member of the kine- sented among these individuals.46 the oculomotor and probably the sin family of molecular motors that This finding suggests that these dif- trochlear nerves bilaterally.47 There- transport cargo along microtu- ferent recurrent mutations pro- fore, clinical presentation, neuro- bules and, in neurons, are respon- duce the same protein dysfunction, imaging, and Phox2a−/− animal mod- sible for anterograde axonal trans- likely resulting in absent or aber- els all support the concept that port.33 The motor domain contains rant cargo delivery to the growth CFEOM2 is a primary neurogenic the microtubule binding site. The tail cone of the developing ocular mo- abnormality of oculomotor and domain is where cargo is loaded and toneuron. trochlear motoneuron develop- carried, often via an adaptor or scaf- ment with secondary myopathic folding protein or protein com- CFEOM2 (OMIM: 602078) changes. plex.34 The stalk domain is a flex- as a Result of PHOX2A Mutations ible connector between the motor Phenotypical and Genetic and tail that typically contains ␣-he- Individuals with this recessive phe- Heterogeneity of CFEOM3 lical coiled-coil repeats through notype are born with bilateral ptosis which kinesin can homodimerize or with their eyes primarily fixed in an In a CFEOM3 pedigree, at least 1 af- heterodimerize, permitting 2 kine- exotropic position. This eye posi- fected family member does not meet sin motors to “walk” down the mi- tion suggests that the only normally CFEOM1 criteria (and the pedi- crotubule. In some instances, the dis- functioning extraocular muscle is the gree is not CFEOM2). The CFEOM3 tal stalk also interacts with cargo.35,36 abducens innervated lateral rectus, pedigrees typically express CFEOM Mouse Kif21a is expressed abun- which succeeds in pulling each eye as a dominant trait with broader phe- dantly in the brain, including neu- outward. Central ocular motility re- notypic variability than found in ronal cell bodies, axons, and den- flexes are intact except for conver- CFEOM1 and CFEOM2, including drites33; its cargo is not known. Other gence. Interestingly, pupillary light individuals with unilateral involve- kinesin family members regulate and near reflexes are not present, but ment and/or residual upgaze. In many aspects of neuronal differen- irises are anatomically normal and re- some families all affected individu- tiation, including neurite exten- spond to pupillary pharmacologic als have CFEOM3,55,56 and in other sion,37,38 collateral branching,39 and treatment.47 families some affected individuals

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 have CFEOM3 and some have horizontal gaze and retraction of the DRS With Associated Anomalies CFEOM1.57 into the orbit on attempted adduction, resulting in secondary Duane retraction syndrome can Mapping of CFEOM3 narrowing of the palpebral fissure. occur in association with other con- and CFEOM1 to the FEOM3 Although early studies of DRS sug- genital anomalies of the skeleton, Locus on Chromosome 16 gested a primary myopathic origin, ear, eye, and kidney in up to 60% several postmortem examinations of cases73-75 and can define various The first genetic locus established for of patients with isolated DRS re- malformation syndromes, includ- CFEOM3 was FEOM3 on chromo- vealed absence of the abducens nerve ing Duane radial ray, Holt-Oram, some 16qter; 2 large pedigrees map and motoneurons on the affected acro-reno-ocular, oculo-acoustic, to this locus.55,57 Some affected mem- side and partial innervation of the Wildervanck (cervico-oculo- bers of FEOM3-linked pedigrees have lateral rectus muscles by branches acoustic), and oculo-acoustic- CFEOM1, and not surprisingly, 2 from the oculomotor nerve.20,21 Ab- radial syndromes. small CFEOM1 pedigrees that do not errant innervation is supported by Duane radial ray syndrome harbor KIF21A mutations were electromyographic63,64 and mag- (OMIM: 607323) is dominant and shown to be consistent with link- netic resonance imaging65 studies, incompletely penetrant, and af- age to this locus.30,32 Therefore, it is suggesting that at least a subset of fected individuals can have DRS anticipated that at least a subset of DRS results from abducens moto- and/or radial dysplasia ranging from CFEOM1 pedigrees and sporadic in- neuron or nerve dysfunction with hypoplasia of the thenar eminence dividuals without KIF21A muta- anomalous innervation of the lat- to absent forearm.76,77 Hearing loss, tions will also harbor mutations in eral rectus muscle by the oculomo- dysmorphic facies, and cardiac, re- the unidentified FEOM3 gene. tor nerve. nal, and vertebral anomalies are vari- ably expressed. Duane radial ray syn- CFEOM3 as the Result drome maps chromosome 2078 and Isolated DRS of KIF21A Mutations results from heterozygous non- sense, frame shift, and deletion mu- In 1 series, KIF21A mutations were Although a positive family history is tations in SALL4, a member of the identified in 2 (9%) of 22 CFEOM3 reported in 2% to 20% of cases of iso- SAL family of proposed C2H2 zinc probands, altering the same amino lated DRS, only 1 genetic locus has finger transcription factors.78,79 The acids as in CFEOM1.58 In a separate been mapped. The DURS2 locus on SALL4 gene has also been impli- publication, a third CFEOM3 pedi- chromosome 2q31 (OMIM: 604356) cated in DRS associated with Holt- gree was also found to harbor the was established by linkage analysis Oram and acro-renal-ocular syn- most common KIF21A mutation.44 of a large dominant DRS pedi- dromes.80 How SALL4 mutations gree.66 Of the 25 affected partici- lead to DRS has not been eluci- Mapping of CFEOM3 pants, 80% had DRS I and 20% DRS dated. to the FEOM4 Locus III, and 96% were bilaterally af- fected.67 Subsequent analysis of a sec- Bosley-Salih-Alorainy Cosegregation of a balanced or un- ond pedigree confirmed linkage and and Athabascan Brainstem balanced translocation t(2;13)(q37.3; reduced the critical region to 8.8 Dysgenesis Syndromes as the q12.11) was identified in a small cM.68 The DURS2 gene has not been Result of Mutations in HOXA1 dominant CFEOM3 pedigree.59 The identified. chromosome 13 break point inter- The DURS1 locus (MIM: 126800) The Athabascan brainstem dysgen- rupted an uncharacterized tran- is assumed to reflect disruption of esis syndrome (OMIM 601536) script expressed in the brain and a gene for isolated DRS and is de- described in Native American muscle that is proposed as FEOM4. fined by cytogenetic abnormalities children81 and the Bosley-Salih- of 8q12.2-8q21.2 in 3 patients with Alorainy syndrome (OMIM 601536) Tukel Syndrome DRS69-72; no DRS pedigrees have been described in Saudi Arabian and reported to map to this locus by link- Turkish children82 overlap. Chil- A new recessive syndrome was re- age analysis. One patient had DRS, dren with Bosley-Salih-Alorainy syn- cently reported in a Turkish pedi- hypoplastic external genitalia, and drome have bilateral DRS, and sub- gree with CFEOM and ulnar hand a reciprocal translocation of t(6;8) sets have congenital sensorineural anomalies. The syndrome maps to (q26;q13). The chromosome 8 break deafness secondary to bilateral ab- an approximately 1.5-megabase re- point was fine-mapped between ex- sence of the cochlea, semicircular ca- gion of chromosome 21qter.60 ons 1 and 2 of a carboxypeptidase nals, and vestibule; variable malfor- gene, CPA6 (CPAH),72 which is pro- mations of the internal carotid posed to play a role in peptide pro- arteries; delayed motor milestones; cessing in the brain.72 No CPA6 mu- and autism spectrum disorder. Simi- Named for Alexander Duane,61 DRS tations were identified in 18 patients larly, children with Athabascan brain- is the most common of the CCDDs with sporadic DRS without cytoge- stem dysgenesis syndrome have hori- and accounts for 1% to 5% of stra- netic abnormalities.72 It remains to zontal gaze restriction, sensorineural bismus cases.62 The affected eyes of be confirmed that CPA6 is the deafness, delayed motor develop- individuals with DRS have limited DURS1 gene. ment,81 and internal carotid artery

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 anomalies.82 In addition, however, gressive scoliosis starting in in- zontal gaze. The underlying gene de- children with Athabascan brainstem fancy or childhood. The gaze palsy fects lead to errors at various devel- dysgenesis syndrome have central hy- is congenital and nonprogressive. opmental time points and locations poventilation and mental retarda- Ocular alignment, congenital nys- along the developing neuroaxis, in- tion, and subsets have facial weak- tagmus, and vertical smooth pur- cluding predicted errors in hind- ness, vocal cord paralysis, and suit defects are variable among in- brain segmentation (HOXA1), mo- conotruncal heart defects.81 dividuals.86 Convergence is retained toneuron specification (PHOX2A), Bosley-Salih-Alorainy syn- in a subset of patients and can be sub- and axon targeting (CFEOM1, drome is inherited as a recessive trait stituted for conjugate tracking move- ROBO3). Genetic diagnostic tests are and has been identified in consan- ments.86 Neuroimaging typically re- now available for these rare strabis- guineous pedigrees in the Middle veals hypoplasia of the pons and mus syndromes. East. Athabascan brainstem dysgen- cerebellar peduncles with both an- Future studies are also likely to esis syndrome has been identified as terior and posterior midline clefts of define the genetic defects that place a sporadic trait in Native American the pons and medulla.86-88 Unlike individuals at risk for the common children from the American South- other CCDDs, the abducens nerve forms of concomitant strabismus, west. Linkage analysis of pedigrees is present bilaterally and the orbital since these disorders appear to be in- with Bosley-Salih-Alorainy syn- extraocular muscles are normal in herited as complex genetic traits. In- drome localized the gene to chro- both configuration and size.88 sight into the genetic basis of com- mosome 7p15.2, encompassing the Horizontal gaze palsy with pro- mon strabismus should lead to an HOXA gene cluster, and genetic gressive scoliosis maps to chromo- improved ability to detect and pre- analysis of children with Athabas- some 1189 and results from homo- vent loss of binocular vision and am- can brainstem dysgenesis syn- zygous or compound heterozygous blyopia. drome revealed that their maternal nonsense, missense, splice site, and and paternal alleles were identical frame shift mutations in ROBO3.88,90 across the 7p15.2 region, suggest- The nature and distribution of these Submitted for Publication: July 7, ing linkage of a recessive trait to this mutations suggest that horizontal 2006; final revision received Au- locus as well. Affected individuals gaze palsy with progressive scolio- gust 6, 2006; accepted August 15, from each of the 3 founder popula- sis results from the complete loss of 2006. tions (Saudi Arabian, Turkish, and ROBO3 function. Correspondence: Elizabeth C. Native American) were found to har- The ROBO3 gene encodes a trans- Engle, MD, Enders Bldg, Room bor a unique homozygous truncat- membrane receptor important in 560.2, Children’s Hospital Boston, ing HOXA1 mutation that is pre- axon guidance and neuronal migra- 300 Longwood Ave, Boston, MA dicted to result in complete loss of tion, is expressed in the human fetal 02115 (elizabeth.engle@childrens gene function.82 hindbrain,88 and is homologous to .harvard.edu). The phenotypes reported in 2 mouse Robo3 (Rig1). When Robo3 Financial Disclosure: None re- Hoxa1−/− mouse models83-85 are re- function is removed in mice, there is ported. markably similar to those in the hu- failure of hindbrain precerebellar man HOXA1 syndromes. 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