American Journal of Medical Genetics 139A:123–126 (2005)

Clinical ReportA Family With Duane Anomaly and Distal LimbAbnormalities: A Further Family With theArthrogryposis-Ophthalmoplegia SyndromeEmma McCann,1 Alan E. Fryer,1* William Newman,2 Richard E. Appleton,3 and Jurgen Kohlhase4

1Department of Clinical Genetics, Royal Liverpool Children’s Hospital, Liverpool, United Kingdom2Department of Ophthalmology, Royal Liverpool Children’s Hospital, Liverpool, United Kingdom3Department of Paediatric Neurology, Royal Liverpool Children’s Hospital, Liverpool, United Kingdom4Institute for Human Genetics and Anthropology, University of Freiburg, Freiburg, Germany

A two-generation family is reported in whichthree members have Duane anomaly and distallimb abnormalities. All three affected have photo-pic electroretinogram responses that are abnor-mal or at the lower limit of the normal range withnormal scotopic responses. Two affected familymembers also have hearing loss. The likeliestdiagnosis is the syndrome listed as ‘‘arthrogrypo-sis-ophthalmoplegia syndrome’’ on the LondonDysmorphology Database or as ‘‘arthrogryposiswith oculomotor limitation and electroretinalabnormalities’’ or ‘‘oculomelic aplasia’’ in OMIM[MIM 108145]. In view of the similarities withOkihiro syndrome, a search for mutations withinthe SALL4 gene was undertaken, but none wereidentified. � 2005 Wiley-Liss, Inc.

KEY WORDS: Duane anomaly; arthrogryposis;arthrogryposis-ophthalmoplegia;SALL4

INTRODUCTION

Duane retraction anomaly is a congenital eye movementdisorder characterized by failure of normal development of thesixth [VI] cranial nerve, resulting in restriction or absence ofabduction, restricted adduction, narrowing of the palpebralfissure, and retraction of the globe on attempted adduction.The latter features are thought to be due to co-contraction ofthe medial and lateral recti. Autopsy examination of twopatients with Duane anomaly has shown hypoplasia of the VInerve nucleus and absence of the VI nerve on the affected side,the ipsilateral lateral rectus being innervated by branches ofthe third nerve [Hotchkiss et al., 1980].

The prevalence is approximately 0.1% in the generalpopulation, and Duane anomaly accounts for 5% of all casesof strabismus [Appukuttan et al., 1999]. Up to 10% of cases arefamilial and follow an autosomal dominant pattern of inheri-tance. Intrafamilial variability between different types is seen.The condition is bilateral in 20% of cases.

One autosomal dominant form (DURS2) has beenmapped to2q31 [Appukuttan et al., 1999; Evans et al., 2000]. Cytoge-netic abnormalities in patients with Duane anomaly suggest a

further locus at 8q13 [Pizzuti et al., 2002]. Other possible lociinclude 22q [Cullen et al., 1993; Versteegh et al., 2000] and 4q[Chew et al., 1995]. Duane anomaly can also be associatedwithTownes–Brocks syndrome caused by mutations of SALL1 on16q12.1 [Kohlhase et al., 1999].

Duane anomaly is associated with other features includinghearing loss in 10–20% [Shauly et al., 1993; Marshman et al.,2000]. Other reported associated abnormalities include cleftpalate, rib anomalies, Chiari 1 malformation, Marcus-Gunnphenomenon, ocular dermoids, and hypoplasia of the opticdiscs. It is a feature of several well-recognized syndromes,including Okihiro [MIM 607323] and arthrogryposis-ophthal-moplegia syndrome.

CLINICAL REPORT

Amother and two of her four children are described (Fig. 1).All had a Duane anomaly, photopic ERG abnormality, muscleweakness, and similar dysmorphic features. Their individualpresentations are as follows.

II–4

The propositus had bilateral congenital talipes equinovarusdetected on routine 20-week gestation ultrasound scan.Corrective surgery was performed at age 2, 3, and 8 years.The patient was found to be hypotonic in infancy with delayedmotor milestones, and hyperextensible joints of both fingersand toes. Clinical examination at 8 years of age showed aproximal muscle weakness affecting the shoulders and upperlimbs more than the lower limbs. There was also evidence ofwasting of the small muscles of the hands. Muscle texture wasnormal.Muscle stretch reflexeswere present in bothupper andlower limbs. The patient had no hearing impairment but hadmild learning difficulties.

Thepatient’s facial features (Fig. 2a,b) illustratehis deep-seteyes, convexnasal profile, andbrowptosis. Thepatient alsohassloping shoulders and a prominent sternum.

Ophthalmology examination revealed bilateral Type ADuane anomaly, brow ptosis (in the presence of normal levatorfunction), bilateral epicanthic folds, small corneal diameters(11 mm), small optic discs, and hypermetropia. There was noevidence of pigmentary retinopathy.

The patient has been extensively investigated includingcreatine kinase (CK), plasma amino acids, carnitine, lactate,calcium and white cell enzymes, and a standard karyotype allof which were normal. Muscle histology on microscopy, usingstains NADH-TR, phosphoylase, phosphofructokinase, succi-nic dehydrogenase, adenylate deaminase, and cytochromeoxidase, was normal. Muscle ultra-structure was normal onelectron microscopy. Immunohistochemical labeling of inquadriceps and triceps muscles was normal for dystrophin,alpha sarcoglycan, emerin, and laminin. Muscle biochemistry

*Correspondence to: Dr. Alan E. Fryer, Department of ClinicalGenetics, Royal Liverpool Children’s Hospital, Eaton Rd, Liver-pool L12 2AP, United Kingdom. E-mail: alan.fryer@rlc.nhs.uk

Received 22 March 2005; Accepted 28 July 2005

DOI 10.1002/ajmg.a.30962

� 2005 Wiley-Liss, Inc.

showed normal activity of the mitochondrial complexes I, II,IV. The ERG showed an abnormal photopic response withnormal scotopic responses.

I-1

The mother of the propositus was assessed following thebirth of II-4. A contracture affecting the right second toe andhigh arched feet was detected at birth. Clinical examinationrevealedmild lower facial weakness, weakness of neck flexion,andmild right-sided scapular winging. There was weakness of

the wrist and wasting of the small muscles of the hands withhyperextensible fingers and toes. There was no lower limbweakness. The patient has a unilateral sensorineural hearingloss.

The patient’s facial appearance is illustrated (Fig. 2c,d) andis similar to the proband. The patient also has slopingshoulders and a prominent sternum.

Ophthalmology examination showed a right-sided Type ADuane anomaly, brow ptosis, bilateral epicanthic folds, smallcorneal diameters (10.5 mm), small optic discs, and hyperme-tropia. There was no evidence of retinopathy.

Investigations included a normal CK and nerve conductionvelocities. An electromyogram showed non-specific changes,and DNA testing for facioscapulohumeral dystrophy showedno abnormal-sized fragment. A muscle biopsy showed non-specific features—a few fibers were said to have centralinactive core-like areas. The ERG had an abnormal photopicresponse.

II-2

A 12-year-old sibling was noted to be floppy in infancy. Nocontractures were evident but the patient had hyperextensiblefingers and toes. There was wasting of the small muscles of thehand. At 3 years of age, bilateral profound sensorineuraldeafness was detected. The patient’s facial features and bodyhabitus are very similar to the other affected family members.A Type C Duane anomaly, brow ptosis, small optic discs, andhypermetropiawere found on examination. TheERG showed areduced photopic response.

Fig. 1. Pedigree of affected family. I-1: Duane type A, proximal anddistal myopathic changes, photopic ERG abnormality, unilateral hearingloss. II-2: Duane type C, distal myopathic changes but no contractures,photopicERGabnormally, bilateral hearing loss. II-4:Duane typeA, talipes,proximal and distal myopathic changes, photopic ERG abnormality, normalhearing.

Fig. 2. Illustrating the facial appearance of (a) and (b) the proband; (c) and (d) the mother; note the triangular-shaped face, deep-set eyes, and convexprofile of the nose. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

American Journal of Medical Genetics: DOI 10.1002/ajmg.a

124 McCann et al.

Mutation Analysis

SALL4 mutation was undertaken because of similarities ofthe cases to Okihiro syndrome (Duane anomaly, hearing loss,epicanthic folds [Kohlhase et al., 2003]). The four coding exonsof the SALL4 gene were amplified and directly sequenced withinternal primers as described [Kohlhase et al., 2002] fromDNAfrom II-4; no mutation was detected. Deletions of the coding

exonswere sought using real-timePCR [Borozdin et al., 2004a]but none found. The method applied does not exclude smallerdeletions not detected by the amplicons used, but such smallerdeletions would in most instances be visible as shortened PCRamplification products during mutation analysis. It also doesnot exclude deletions upstream or downstream of the codingregions, but disease-causing deletions not involving the codingregion have yet to be reported.

Fig. 2. (Continued)

TABLE I. Clinical Features of the Arthrogryposis-Ophthalmoplegia Syndrome

Lai Schrander-Stumpel Our cases

1 2 3 4 5 6

Congenital contractures þ þ þ þ þ �Stiff trunk þ þ � � �Large joint limitation of movement þ þ þ � � �Dimples þ þ { � �Ophthalmoplegia/Duane anomaly þ þ þ þ þ þElectroretinogram abnormalities þ þ þ þ þPtosis þ þ þ þ þ þMuscle involvement þ þ þ þ þ þSloping shoulders þ þ þ þ þ þPectus deformity þ þ þ þ þ þDeep-set eyes þ þ þ þ þ þAbnormal ears þ þ þ þ þ þAdditional features High

palateBilateral

inguinal herniasPyloricstenosis

Unilateralhearing loss

Bilateralhearing loss

þ, feature present; �, feature absent; {, feature not reported.

American Journal of Medical Genetics: DOI 10.1002/ajmg.a

Duane Anomaly and Distal Limb Abnormalities 125

DISCUSSION

The family described most closely resembles the arthrogry-posis-ophthalmoplegia syndrome. This was initially describedby Lai et al. [1991], in a father and son with a further casereport by Schrander-Stumpel et al. [1993] in a 17-year-oldmale. The features of all cases are shown in Table I. Thearthrogryposis phenotype is less prominent in our familyaffecting mainly the feet, and at present there is no limitationof movement of large joints. All cases have a Duane anomaly,abnormal ERG responses, and dysmorphic features. In addi-tion, two of the family members have hearing loss that has notbeen a feature of the previous cases but is a recognizedassociation of Duane anomaly. The presence of hyperextensi-bility of the fingers has not been documented. It is also possiblethat the family described represent a new arthrogryposissyndrome.

The othermain differential diagnosiswasOkihiro syndromein view of the Duane anomaly, hearing loss, and limbabnormalities. The limb anomalies in Okihiro affect the radialray,whichwasnot the case in our family.Thegenewasmappedto 20q13 with truncating mutations in SALL4 subsequentlyidentified [Kohlhase et al., 2002]. SALL4 represents the firstgene definitively identified in autosomal dominant Duanesyndrome. It encodes a zinc finger transcription factor. Morerecently,mutations in this gene have been identified in a rangeof other clinically overlapping conditions including acro-renal-ocular, Holt-Oram, and patients previously reported torepresent thalidomide embryopathy [Kohlhase et al., 2003;Borozdin et al., 2004b]. Wabbels et al. [2004] recentlydemonstrated that there was no evidence of SALL4mutationsin the isolated sporadic ‘‘Duane syndrome’’ population.

Another locus worth considering is DURS1 located on 8q13.Calabrese et al. [1998] reported on a young girl with Duaneanomaly, short neck, brachydactyly, and unilateral talipes.However, she had a complex chromosomal rearrangementinvolving a deletion in the DURS1 region, and other deletedgenes may account for her features.

Freeman–Sheldon syndromevariant (FSSV, arthrogryposismultiplex congenita, type 2B) is known to be caused bymutations in fast-twitch contractile proteins TNNI2 andTNNT3 [Sunget al., 2003]. This condition shares some featureswith arthrogryposis-ophthalmoplegia including talipes,camptodactyly, similar shaped face, and dominant inheri-tance. However, the absence of eye involvement and thepresence of short stature in FSSV make this diagnosisunlikely. The distal arthrogryposis type IIB syndrome [Hallet al., 1982] was considered in this family because of theassociated eye problems. The absence of short stature and thepresence of the other features in the familymake this diagnosisunlikely.

SALL4 mutation analysis as well as deletion screeningproved negative in our family and indicated that arthrogry-posis-ophthalmoplegia syndrome is not allelic to Okihirosyndrome. It is possible that the arthrogryposis-ophthalmo-plegia and distal arthrogryposis type IIB syndromes may beallelic, and it would be important to investigate this as andwhen the gene for this condition is identified.

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