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American Journal of Medical Genetics 22:273-280 (1985)

The Okihiro Syndrome of Duane Anomaly, Radial Ray Abnormalities, and Deafness

Ailish Hayes, Teresa Costa, and Robert C. Polomeno

Department of Medical Genetics, The Montreal Children’s Hospital, Montreal, Quebec, Canada (A. H., 7: C.) and Ophthalmology Service, McGill University, Montreal, Quebec, Canada (R. C. P.)

We report on a child with Duane anomaly, deafness, cervical spine, and radial ray abnormalities. A sister of the proposita had hemifacial microsomia, cervical abnormalities, and hypoplasia of the thenar eminence. Four relatives had hypoplasia of the thenar eminence. A fifth had preaxial polydactyly. Duane anomaly was present in two sixth-degree relatives. This appears to be an autosomal dominant trait. Singly or in combination the abnormalities seen in this family have all been described in association with Duane anomaly. Their occurrence in the same family suggests that they are not independent entities but represent pleiotropic effects of the same gene.

Key words: Duane syndrome, deafness, Goldenhar syndrome, Wildervanck syndrome, hand abnormalities, autosomal dominant inheritance, pleiotropy, extraocular muscles, ahdu- cens nerve, strabismus, multiple abnormalities

INTRODUCTION

Duane anomaly (Duane retraction syndrome, Stilling-Tuerk-Duane syndrome) is a congenital disorder of ocular motility characterized by absence or severe limitation of abduction, variable limitation of adduction, and both globe retraction and narrowing of the palpebral fissure on adduction [Duke-Elder, 19641. It is not a rare problem, comprising about 1 % of all cases of strabismus [Kirkham, 1970al. Large series show a preponderance of affected females and of unilateral involvement; in the latter, the left eye is most frequently affected [Kirkham, 1970a; Pfaffenbach et al, 1972; Issenberg and Urist, 1977; Marvo et al, 19791. The anomaly is often associated with other ocular or nonocular abnormalities [Pfaffenbach et al, 19721.

The cause of Duane anomaly is obscure. Histopathologic and electromyographic data indicate that, at least in some cases, the cause is absence or hypoplasia of the Received for publication December 1, 1984; revision received April 19, 1985

Address reprint requests to Dr. Ailish M. Hayes, Joint Program in Neonatology, Harvard Medical School, 75 Francis Street, Boston MA 02115.

0 1985 Alan R. Liss, Inc.

274 Hayes, Costa, and Polomeno

abducens nuclei with absence of cranial nerve VI and partial innervation of the lateral rectus muscle with branches from the oculomotor nerves [Marvo et al, 1979; Hotch- kiss et al, 19801. In a large proportion of patients the disorder undoubtedly has a genetic basis. To date, over 40 families in which more than one member was affected by the disorder have been reported [Waardenburg et al, 1961; Goldfarb and Gannon, 1964; Calmettes et al, 1968; Garrec et al, 1970; Kirkham, 1970a; Singh and Patnaik, 1971; Baikoff, 1973; Sevel and Kassar, 1974; Mehdorn and Kommerell, 19791. An autosomal dominant mode of transmission best fits these pedigrees.

Although a family history of Duane anomaly is elicited in only 5-10% of reported cases, this figure must be an underestimate of the actual proportion of familial cases. Reduced penetrance of the gene has frequently been encountered, and in some cases the disorder is so mild as to be missed [Calmettes et al, 19681. An apparent preponderance of sporadic cases would also be observed if Duane anomaly were but one manifestation of a pleiotropic gene, a possibility illustrated by the family reported here. Although the proposita had Duane anomaly, none of her close relatives had the eye abnormality. Hence, she would normally be considered as a case of sporadic Duane syndrome. However, pedigree analysis showed segregation of a gene with variable expressivity involving eye, ear, craniofacial, and radial ray structures.

CLINICAL REPORT

A 15-month old white girl presented with bilateral sensorineural hearing loss. The prenatal course had been uncomplicated. She was born normally at 37 weeks. Birthweight (2.6 kg) and birthlength (51 cm) were appropriate for gestational age. Her growth and psychomotor development were normal apart from language delay.

When examined at 15 months, height, weight, and head circumference were appropriate for age; face was normal (Fig. 1). She had bilateral hypoplasia of the thenar eminence with an inability to flex the interphalangeal joint of the thumb (Fig. 2). The neck was normal. Results of Denver developmental assessment were normal except for delayed speech development. Ophthalmological assessment showed absent abduction and globe retraction on adduction bilaterally. The eyes were otherwise normal. Audiological examination showed severe bilateral sensorineural hearing loss (90 dB). Radiographs of the hands were normal apart from soft tissue atrophy of both thenar muscles. The metacarpal index was normal. Radiographs of the cervical spine showed fusion of C2 and C3.

FAMILY HISTORY

The pedigree is shown in Figure 3 . The proposita is the second child of nonconsanguineous French Canadian parents. A 4-year-old sister was born at 40 weeks gestation following an uncomplicated prenatal course. Birthweight (2.7 kg) and birth length (52 cm) were appropriate for gestational age. At birth unilateral microtia and facial asymmetry were noted. When examined at 4 years, height, weight, and head circumference were appropriate for age. There was right microtia with atresia of the acoustic meatus and a vertical fold in the rudimentary ear (Fig. 4). She had facial asymmetry with hypoplasia of the right side, a right epicanthic fold, and a mongoloid slant of the palpebral fissures (Fig. 5) . There was hypoplasia of the right thenar eminence and elongated thumbs which were functionally normal (Fig. 6). The

Okihiro Syndrome 275

I f ' v3 1 1

I1

I11

IV I 2 3 8

1 2 3 4 5 6 f 7 8 9 10 I1 12

3 Fig. I. Facial appearance of proposita.

Fig. 2.

Fig. 3 . Pedigree: 6, U, individuals examined; 0 , id , Duane anomaly; (3, n, radial ray ahnormali- ties; a, el, deafness; 0. il, hemifacial microsomiaiabnormal pinna; and (0) 6, obligate carrier.

Proposita. Bilateral hypoplasia of thenar eminence

+ . . .

neck was normal. Results of ophthalmological examination were normal. Denver developmental assessment showed psychomotor development appropriate for age. Audiological examination showed a 50-dB loss bilaterally. Radiographs of the hands showed right thenar soft tissue atrophy. Metacarpophalangeal pattern profile analysis was normal. Radiographs of the facial bones and skull showed asymmetry, plag. rioce- phaly, and hypoplasia of the right mandible. Radiographs of the neck showed fusion of C2 and C3.

The parents were clinically normal. A maternal aunt, grandaunt, and two cousins had hypoplasia of the thenar eminence with limited motion at the interphalangeal joint (111-13, 11-7, 111-6, 111- 11). A maternal grandaunt had preaxial polydactyly and hypoplasia of the thenar eminence on the right side (11-2). Three relatives had Duane anomaly (11-1, 111-5, 111-7). A female cousin had a minor anomaly of the pinna


Fig. 4. Sister of the proposita. Microtia with atresia of acoustic meatu

Fig. 5.

Fig. 6.

Sister of the proposita. Hemifacial hypoplasia.

Sister of the proposita. Hypoplasia of right thenar eminence

but had no evidence of hemifacial microsomia or hearing loss (IV-5). Films of the hands of 11-8, 111-12, 111-14, IV-8, IV-9, and 1V-10 were normal. Relatives of 11-8 and 111-12 were examined for cervical spine abnormalities and were clinically and radio- logically normal.


DISCUSSION

In the family described here several individuals presented with an unusual array of abnormalities, all of which can be ascribed to a highly pleiotropic single mutant gene transmitted in an autosomal dominant fashion. This gene is frequently nonpene- trant; four obligate carriers (1-1, 1-2, 11-8, and 111-12), two of whom were examined personally, had no evidence of the syndrome. So great is its variability of expression that taken in isolation the proposita and her sister might be thought to have two different disorders. The association of Duane anomaly, deafness, and defective cervical spine segmentation in the proposita suggests a diagnosis of Wildervanck syndrome [Konigsmark and Gorlin, 19761, whereas the microtia, facial asymmetry, and cervical spine abnormalities in the sister are seen in hemifacial microsomia (Golden- har syndrome, facio-auriculo-vertebral “spectrum” [Smith, 19821. In fact, each spe- cific abnormality seen in this pedigree-radial ray abnormalities, deafness, auricular malformations, facial asymmetry, cervical spine abnormalities-has been, described singly or in various combinations in sporadic cases of Duane anomaly [Cross and Pfaffenbach, 1972; Pfaffenbach et al, 1972; Aleksic et al, 19761. Wildervanck and Goldenhar manifestations have been observed in the same patient [Cross and Pfaffen- bach, 19721. It would appear then, that the so-called Duane syndrome is not as heterogeneous an entity as might be thought from a superficial appraisal of the literature.

A review of the literature yielded 15 other families in which the Duane anomaly was associated with one or more nonocular abnormalities; these are summarized in Table I. There is a striking overlap between families in terms of associated anomalies. Deafness was seen in at least one individual in 13 families [this report; Kirkham, 1969a,b; Kirkham, 1970a,b; Okihiro et al, 1977; Temtamy and McKusick, 19781. In several families, signs of the facio-auriculo-vertebral “spectrum” were seen. Hemi- facial microsomia was present in our patient’s sister and in the mother of two girls with Duane anomaly reported by Waardenburg et a1 [1961]. Kirkham [1969b] noted “facial asymmetry” in one of his patients. Patient 5 of Halal et a1 [1984] had a unilateral preauricular tag and a conjunctival dermolipoma. Spinal abnormalities have been seen in persons in only three families, but they are rarely searched for-an important point since in our proposita, her sister, and in patient 2 of Halal et al [1984] they were clinically inapparent (fusion of C2 and C3 in the first two; spina bifida occulta at C7, L5, and S l in the third). On the other hand, they may be extensive, as in a patient with the Klippel-Feil anomaly reported by Kirkham [1969a]. Cardiac defects were reported by Ferrel et a1 [1966] (ASD in the proband) and Halal et a1 [1984] (pulmonic stenosis in patient 5) . The proband in the family described by Oluhiro et a1 [1977] had a heart murmur and right axis deviation on ECG. Urinary tract abnormalities have been seen in individuals of only two families, but in most cases, including our own, adequate investigations were not carried out. Temtamy and McKusick [ 19781 reported probable right renal agenesis and malrotated left kidney in their proband; his sister had died of “congenital anuria” in the neonatal period. All seven affected individuals described by Halal et a1 [ 19841 had urinary abnormalities that included mild renal malrotation, crossed renal ectopia without fusion, vesiculour- eteral reflux, and bladder diverticula. Recurrent urinary tract infections were a problem in three patients. Upper limb abnormalities are prominent in persons of several families [Ferrel et al, 1966; Okihiro et al, 1977; Temtamy and McKusick,


TABLE I. Duane Anomalv With Associated Nonocular Abnormalities: Summarv of ReDorted Families

Reference

Waardenburg et al [I9611

Ferrel et al [ 19661

Kirkham 11969al

Kirkham [ 1969bl

Kirkham

Kirkham

Okihrro [ 19771

[ 19704

[1970b]

Tenitaniy and McKusick

[ 19781 Halal et al

[ 19781

This report

No. Families

1

1

1

1

5

2

1

I

I

I

Index case - ____.~ ___ Abnormalities

Other relatives”

D A ~

Hypoplastic thumbs; ASD

DA; Klippel-Feil anomaly; deafness

DA; deafness; facial asymmetry; mental retardation

DA: deafness

DA; deafness; cleft palate

DA; hypoplastic thenar eminences; Hirschsprung disease; heart murmur

Hypoplastic arms; malrotation L. kidney; absent (’?), R, kidney

unilateral choanal atresia; vesicoureteral reflux

Preaxial polydactyly;

Hypoplastic thumbs; deafness; DA; cervical spine anomalies

Duane anomaly (I)‘ Horner anomaly/

Hypoplastic thumbsiDA (2); hypoplastic

Deafness

hemifacial microsomia ( I )

thumbs ( I )

Deafness (20): deafnessiDA (1)

Deafness (2, I , I , 2 , 2 )

Deafness (2); DA (1)

Hypoplastic L. arm; R. thumbimetatarsus adductusideafness ( I ) ; DAihypoplastic thumbsideafness ( I ) ; DAihypoplastic R. thenar eminence ( I ) ; DA ( I )

Hypoplastic arrnsianuria ( I ) ; DAifacial palsy/ hypoplastic L. arm, R. handideafness (1)

Hypoplastic thumbsirenal ectopia (3); DA/ hypoplastic thumbsibladder diverticula/ spina bitida occulta (1); hypoplastic thumhsiuveal coloboma; R. microcorneai ptosis, rnalrotation R . kidney (1): pulmonic stenosisicoloboma optic nerve, conjunctival dermoliponiai preauricular tagihypoplstic thurnbsimalrotation R.

kidney ( I ) Facial asymmetryimicrotiaicervical spine

anomaliesihypoplastic thenar eminence ( I ) ; hypoplastic thcnar eminence (4); preaxial polydactyly (1); DA (3); abnormal pinna ( I )

“First to fourth-degree relatives, with occasional skipped generation. ’DA, Duane anomaly; ASD, atrial septa1 defcct; L . , left; R . , right. ‘Number of family members with the listed constellation of abnormalities is given in parentheses; when more than one family described, the number in each family is written separately.

1978; Halal et al, 1984; this report]. Hypoplasia of the thenar: eminence was the most frequent anomaly noted and may be so subtle as to be missed by an examiner unaware of its association with the ocular abnormality. It may be accompanied by an inability to flex the interphalangeal joint of the thumb [Okihiro et al, 1977; Halal et al, 1984; this report]. However, the radial ray abnormality may be much more extensive and may present not only as hypoplastic thumbs but also as hypoplastic “clubbed” upper limbs [Okihiro et al, 1977; Temtamy and McKusick, 19781.

Heterogeneity is the rule rather than the exception in biochemically defined genetic disorders and there is no reason to believe that dysmorphogenetic syndromes


are any different [Orkin et al, 19831. Therefore, it is possible that the mutation responsible for the disorder is unique in each of the families described. However, this attitude is hardly a productive one for the clinician at this point in time. The differences found in the families described hardly warrant the creation of a separate syndrome for each. Most families reported have been small and inadequately investi- gated and therefore are unlikely to show the whole spectrum of the syndrome. For the moment we propose their “lumping” into a single entity, namely, a syndrome. Duane syndrome and acro-renal-ocular syndrome both are misleading, as none of these changes are constant in the syndrome [McKusick, 1983; Halal et al, 19841. In keeping with the recommendations for naming patterns of malformations, an eponym would be a better designation [Smith, 19821. We propose that the disorder be named the Okihiro syndrome, since Okihiro et a1 [1977] were the first to recognize the constellation of nonocular abnormalities in a single pedigree. We suggest the designation Duane anomaly (not Duane syndrome) be reserved for the eye abnormality alone.

ACKNOWLEDGMENTS

We thank the patients and their families for their kind cooperation, the Montreal Children’s Hospital Research Institute for funding (A.H.), and Ms. Margarita Rosado for her excellent assistance.

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Edited by John M. Opitz and James F. Reynolds