The Williams Syndrome

Spectrum and Significance of Ocular Features

FRANK GREENBERG, MD, 1•2 RICHARD ALAN LEWIS, MD, MS1•2•3

Abstract: Forty-two subjects with classic features of Williams syndrome were evaluated to ascertain the prevalence and severity of the ophthalmologic features associated with the disorder. Twenty-six (62%) had a stellate pattern of the anterior iris stroma which was observed only in individuals with blue or hazel iris color. Twelve (29%) had strabismus, most commonly esotropia. Hyperme­tropic discs were noted in 18 of 33 patients (55%), a simplex vertical branching of the central retinal vessels at the disc in 23 (70%), and situs inversus vasorum in 5 (15%). No subject had accentuated vascular tortuosity, which has been reported previously as a hallmark of this syndrome. No ocular manifestation of infantile hypercalcemia was noted in any subject. [Key words: hypermetropic discs, infantile hypercalcemia, iris, parental age, strabismus, Williams syndrome.] Ophthalmology 95:1608-1612, 1988

Williams syndrome is an infrequent but distinctive dis­order of unknown etiology which consists of a so-called "elfin" facies, supravalvular aortic stenosis and/or other congenital cardiac defects, idiopathic hypercalcemia of infancy, developmental delay, and, frequently, an out­going "cocktail party" personality. 1 The features of Wil­liams syndrome may vary but can be recognized easily both by knowledgeable health professionals and by par­ents. Previous reports, mostly in the pediatric literature, have mentioned several ocular findings associated with patients with Williams syndrome. These include a stellate iris stromal pattern, strabismus, and tortuosity of the ma­jor retinal vessels.2•3 Since no prior systematic evaluation of the ophthalmic features of this disorder has been pub-

Originally received: January 11, 1988. Revision accepted: May 3. 1988.

' Institute for Molecular Genetics and the Department of Pediatrics, Baylor College of Medicine, Houston.

2 Birth Defects Center. Texas Children's Hospital, Houston. 3 Departments of Ophthalmology and Medicine, Baylor College of Medicine,

Houston.

Supported in part by unre.stricted grants from Research to Prevent Blind­ness, Inc, New York, New York, and the Lillian Kaiser Lewis Foundation, Houston, Texas (Dr. Lewis), and from the Texas Department of Health and the Robert J. Kleberg Center for Human Genetics (Dr. Greenberg).

Reprint requests to Frank Greenberg, MD, Birth Defects Center, Texas Children's Hospital, Houston, TX 77030.

lished, we initiated a prospective survey of these individ­uals as part of a large referral center for Williams syn­drome.

MATERIALS AND METHODS

Between June 1982 and December 1987, 42 patients with classic features of Williams syndrome, based on cri­teria of Jones and Smith3 and of Preus,4 were evaluated individually by one (RAL: n = 6, FG: n = 9) or both (n = 27) authors. Patients were ascertained by referral from personal physicians (pediatricians, geneticists, and car­diologists), and from the regional and national Williams Syndrome Associations, and by self-referral.

Of the 42 patients, the diagnosis was suspected in 22 subjects (52%) because of a heart murmur, in 17 (40%) because of developmental and/or growth delay with dys­morphic facial features, and in 2 (5%) because ofinfantile hypercalcemia. One additional subject was evaluated ini­tially at 2 months ofage because of coarse facial features, inguinal hernias, and mild organomegaly suggestive of lysosomal storage disease. Multiple biochemical studies at that evaluation were negative. The patient was reeval­uated at about 1112 years of age and had evolved the dis­tinctive phenotypic features of Williams syndrome.

For each subject, a complete personal, medical, and family history were obtained, with special attention to parental age, status of siblings, order of birth, and birth

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weight. A general physical examination included fronto­occipital circumference and anthropometries of facial features, including the intermedial canthal distance, the interpupillary distance in the (assumed) primary position, the interlateral canthal distance, and length of the phil­trum. We also attended the presence of synophrys, an­gulation of the palpebral fissures, malar dysplasia, prom­inence of the vermilion of the upper lip, and dental anomalies. A complete routine ophthalmologic exami­nation was performed by one of us (RAL) .on 33 subjects, with special attention to binocular stereoscopic biomi­croscopy and indirect ophthalmoscopy of the ocular fundus.

RESULTS

There were 24 male and 18 female subjects (total, 42) including one set of identical male twins, yielding an in­creased sex ratio of 1.28. Mean age at examination was 7.3 years (range, 3 months to 43 years). Racial distribution of the subjects showed 36 whites, 2 blacks, 3 Hispanic, and l Asian Indian.

The mean maternal age at the time of delivery was 27 years and the mean paternal age was 30 years. Although this observation suggests a trend toward advanced paternal age, the result was not statistically significant for this rel­atively small group of patients.5

Mean gestation was 39.7 ± 1.8 weeks, based on cal­culation from last menstrual period or estimated date of confinement. On average, both prenatal and postnatal growth was retarded. The mean birth weight for all infants who were born after 37 weeks gestation was 2800 ± 470 g. The mean height for all subjects at all ages was at the 13th percentile for age and sex.

The mean weight was at the 15th percentile for age and the mean fronto-occipital circumference was at the 20th percentile for age, suggesting proportionately delayed postnatal growth.

Forty of 42 patients had the typical elfin facies (Fig l) ofWilliams syndrome. Two other subjects (both 24 years of age) had more coarse facial features. In general, facial features appear to coarsen with age. We observed pre­mature poliosis of cilia, brows, and scalp hair in three subjects, 24, 24, and 43 years of age.

One objective feature of the elfin facies appears to be ocular hypotelorism. In our series, the mean intermedial canthal distance is at the 34th percentile for age, the mean interpupillary distance is at the 29th percentile for age, and mean interlateral (outer) canthal distance is at the 34th percentile for age. However, the shape and length of the palpebral fissures are normal, and disproportionate blepharophimosis does not occur.

Twenty-nine percent (12 of 42) of our patients had strabismus. Eleven strabismic subjects had infantile ("congenital") esotropia, always with onset or recognition before l year of age, generally before 6 months of age. Accomodative esotropia was observed in one child but

anomalous accommodative convergence/accommodation ratio did not occur in any subject. Four had undergone surgical correction but all operated subjects had residual small-angle esotropia. Of the ll subjects with infantile esotropia, only l had oblique muscle dysfunction in ad­dition to residual esotropia when he was examined at 7 years of age, 51f2 years after his single horizontal muscle surgery.

Refractive errors were hypermetropic (average spherical equivalent, + 1.75; range, plano to+ 6.25) for all but one subject (who was myopic, spherical equivalent, -4.50 in both eyes). No subject had astigmatism greater than 2.00 diopters.

One of the few consistent eye findings previously de­scribed in Williams syndrome is the so-called stellate iris, a coarse and roughly radial or cartwheel striation of the anterior supportive stroma of the iris. 3 The coarse surface architecture is accentuated by either absence or incom­pleteness of the iris collarette. Where the collarette can be identified, it is displaced well outside the mid-radial distance (Fig 2). Despite these structural variations in the anterior iris, however, the remainder of the iris structure is normal, including the pupil and its function, the pu­pillary border, the deeper stromal layers, and the pigment epithelial layer, with the normal absence of iris transil­lumination. One subject had minimal nasal corectopia in each eye. Of 42 subjects, 27 (64%) had blue irides, 6 had hazel, and 9 had brown. All five non-white subjects in our series had brown irides. In total, 29 of 42 patients (69%) had a stellate pattern. No subject with brown irides, regardless of race, had an observable stellate iris pattern. Three individuals with blue irides and one individual with hazel irides also did not have stellate patterns.

On ophthalmoscopic examination (RAL) of 33 pa­tients, the optic nerve appears normal to slightly small and is generally circular rather than vertically oval. In 18 (55%) of the patients, hypermetropic discs were noted, typified by high central branching of the central retinal vessels and a slight dimpling or flattening of the optic cup instead of the usual deep physiologic optic cup. One sub­ject had such dramatic elevation of the optic disc and obscuration of the sclerochoroidal rim that pseudopapil­ledema existed. A mild variation in the branching pattern ofthe central retinal vessels was noted in 18 subjects. The major retinal vessels, especially the arterial tree, bifurcate into two vertical trunks and secondary bifurcations occur outside the margin of the sclerochoroidal rim of the optic disc (Fig 3). In four subjects, an incidental note was made ofsitus inversus vasorum in both eyes, in which the major vascular arcades tend to arch into the nasal retina before bowing into the usual temporal arcades (Fig 4). Although several prior references2•6 mention accentuated tortuosity of the retinal vasculature in Williams syndrome, this fea­ture is not noted in either arteries or venules in any of our patients, regardless of their current or previous cardiac status.

Despite the association of hypercalcemia in infancy in patients with Williams syndrome (including three infants in our series), no ocular manifestations ofhypercalcemia,

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Fig 1. Top left, typical frontal facial features of an 8-year-old boy with Williams syndrome. Notice broad glabella, full nasal tip with anteverted nares, long philtrum, and prominent lower lip. Fig 1. Top right, lateral view shows short nose with full tip, malar flattening with full cheeks. Fig 2. Second row, the typical iris structure of a 12-year-old girl with Williams syndrome shows a coarse anterior iris stroma and an irregular, radially displaced collarette, yielding its characteristic stellate appearance. Fig 3. The right (third row left) and left (third row right) optic discs of the same patient illustrated in Figure 2. Notice the simple disc structure without obvious physiologic cups but vertically branching major arteriolar trunks which bifurcate at or beyond the sclerochoroidal rims. Fig 4. The right (bottom left) and left (bottom right) optic discs of a 24-year-old man with Williams syndrome show situs in versus vasorum and anomalous vascular branching.

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such as calcium deposits in the conjunctiva, calcific band keratopathy of the cornea, or punctate opacities in the lens, were observed in any subject.

DISCUSSION

Since its initial description in 1962, Williams syndrome has become a widely recognized, clinically diagnosable disorder with variable but distinctive characteristics. 1·3The primary diagnostic feature is the so-called elfin facies con­sisting of a broad, flat glabella, epicanthus palpebralis or supraciliaris, medial eyebrow flare, a full or bulbous nasal tip with anteverted nares, malar flattening, full cheeks, long, flat philtrum, and prominent lips with narrow ver­milion (Fig 1 ). Although the flat nasal bridge, epicanthal folds, and relative microcephaly will often give the ap­pearance of hypertelorism, the actual ocular distances when compared with normal standards indicate relative ocular hypotelorism.

The other common features are various congenital heart defects, most frequently supra valvular aortic stenosis, de­velopmental delay, attention deficit disorders, gastroin­testinal problems (regurgitation and/or constipation in infancy), and idiopathic hypercalcemia in infancy. 1

An interesting finding noted in our series of patients was the tendency toward advanced paternal age. Although the etiology ofWilliams syndrome is unknown, autosomal dominant inheritance has been considered, although most cases are isolated and may represent new mutations.7 Ad­vanced paternal age, defined statistically based on the ex­pected mean paternal age for the population studied5has been associated with new mutation of several autosomal dominant disorders. 8

Since many previous reports have mentioned specific 36 9 10ocular findings in subjects with Williams syndrome,2· · • •

we investigated a group of such subjects to assess the fre­quency and severity of ocular findings.

We confirmed the high frequency (29%) of strabismus among subjects with Williams syndrome, similar to the 35% reported by Jones and Smith3but less than the smaller series [55% (5/9)] reported by Pagan et al. 11 This high frequency contrasts dramatically with the reported inci­dence of strabismus at less than 1% in the general popu­lation.12 Only one subject with infantile esotropia had oblique muscle dysfunction, considerably less than other current observations in the range of68%. 12 For this reason, infants and children with Williams syndrome should be evaluated scrupulously for evidence of strabismus.

The report of Jones and Smith3mentions the high fre­quency of blue irides with a so-called stellate iris pattern (74 and 72%, respectively). Although nearly two thirds of our patients had blue irides, they are not as common as previously thought. 11

Because of limitations in the verbal description of iris color, it is difficult to compare reports of iris color distri­bution in the normal or control population. Generally,

about 55% of the normal population has light (blue, gray, or green) irides and 45% has dark (hazel or brown) iri­des.13'14 Among these totals, approximately 41% are de­scribed as "blue." The distribution of iris color among parents and other first degree relatives of our subjects with Williams syndrome does not differ from expected distri­butions.

There also appears to be a high correlation between blue iris color and the presence of stellate anterior iris stromal pattern. Both stellate iris pattern and the lateral displacement or absence ofthe anterior iris collarette rep­resent normal congenital variations of anterior iris struc­ture. Both the embryologic origins and the significance of this correlation are unclear. However, the absence ofeither or both features should not necessarily exclude the diag­nosis of Williams syndrome.

At least one case ofRieger anomaly has been described in associations with Williams syndrome. 10 Since no similar defects were observed in our patients, further observations are needed to confirm this finding as a true association or as purely coincidental.

Although numerous reports implicated a defect in cal­cium, vitamin D, or calcitonin metabolism in the etiology of Williams syndrome, 15 none of our subjects, including those with documented hypercalcemia in the first year of life, had any ocular manifestations of active or residual hypercalcemia. Jensen et al9 reported calcium hydroxy­apatite crystals in corneal and conjunctival cells in one patient postmortem. They suggested that conjunctival bi­opsy for calcium may assist with diagnosis. We did not perform conjunctival biopsy on any of our patients since we believe that the absence of clinical features makes the procedure unlikely to prove helpful in most cases.

The previously unrecognized retinal vascular and optic disc findings may be of greatest interest. We identified several variants which appear to be more common among Williams syndrome patients than in the general popula­tion. These include hypermetropic discs, simplex vertical branching of the retinal vessels, and situs in versus vasa­rum. Although these features do appear to have no clinical effect, they may prove adjunctive aids in clinical diagnosis. We did not observe unusual retinal vascular tortuosity in any of our subjects. Thus, we believe that tortuosity is not a useful criterion for either diagnosis or prognosis.

Because of the high frequency and the potential im­plications of these numerous ocular findings in Williams syndrome, we recommend a detailed ophthalmologic ex­amination as part _of the complete evaluation and care of all infants and children considered at risk for Williams syndrome.

ACKNOWLEDGMENTS

The authors thank both the Williams Syndrome Association for its support and the individuals and families reported herein for their willing participation in the design and objectives of this survey.

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13. Kliman GH, Augsburger JJ, Shields JA. Lack of association between iris color and primary iris cysts. Am J Ophthalmol1986; 102:95-6.

14. Rootman J, Gallagher RP. Color as a risk factor in iris melanoma. Am J Ophthalmol 1984; 98:558-61.

15. Culler FL, Jones KL, Deftos LJ. Impaired Calcitonin secretion in patients with Williams syndrome. J Pediatr 1985; 107:720-3.

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