Ophthalmologic Findings in the Cornelia de Lange Syndrome

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Ophthalmologic Findings in the Cornelia deLange Syndrome

amara Wygnanski-Jaffe, MD,a John Shin, MD, FRCSC,a Enza Perruzza, BA,a

ohamed Abdolell, MSc,b,c Laird G. Jackson, MD,d and Alex V. Levin, MD, MHSc, FRCSCa

ackground: Cornelia de Lange Syndrome (CdLS) is a disorder caused in many patients by a mutation in the NIPBLene with a dominant pattern of inheritance characterized by mental retardation, prenatal and postnatal growthetardation, upper-limb abnormalities, and characteristic facies. Few data exist concerning the ophthalmicndings in this syndrome. Methods: One hundred twenty individuals with CdLS underwent ophthalmic examinationo ascertain the relative frequencies of oculofacial and ophthalmic abnormalities. Results: We confirmed therequent findings of synophrys (99%), long lashes (99%), hypertrichosis of the brows (96%), ptosis (44%), epiphora22%), nasolacrimal duct obstruction (16%), blepharitis (25%), and myopia (58%). In addition, we found peripapillaryigment (83%), and microcornea (21%), which have infrequently been mentioned in the literature. Conclusion:atients with CdLS can have mutiple eye problems. Many of these problems can be readily treated, includingyopia, blepharitis, nasolacrimal duct obstruction, and ptosis. Early examination is recommended for all children

nown or suspected to have CdLS. (J AAPOS 2005;9:407-415)

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ornelia de Lange recognized the pattern of abnor-malities later to bear her name,1-19 but Brachmannprobably described the syndrome 17 years ear-

ier.7-8,12,20,21 Thus, the syndrome also is referred to asrachmann–de Lange, de Lange, and typus degenerativusmstelodamensis.1-25

The prevalence is estimated to be 0.6 to 10 in00,000.13,26 Characteristic findings include mental retar-ation, prenatal and postnatal growth retardation, andimb anomalies that range from absent digits and reduc-ion defects of the arms and/or legs, often with a single-igit to small hands and feet with or without transversealmar creases.14,27 The facies commonly consist of a lownterior hairline, synophrys, long eyelashes, arched eyerows (usually secondary to a brow lift compensation forongenital ptosis), depressed nasal bridge, anteverted na-es, long and smooth philtrum, thin lips, short neck, and arescent shaped mouth with the outer corners turned

rom the aDepartment of Ophthalmology The Hospital for Sick Children University oforonto, Toronto, Canada, bPublic Health Sciences The Hospital for Sick Children Uni-ersity of Toronto, Toronto, Canada, cPopulation Health Sciences The Hospital for Sickhildren University of Toronto, Toronto, Canada, dDivision of Medical Genetics Drexelniversity Medical School, Philadelphia, Pennsylvania, USA.resented in part at the AAPOS annual meeting Washington D.C., March 31, 2004.upported by Brandan’s Eye Research Fund.ubmitted March 9, 2004.evised May 31, 2005.evision accepted May 31, 2005.eprint requests: Alex V. Levin, MD, MHSc, FRCSC, Department of Ophthalmology-158, The Hospital for Sick Children, 555 University Ave. Toronto, Ontario, Canada5G 1X8 (e-mail: [email protected]).

opyright © 2005 by the American Association for Pediatric Ophthalmology andtrabismus.091-8531/2005/$35.00 � 0

coi:10.1016/j.jaapos.2005.05.010

ournal of AAPOS

own.19,28 Other findings include congenital heart disease,left palate, hearing deficiency, poor verbal skills, andastroesophageal reflux.1,5-8,12,15,17,20,24 However, otherhan the report by Levin and coworkers describing inetail the ophthalmic examination in 22 children,26 only 3ther publications address the ocular anomalies associatedith this syndrome. These 3 articles describe case reportsf small numbers of children with partial eye examina-ions.2-4 The present report of eye examinations of 120atients with Cornelia de Lange syndrome (CdLS) is, tour knowledge, the largest series.

UBJECTS AND METHODS

e report the oculofacial findings in 120 children withdLS that were examined by the senior author and 3

hildren that were examined by other pediatric ophthal-ologists. The 22 patients previously reported26 are in-

luded herein.There are no established diagnostic criteria for CdLS.

n each case enrolled in this study, the diagnosis wasonfirmed by a geneticist, with the majority being con-rmed by one coauthor (L.G.J.), the founder of the CdLSoundation, former Chair of their Scientific Advisoryommittee, who has examined more children with CdLS

han any other individual in the world (more than 2000ffected children). Fortunately, as described previously, inhe majority of cases the classic phenotype is present andasily recognizable. We excluded all cases with uncertainiagnosis. Molecular genetic testing was not available athe time our subjects were enrolled.

Each child underwent an ophthalmic evaluation as tol-rated. Twenty-two children had their eye examinations
onducted by one of the authors (A.V.L.) either at the Eye
October 2005 407

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Journal of AAPOSVolume 9 Number 5 October 2005408 Wygnanski-Jaffe et al

linic26 or at the Annual National or International meet-ngs of the Cornelia de Lange Syndrome Foundation Inc.held in the United States) or the Annual Medical Day ofdLS Canada. These conferences are run by the parent-ased support associations as opportunities for family ed-cation and multidisciplinary medical consultation. Theenior author attended these meetings and provided ser-ices ranging from full eye examinations (including a di-ated fundus examination of both eyes) to an external penight examination depending on the circumstance and theolerance of the child. As a result, not all of the childrenad a complete eye examination. The minimum eye ex-mination consisted of an external eye examination, assess-ent of visual fixation, penlight anterior segment exami-

ation, eye movement strabismus assessment, and pupilesting. Thirty-nine percent had a complete ophthalmicvaluation. Visual acuity was assessed by either observationf fixation or, with a projected Allen picture card (Rich-ond Products Boca Raton FL) in the one patient that

ould perform this test.Oculofacial measurements included direct measure-

ent of outer and inner canthal distance (OCD and ICD,espectively, in mm). In girls between 1 and 4 years of age,he measured OCD was adjusted by adding a value of 0.2m as described by Feingold and Bossert.29 OCD, ICD,nd interpupillary distance (IPD) were plotted against theormal standards of children 14 years of age or younger aseveloped by Feingold and Bossert.29 We are unaware oformal values in the literature for patients older than 14ears of age. IPD was calculated by the Feingold andossert method29 using the following formula: IPD � 0.7

(0.59 � ICD) � (0.41 � OCD). A downslanting pal-ebral fissure was defined as one in which the lateralanthus was lower than the medial canthus.

To distinguish hypertelorism from telecanthus, we usedhe Mustardé index,30 which refers to a relatively widentercanthal distance in the presence of a normal interpu-illary distance and defines telecanthus as a ratio of ICD/PD �0.55. We also calculated indices based on measuredPD, as did Mustardé, although it was difficult to measurePD reliably in these children.

Calculated palpebral fissure length (PFL) for 36 chil-ren was plotted for children aged 6 years or younger asefined by Chouke.31 The formula used to calculate theFL was PFL � (OCD � ICD)/2. In children who hadrevious ptosis surgery, we recorded data from the unop-rated affected eye but did not assess residual ptosis.

At family conferences, children had either a hand-heldortable slit-lamp examination or an examination by theagnification and illumination of a direct ophthalmo-

cope. Clinic examinations included slit-lamp examinations tolerated by the child.

Corneal diameter was measured by either templateings or by ruler. If these objective measurements were noteasible, then corneal diameter was assessed grossly. Mi-
rocornea was defined as a corneal diameter smaller than w
0 mm or, in a newborn (up to age 4 months), smaller thanmm.Cycloplegic refraction using phenylephrine 2.5% and

ycloplentolate 1% or 2% was obtained by retinoscopynd a sample of hand-held lenses to allow estimation to theearest spherical equivalent. Cylinder values were not usedor the purposes of this study because astigmatism was notound to be greater than 2.00 diopters (4 patients), withhe exception of a single case of 3 diopters in whom theefraction was quite difficult and perhaps not accurate.lit-lamp biomicroscopy and ophthalmoscopy also wereerformed when tolerated.

Special attention was paid to the absence or presence oflepharitis. We considered blepharitis to be present whenhe patient demonstrated eyelid margin erythema, crustingn the lashes, collarettes, and madarosis. This assessmentas made either by penlight examination, magnified viewsing the plus lens settings of a direct ophthalmoloscope,r by slit-lamp examination as tolerated.

Developmental delay, skeletal anomalies, and staturelso were noted and recorded. We used a subjective as-essment based on parental report and examination. Inome cases, we also had written or verbal assessments fromther specialists, including geneticists, who had evaluatedhe patient. Four categories were used for each of these 3ariables independently: not affected (normal develop-ent, normal limbs, normal stature), mild (minimal be-

avior/learning difficulties, no limb abnormality otherhan small hands/feet or proximalized thumb, mildly smallor age [3rd to 5th percentile]), moderate (moderate de-elopmental delays or behavioral issues, obvious limb ab-ormalities not categorized as severe, moderate small stat-re [�3rd percentile]), and severe (severe developmentalelay or behavioral issues requiring medication and/oronstant care, severe characteristic limb reduction defects,xtreme small stature).

In addition, we had the opportunity to review theecords of 3 children with CdLS provided to us by otherediatric ophthalmologists. Information specifically abouthildren with CdLS and anterior segment anomalies, cat-racts and glaucoma were reported and sent to us on 5dditional patients by other pediatric ophthalmologists.

e have excluded all reports from other ophthalmologistsrom our statistical analysis but include comments regard-ng unique ophthalmic findings.

Pearson correlation coefficients were computed forontinuous variables (age ICD, OCD, IPD, PFL, cornealiameter, and spherical equivalent). Chi-square andisher’s exact tests were conducted for 2 � 2 and n � kontingency tables of categorical variables, as appropriate.-tests were conducted to test for differences betweenroups (binary categorical variables) for each continuousariable. One-way analysis of variance was conducted toest for differences between groups (categorical variables
ith more than 2 levels) for each continuous variable.

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Journal of AAPOSVolume 9 Number 5 October 2005 Wygnanski-Jaffe et al 409

In light of the fact that this study is an hypothesis-enerating study and that multiple hypotheses were tested,he statistical problem of multiplicity must be addressed.

ultiplicity in the statistical sense refers to the scenario inhich multiple hypotheses are tested and requires someenalty to be applied to the nominal significance level tohich computed P values are being compared. One typical

pproach for dealing with this problem is to apply theonferroni correction for multiple testing whereby, forny given number of hypotheses tested K, the nominal � �.05 level against which computed P values usually areompared, is adjusted to �= � 0.05/K. For the purpose ofefining and testing primary research hypotheses we chose1 primary pairs (K), and 13 secondary pairs (not countedn K) tested for correlation (Tables 1 and 2). Pairs wereesignated as primary or secondary based on possible clin-cal significance should the correlations prove to be sig-ificantly correlated either positively or negatively. Theecondary hypotheses are exploratory in nature, and wenterpret them in a hypothesis-generating rather than in aypothesis-testing context. The Bonferroni correctionields a new alpha level required for significance of 0.0012:nly those P values �0.0012 related to the primary pairsre considered significant. For the remaining 13 secondaryairs we considered the generated p values which were0.05 as potentially worthy of further investigation (ie,

ypothesis generating). Primary pairs of clinical findingsere those that, if related, would have a higher biologic

ignificance in the opinion of the authors, for example,eripapillary pigment-refractive error as opposed to a sec-

ABLE 1 Systemic findingsSample size Frequency in %

evelopmental delay 106 100keletal anomalies 108 76mall stature 104 78ypical facies 117 99

ABLE 2 Ophthalmologic manifestationsOcular finding Sample size Prevalence in %

ong lashes 115 99ynophrys 116 99ypertrichosis 110 96eripapillary pigment ring 47 83elecanthus 62 60yopia 62 58

tosis 117 44lepharitis 107 25piphora 97 22icrocornea 106 21

trabismus 113 16ystagmus 111 14own-slanting palpebral fissures 96 7

ndary pair developmental delay and refractive error. h

ESULTS

he clinical diagnosis of all patients was confirmed eithery L.G.J., who is the Medical Director of the Cornelia deange Foundation Inc., or another clinical geneticist.ixty-three patients were boys (male:female ratio 1.1:1.0).ean patient age at the time of examination was 7.88 years

range, 3 months to 38 years). All children, except 2, wereaucasian.Many of the children exhibited abrupt and aggressive

ehavioral changes when their eyes were approached byight or by touch. This behavior limited the ability tobtain a complete examination in 61% of subjects.

A subjective annotation regarding developmental statusas made by the examining ophthalmologist in 106 chil-ren. Eighteen children were categorized as mildly (17%),7 (44%) as moderately, and 41 (39%) as severely mentallyisabled. An annotation regarding skeletal anomalies wasade by the examining ophthalmologist in 108 children.wenty-six were categorized as normal (24%), whereas 32

30%) had mild, 27 (25%) had moderate, and 23 (21%)

IG 1. Affected boy with arched eyebrows, synophrys, long eye-ashes, left ptosis, oval downturned mouth with thin lips, and ante-erted nares.

ad severe skeletal anomalies. Mention of stature was

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oted in 104 children. Thirteen percent had mild, 40%oderate, and 25% severe small stature (Table 1). The

requencies of ocular findings are listed in Table 2.

culofacial Features

he typical CdLS facies was observed in 99% of thehildren (Figure 1). Only a single mildly affected child didot have this appearance. One hundred sixteen childrenere assessed for synophyrs. All but one (99%) had thisnding. Almost all had a downsloping V-shaped configu-ation of the eyebrows as they met and extended onto thepper part of the nasal bridge. A small number of childrenere having the midportion of the eyebrows shaved orpilated by the parents for cosmesis. Long eye lashes werebserved in 99% of patients. Brow hypertrichosis was seenn 96%. Downslanting of the palpebral fissures was ob-erved in only 7 of 96 (7.3%) patients examined for thisnding, unlike previous reports in the literature.6

We were able to obtain OCD values for 62 of the

IG 2. Plot of outer canthal distance against normal standards forge.27

IG 3. Plot of inner canthal distance against normal standards forge.27

atients. Fifty-five of those measured were 14 years old I

nd younger. Thirteen percent (7/55) fell below the thirdercentile (Figure 2).29 Mean OCD was 75.6mm � 6.8range, 56-95). ICD was measured for 68 children, ofhich 60 were younger than 14 years of age. Mean ICDas 26.3mm � 3.2 (range, 18-37). Forty-seven of the 60

78%) were within the normal range, with 13 children lesshan or equal to the third percentile, which is suggestive ofild hypotelorism (Figure 3).29

As demonstrated in Figure 4, we did not find hyperte-orism using the calculated IPD. It is difficult to accurately

easure the IPD directly in these developmentally andehaviorally challenged individuals. However, when the9 patients for whom the IPD was measured directly werelotted on the same curve of normal standards, there wassuggestion that there is no tendency toward hypertelor-

sm (Figure 5).Of the 61 subjects who had both ICD and calculated

IG 4. Plot of calculated interpupillary distance, using method ofeingold and Bossert,27 against normal standards for age.

IG 5. Plot of measured interpupillary distance against normal stan-ards for age.27

PD obtained, 37 (60%), had an increased Mustardè Index

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uggestive of telecanthus. Using measured IPD, 9 of 2045%) Mustardé values were abnormally high, we found8 children to be over the 50th centile and 17 below the0th centile.

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ifty-one of our 117 (44%) children had varying degreesf ptosis, ranging from mild cosmetic changes to func-ional obstruction of the visual axis. A compensatory chinift was observed in 29 (57%) of those with ptosis. Brow liftas present in 36% of the children with ptosis. Twenty-

even percent of the children had bilateral ptosis; in 16%,he ptosis was unilateral. In 75% of the children withtosis, the levator function was limited or absent, indicatedy no apparent upper lid fold or by weak levator function.our patients underwent surgical repair of the ptosis prior

o the examination.By history, 22% of patients suffered from epiphora,

ischarge, or red eyes. One hundred seven children of the20 patients were assessed for blepharitis. Of these, 2725%) had active blepharitis. All children were checked forresence of a sty; however, only 5.8% (7 children) wereositive for this finding.

ystagmus

ifteen of 111 (13.5%) children had nystagmus. The nys-agmus was horizontal pendular in all cases. We found noorrelation between nystagmus and other phenotypicharacteristics, such as refractive error or developmentalelay.

cular Alignment

ne hundred thirteen children (94%) children had anssessment of ocular alignment. Ninety-four children84%) were orthotropic, 11 (10%) were esotropic, 7 (6%)ere exotropic, and 1 patient had undergone previous

trabismus surgery for an unknown deviation.

efraction and Visual Acuity

orty-six (38%) of the 120 children underwent cycloplegicefraction of at least the right eye. The mean sphericalquivalent in the right eye was minus 2.9 � 5.1 (range,20 to 7). Forty seven (39.2%) had cycloplegic refraction

f the left eye. The mean spherical equivalent of the leftye was minus 3.3 � 5.4 (range, �20 to 11.8). The refrac-ion of each eye was analyzed separately to evaluate theresence or absence of anisometropia. Only 42% of thehildren who were refracted were not myopic. Eight eyesad a cycloplegic refraction of more than �10.00 sphericalquivalent.

Forty-six (38%) had a spherical equivalent of greaterhan �5.00 sphere. Only 3 eyes had a spherical equivalentf greater than � 3.50; one � 5.00, and one � 11.50phere.

Visual acuity in 86 patients was equal in both eyes as
ssessed by a central steady and maintained fixation behav- 4
or at near. However, it is certainly possible (if not likely)hat some patients (eg, those with cataract) would showeduced visual acuity if tested by a more objective method.nly one child was able to perform projected Allen picture

isual acuity testing and had a visual acuity of 20/40 in eachye. Contrary to the findings of Cassidy and Allanson,27 inhich half of their subjects had some verbal skills, it is ourxperience with our larger sample size that this degree ofommunication is less common and, in combination withther behavioral challenge, rendered no other childrenble to cooperate with quantitative visual acuity modesvailable in the examination settings.2-13

asolacrimal System

igns of nasolacrimal duct obstruction (epiphora, tearing,atting of lashes) were recorded in 97/120 (80%). By

istory, 39 (33%) children had such signs, and 22% spe-ifically had epiphora alone or with discharge. Twenty-sixf 95 (27%) had, by history, prior probing or intubation ofhe nasolacrimal duct system. Eleven of these children11/26, 42%) still had epiphora despite prior nasolacrimalystem draining procedures.

nterior Segment

ne hundred eight (90%) individuals had a slit-lamp ex-mination or an examination by the magnification andllumination of a direct ophthalmoscope. No patientsemonstrated blue sclera or corneal opacities as reportedy others.6,7,22 Corneal diameter was assessed in 106 chil-ren: 24 children had a corneal diameter measured byither template rings or ruler, and in 82 the corneal diam-ter was grossly assessed. Microcornea was found in 22 of06 (21%).

One child had a mature nuclear unilateral cataract thatas suspected to be secondary to self induced trauma. This

hild has an observed tendency to self abuse involving theeriocular region, although the exact causative event wasot observed. Three additional reports by other ophthal-ologists noted one unilateral dense cataract and bilateral

ataracts in 2 patients. In one case, the opacities were onlyeripheral. One patient had glaucoma by history but noigns of glaucoma were found on examination. He actuallyad microcornea. However, no refraction could be per-ormed and he did not undergo a fundus examination.

osterior Segment

retina examination was performed in 40% of the patientsnd was considered to be normal in all patients except for. One child had bilateral pigmentary changes of the retinand the electroretinogram revealed widespread retinal dys-unction, there was no family history of retinal dysfunc-ion. One child had slight disk pallor with temporal drag-ing of the macular vessels in both eyes, in a fashion thatesembled retinopathy of prematurity, although the childas born at 38 weeks’ gestational age and a birth weight of
.5 pounds. One patient had a posterior staphyloma and

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nother giant retinal breaks in one eye felt to be consistentith self abuse.The optic discs were examined in 47 children. Five

atients (11%) were entirely normal. Thirty-nine (83%)howed a peripapillary pigment ring surrounding botherve heads. One had optic nerve pallor. The child waseferred back to their home eye care provider for furthervaluation the results of which are not known to us. Onead bilateral physiological optic nerve cupping.

orrelations

ith the exception of those correlations that were biolog-cally expected (eg, age vs corneal diameter, hypertrichosiss synophyrs) and those which define the syndrome (eg,mall stature vs limb abnormality), we found no statisti-ally significant correlations between any individual ocularbnormality and a systemic feature of the syndrome.here were very weak correlations between microcornea

nd the presence of limb anomalies (P � 0.047), shortalpebral fissure length and small stature (P � 0.029),hort palpebral fissures and strabismus (P � 0.035), andyopia and small stature (P � 0.011). These correlations

o not seem strong enough to allow for a conclusion thathe paired features are likely to be related on a genetic oriologic basis. Likewise, there were no significant corre-ations when comparing one eye finding to another eyending with the exceptions of those that would be biolog-

cally expected (eg blepharitis vs lid margin erythema).here was a significant correlation between the vision of

he 2 eyes (P � 0.001). There was a weaker correlationetween epiphora and blepharitis (P � 0.025) than epi-hora and nasolacrimal duct obstruction (P � 0.001),uggesting that the latter is more likely to be a cause forpiphora. There was also a significant correlation betweenhistory of prior nasolacrimal duct probing and persistentpiphora (P � 0.001), which suggests either that one mustonsider failed probing as the cause or that blepharitis ishe true cause of the persistent epiphora only after naso-acrimal duct obstruction is ruled out. Prior probing and aiagnosis of nasolacrimal duct obstruction also were cor-elated with younger age (P � 0.001) which suggests thathe older the patient, the less likely that epiphora is causedy nasolacrimal duct obstruction.

ISCUSSION

e report the ophthalmic examinations of 120 patientsith CdLS. We were able to confirm the findings in therevious report by Levin and coauthors and other previouseports and, as the result of our large sample size, provideore accurate frequency figures for brow hypertrichosis,

ynophrys, long eye lashes, ptosis, nystagmus, downslant-ng of the palpebral fissures, hypertelorism, arched eye-rows, telecanthus, myopia, strabismus, photophobia,lepharitis, and chronic conjunctival symptoms. In addi-ion, we report peripapillary pigmentation and microcor-
ea, which were reported only in single or rare case C
eports in other studies.2,4 We again examined variousethods of measuring facial characteristics in these indi-

iduals and conclude that telecanthus rather than hyper-elorism is common.

All of the patients in our series exhibited features con-istent with the diagnosis of CdLS including growth re-ardation of varying degrees (100%), developmental delayr mental retardation to a variable degree (100%), andimb anomalies (76%). Although in their series of morehan 300 children Jackson and coauthors30 found limbbnormalities in only 27% of cases, limb abnormalitiesemain one of the most useful diagnostic characteristics.

We examined all English and French (and other lan-uages when translation available) literature reports andeviews of oculofacial abnormalities in CdLS. Most refer-nces in the literature do not include a complete ophthal-ic examination.1-25 Synophrys is apparent in 85-100% ofdLS patients.1,2-8,13-17,19,21-25 In the present study, we

ound synophrys to be present in 99% of the children.nly 4 children did not have this finding. Many authors

ave been impressed by the long and curved eye lashesescribed in 7-100% of patients.1, 2-7,15-17,20-22,25-27 In theresent series, we found long lashes were present in 99%f the children. Only one child was noted not to have thisnding.

Downslanting of palpebral fissures, in which the lateralanthus is positioned below the medial canthus of the eye,as been reported in 16-88% of patients withdLS.3,9,19,22 We found this feature in only 7%, whichay simply reflect our large sample size or specific atten-

ion paid to this detail.In several of the previous studies, patients with CdLS

ere noted to have telecanthus or hypertelorism.2,4,26 Therevious review by Levin and coworkers26 indicated thatoth hypertelorism and telecanthus could be features ofdLS. In the present series using the same measurement

echniques and the Mustardè index, we found that hyper-elorism was uncommon. Using the calculated IPD, 60%f subjects had evidence of telecanthus. Using the mea-ured IPD, 45% still had telecanthus. We believe there arerrors inherent in using direct IPD measurement partic-larly in this population where patients may be combative,nable to fixate long enough for accurate measurementnd resist instrumentation close to the face or converge onhe near target. Therefore, according to our data includingalculated IPD it appears that telecanthus (60%) and notypertelorism (30%) is a feature more frequently associ-ted with CdLS.

Horizontally short palpebral fissures also have beeneported by other authors to occur in as many as 100% ofdLS patients.2,6,23 In our study PFL was not measuredirectly in any of the patients, although direct measure-ent may be more desirable because it does not introduce

n error that is obtained by using both the OCD and ICDn the formula. We are not aware of normal standards for
aucasians using direct or calculated PFL measurements.

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e were however able to document the occurrence ofhort PFL by calculation in 31% of our patients (Figure 6).

Mild or visually significant ptosis, either unilateral orilateral, occured in 44% of patients and appear to beostly a consequence of poor levator function.3,4,6,8,24,25

n the present study, the incidence of ptosis was lower thanhat reported in the previous series by Levin and cowork-rs26 in which the rate of ptosis reached 67%. In our series,1% of the patients with ptosis still had a lid crease. Oncegain, this result may simply reflect the increased accuracynherent in a larger sample size. Surgical correction oftosis, usually with a sling procedure particularly whenhere is poor levator function, may aid these children inttaining a clear visual axis and preventing the develop-ent of an abnormal head position (chin lift) and/or brow

ift. In our experience, ptosis surgery may dramaticallymprove gross motor skills and ambulation in someatients.

Blepharitis and chronic conjunctivitis also have beeneported commonly with CdLS.5,11 In a previous series,26

9% of the patients in the group had blepharitis, chroniconjunctivitis, recurrent hordeolum, or nasolacrimal ductbstruction. In our current series, 25% of the patientsxamined suffered from blepharitis, 5.8% of the patientsad a sty, 10% of the patients had a red lid margin, and6% of the patients had history of nasolacrimal duct ob-truction. It remains unclear whether recurrent externalye symptoms are caused by nasolacrimal duct obstructionr meibomian gland dysfunction. Because the latter maye ameliorated by simple lid hygiene as opposed to surgi-al intervention for the former, we recommend that eachhild with CdLS experiencing recurrent ocular dischargehould first undergo treatment with simple lid hygiene forlepharitis. If symptoms persist, then nasolacrimal ductrobing with or without silicone tube intubation should bendertaken. Many parents stated that treatment with lidygiene alone has resulted in dramatic improvement inome children. Nevertheless, if only epiphora was found,t was most commonly correlated with nasolacrimalbstruction.

Nystagmus also was found less commonly in our currenteport (14%) than in the previous reports.1,2-7,14,16,17,25 Levinnd coworkers26 noticed nystagmus in 36% of their children,nd previous reports noted nystagmus in as many as 67% ofhe individuals examined but with smaller sample sizes. Thetiology is unknown.

Horizontal strabismus has been previously reported in0-50% of cases.1,2,4-7,15,16 We only found 16% of our pa-ients to have strabismus. None had a vertical component. Its possible that a certain number of these cases are secondaryo untreated refractive error especially those who are myopicnd exotropic.

Myopia is a well-recognized ocular feature of CdLS oc-urring in 60-73% of previously reported patients.2-7,8,16,17,22

n our study 60% of the children had myopia. It has not
een determined if the myopia is due to corneal, lenticular, d
r axial elements. However, because one of our patientsad a posterior staphyloma and a second patient had giantetinal breaks, axial myopia is suggested in at least theseases. Self-inflicted ocular trauma may also have played aole in at least one of our patients with myopia. No childas wearing glasses at the time of our examination and, in

he previous study by Levin 3, children who had beenrescribed glasses subsequently refused them. Neverthe-ess, we still advocate prescribing glasses to the childrenith high refractive errors, since this may change theiruality of life.

There was no correlation between the presence of mi-rocornea and myopia or hyperopia suggesting that theature of these refractive errors in this population is axialr lenticular. Although occlusion myopia is a well recog-ized phenomena, no correlation was found between my-pia and ptosis (P � 0.05), suggesting that ptosis andefractive error may not be an association related to oc-lusion but rather to other genetic factors.

Because myopia is very common in this group of chil-ren, early refraction is recommended to improve visualcuity and prevent amblyopia. Nevertheless, because ofehavioral difficulties, it is our experience that not all ofhese children will be willing to wear glasses. At least onef our patients with myopia had a total retinal detachment,yphema, and a vitreous hemorrhage as the result of self-

nflicted injury. Another with cataract also may have ex-erienced self-induced ocular injury.

Although cataract and glaucoma also have been de-cribed in association with CdLS, the number of affectedeported children remains small. We only found 2 cases ofataract among all 120 children examined and thereforeeel that in this series we did not convincingly establish aorrelation between CdLS and cataracts. Until furtheresearch is obtained to indicate otherwise, it is not certainf there is a true association between cataract and glaucomaith CdLS or if these are just coincidental findings.Microcornea was found to be present in 21% of our

atients. Therefore, it is possible that microcornea is an-ther feature of CdLS. The subjective assessment of cor-eal diameter by gross inspection in 12.5% of the patientsxamined suggests the true prevalence of microcornea mayave been underestimated as gross examination wouldave detected only the more obvious.

Peripapillary pigment was assessed in 47 patients haseen previously described only in a single case report.2 Inhis series, it appeared in 83% of the examinees assessedor this anatomic variation and, hence, may be typical forhis syndrome. Peripapillary pigmentation was not corre-ated with myopia or hyperopia, suggesting that this is arimary anatomic change rather than a change caused byn alteration in axial length. The pigmentary changes ofhe retina in a single child and the electroretinogramevealing wide retinal dysfunction is probably a coinci-
ence, since it has not been reported in other children.

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Although CdLS has been known for decades, the dis-overy of the mutated gene has been published only re-ently by 2 independent studies.31,32 The “Nipped B like”NIPBL) gene, named after is counterpart in Drosophilaruit flies, encodes a key protein, delangin, which is in-olved with the development of many organs in the grow-ng embryo. This gene is believed to have an architecturalole in facilitating long distance interactions between en-ancers and promoters of the homeobox regulatory ele-ents. To date, all mutations identified appear to result in

unctional haploinsufficiency and an autosomal-dominantattern of inheritance.31,33 Mutations in this gene areresent in approximately half of the patients,34 suggestinghat other genetic loci may be important or that there areenetic elements relevant to NIPBL (eg, intronic se-uences, promoter) that have and that carry mutations yeto be discovered. The phenotypic similarity betweendLS and duplication 3q have been long recognized,16,31

hich suggests a chromosomal localization of a contiguousene.32 Ireland et al35 located the disorder to areas ofhromosome 3q. They performed chromosome analysisnd found a translocation with breakpoints at 3q26.3 and7q23.1 and proposed that the gene for CdLS could beocated at 3q26.3. Nevertheless Lopez-Rangel36 reported

case of a duplication in the 3q25.1-q26.1 that did notave a phenotype resembling CdLS or duplication 3q.

It is possible that our sample suffered from a selectionias because CdLS children with ocular problems may beore likely to undergo an ophthalmic examination than

hose without ocular problems, particularly in the settingf the annual conferences, where families are given theption to chose which medical subspecialty consultationhey desire.

In conclusion, patients suffering from CdLS have manyye problems, some of which are readily treatable andemand early ophthalmic attention. On the basis of theur extensive experience, ophthalmologists examining pa-ients with CdLS should look for myopic refractive errorsnd, once signs of blepharitis have been treated, consider

IG 6. Palpebral fissure length (PFL) in CdLS plotted against normaltandards. Each dot represents a patient’s measured PFL.29

robing and/or intubation of the nasolacrimal system.

ost patients with ptosis will require surgical correction.elf-abusive patients and those with combative behavioray require examination under anesthesia.

The authors wish to thank the following for contributing infor-ation regarding CdLS patients they examined: M. Steele MD,ivision of Pediatric Ophthalmology and Strabismus, New Yorkniversity Medical Center; R. Bachman MD, Medical Geneticist,alnut Creek, CA; M. Holmes MD, Ophthalmology, Pleasanton,

A; E. Ceisler MD, Pediatric Ophthalmology Consultants, NY;nd A. Biglan MD, Pediatric Ophthalmology and Strabismus,raneberry Township, PA. We are also grateful for the invaluablessistance of our research assistants Enza Perruzza and Erica Bell.

References1. Berg JM, McCreary BD, Ridler MAC, Smith GF. The de Lange

syndrome. New York: Pergamon Press; 1970.2. Nicholson DH, Goldberg MF. Ocular abnormalities in the de Lange

syndrome. Arch Ophthalmol 1966;76:214-20.3. Evens L, Vinken L, Fryns JP. Ocular symptoms in the Cornelia de

Lange syndrome. Bull Soc Belge Opthalmol 1977;175:34-43.4. Milot J, Demay F. Ocular anomalies in de Lange syndrome. Am J

Ophthalmol 1972;74:394-9.5. Silver HK. The de Lange syndrome. Am J Dis Child 1964;108:

523-9.6. McArthur RG, Edwards JH. De Lange syndrome: report of 20 cases.

Can Med Assoc J 1967;96:1185-98.7. Barr AN, Grabow JD, Matthews CG, Grosse FR, Motl ML, Opitz

JM. Neurologic and psychometric findings in the Brachmann-de Lange syndrome. Neuropädiatrie 1971;3:46-66.

8. Hawley PD, Jackson LG, Kurnit DM. Sixty-four patients with Brach-mann-de Lange syndrome: a survey. Am J Med Genet 1985;20:453-9.

9. Johnson HG, Ekman P, Friesen W. A behavioral phenotype in the deLange syndrome. Pediatr Res 1976;10:843-50.

0. Cameroon TH, Kelly DP. Normal language skills and normal intel-ligence in a child with de Lange syndrome. J Speech Hear Disord.1988;53:219-22.

1. Beck B. Psycho-social assessment of 36 de Lange patients. J MentDefic Res 1987;31:251-7.

2. Opitz JM, Segal AT, Nadler HL. The etiology of the Brachmann-de Lange syndrome. Birth Defects Reprint Series The NationalFoundation-March of Dimes 1965:22-33.

3. Beck B. Epidemiology of Cornelia de Lange syndrome. Acta PaediatrScand 1976;65:631-8.

4. Schlesinger B, Clayton B, Bodian M, Jones KV. Typus degenerativusAmstelodamensis. Arch Dis Child 1963;38:349-57.

5. Hartz ZH, Jaslow RI, Gomez MR. The de Lange syndrome. Am JDis Child. 1965;109:325-32.

6. Falek A, Schmidt R, Jervis GA. Familial de Lange syndrome withchromosome abnormalities. Pediatrics. 1966;37:92-101.

7. Ptacek LJ, Opitz J, Smith DW, Gerristen T, Waisman HA. TheCornelia de Lange syndrome. J Pediatr 1963;63:1000-20.

8. Beck B, Fenger K. Mortality, pathological findings and causes ofdeath in the de Lange syndrome. Acta Pediatr Scand 1985;74:765-9.

9. De Lange C. Sur un type nouveau de degeneration (typus Amstelo-damensis). Arch Med Enf 1933;36:713-9.

0. Opitz JM. The Brachmann-de Lange syndrome. Am J Med Genet1985;22:89-102.

1. Lieber E, Glaser JH, Jhaveri R. Brachmann-de Lange syndrome.Am J Dis Child 1973;125:717-8.

2. Vilo-Coro AA, Arnoult JB, Robinson LK, Mazow ML. Lacrimalanomalies in Brachmann-de Lange syndrome. Am J Ophthalmol
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4. Vorechovsky J, Podhradská O, Kasparková Z, Matusková D. Syn-drome Brachmann-de Langeove u ctyr kojencu. Cesk Pediatr 1988;43:81-4.

5. Bankier A, Haan E, Birrell R. Familial occurrence of Brachmann-de Lange syndrome. Am J Med Genet 1986;25:163-5.

6. Levin AV, Seidman DJ, Nelson LB, Jackson LG. Ophthalmologicfindings in the Cornelia de Lange syndrome. J Pediatr OphthalmolStrabismus 1990;27:94-102.

7. Jackson L, Kline AD, Barr MA, Koch S. De Lange syndrome: aclinical review of 310 individuals. Am J Med Genet 1993;47:940-6.

8. Cassidy SB, Allanson JE. Management of genetic syndromes. NewYork: John Wiley and Sons; 2001. p. 86-88.

9. Feingold M, Bossert WH. Normal values for selected parameters: anaid to syndrome delineation. Birth Defects: Original Article Series.The National Foundation-March of Dimes. 1974;10:1-15.

0. Mustardé J. Epicanthal folds and the problem of telecanthus. TransOphthalmol Soc UK 1963;83:397-411.

1. Krantz ID, McCallum J, DeScipio C, et al. Cornelia de Lange
syndrome is caused by mutations in the NIPBL, the human
homolog of Drosphilia melanogaster Nipped-B. Nat Genet2004;36:631-5.

2. Tonkin ET, Wang TJ, Lisgo S, et al. NIPBL, encoding a homologof fungal Scc2-type sister cromatid cohesion proteins and flyNipped –B, is mutated in Cornelia de Lange syndrome. NatGenet 2004;36:636-41.

3. Robinson LK, Wolfsburg E, Jones KL. Brachmann-de Lange syn-drome: evidence for autosomal dominant inheritance. Am J MedGenet 1985;22:109-15.

4. Gillis LA, McCallum J, Kaur M, DeScipio C, Yaeger D, Mariani A,Kline AD, LI HH, Devoto M, Jackson LG, Kranz ID. NIPBLmutational analysis in 120 individuals with Cornelia de Langesyndrome and evaluation of genotype-phenotype correlations.Am J Hum Genet 2004;74:610-23.

5. Ireland M, English C, Cross I, et al. A de novo translocationt(3;17)(q26.3;q23.1) in a child with Cornelia de Lange syndrome.Am J Med Genet 1991;28:639-40.

6. Lopez-Rangel E, Dill FJ, Hrynchak, et al. Partial duplication of3q(q25.1-q26.1) without Brachmann-de Lange phenotype. Am J
Med Genet 1993;47:1068-71.
An Eye on the Arts – The Arts on the Eye

How did all those Easter Islanders, lacking cranes, succeed in carving, transporting, anderecting those statues? Of course we don’t know for sure, because no European ever sawit being done to write about it. But we can make informed guesses from oral traditions ofthe islanders themselves (especially about erecting statues), from statues in the quarries atsuccessive stages of completion, and from recent experimental tests of different transportmethods.

In Rano Raraku quarry one can see incomplete statues still in the rock face andsurrounded by narrow carving canals only about two feet wide. The hand-held basalt pickswith which the carvers worked are still at the quarry. The most incomplete statues arenothing more than a block of stone roughly carved out of the rock with the eventual faceupwards, and with the back still attached to the underlying cliff below by a long keel ofrock. Next to be carved were the head, nose, and ears, followed by the arms, hands, andloincloth. At that stage the keel connecting the statue’s back to the cliff was chippedthrough, and transport of the statue out of its niche began. All statues in the process ofbeing transported still lack the eye sockets, which were evidently not carved until the statuehad been transported to the ahu and erected there. One of the most remarkable recentdiscoveries about the statues was made in 1979 by Sonia Haoa and Sergio Rapu Haoa, whofound buried near an ahu a separate complete eye of white coral with a pupil of red scoria.Subsequently, fragments of other similar eyes were unearthed. When such eyes are insertedinto a statue, they create a penetrating, blinding gaze that is awesome to look at. The factthat so few eyes have been recovered suggests that few actually were made, to remain underguard by priests, and to be placed in the sockets only at times of ceremonies.

—Jared Diamond (from Collapse: How Societies Choose to Fail or Succeed, Viking)

Documents

Ophthalmologic Findings in the Cornelia de Lange Syndrome