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Ophthalmologic Findings in the Cornelia de Lange Syndrome
Ophthalmologic Findings in the Cornelia de Lange Syndrome Tamara Wygnanski-Jaffe, MD,a John Shin, MD, FRCSC,a Enza Perruzza, BA,a Mohamed Abdolell, MSc,b,c Laird G. Jackson, MD,d and Alex V. Levin, MD, MHSc, FRCSCa Background: Cornelia de Lange Syndrome (CdLS) is a disorder caused in many patients by a mutation in the NIPBL gene with a dominant pattern of inheritance characterized by mental retardation, prenatal and postnatal growth retardation, upper-limb abnormalities, and characteristic facies. Few data exist concerning the ophthalmic findings in this syndrome. Methods: One hundred twenty individuals with CdLS underwent ophthalmic examination to ascertain the relative frequencies of oculofacial and ophthalmic abnormalities. Results: We confirmed the frequent findings of synophrys (99%), long lashes (99%), hypertrichosis of the brows (96%), ptosis (44%), epiphora (22%), nasolacrimal duct obstruction (16%), blepharitis (25%), and myopia (58%). In addition, we found peripapillary pigment (83%), and microcornea (21%), which have infrequently been mentioned in the literature. Conclusion: Patients with CdLS can have mutiple eye problems. Many of these problems can be readily treated, including myopia, blepharitis, nasolacrimal duct obstruction, and ptosis. Early examination is recommended for all children known or suspected to have CdLS. (J AAPOS 2005;9:407-415) ornelia de Lange recognized the pattern of abnormalities later to bear her name,1-19 but Brachmann probably described the syndrome 17 years earlier.7-8,12,20,21 Thus, the syndrome also is referred to as Brachmann– de Lange, de Lange, and typus degenerativus amstelodamensis.1-25 The prevalence is estimated to be 0.6 to 10 in 100,000.13,26 Characteristic findings include mental retardation, prenatal and postnatal growth retardation, and limb anomalies that range from absent digits and reduction defects of the arms and/or legs, often with a singledigit to small hands and feet with or without transverse palmar creases.14,27 The facies commonly consist of a low anterior hairline, synophrys, long eyelashes, arched eye brows (usually secondary to a brow lift compensation for congenital ptosis), depressed nasal bridge, anteverted nares, long and smooth philtrum, thin lips, short neck, and a crescent shaped mouth with the outer corners turned
C
From the aDepartment of Ophthalmology The Hospital for Sick Children University of Toronto, Toronto, Canada, bPublic Health Sciences The Hospital for Sick Children University of Toronto, Toronto, Canada, cPopulation Health Sciences The Hospital for Sick Children University of Toronto, Toronto, Canada, dDivision of Medical Genetics Drexel University Medical School, Philadelphia, Pennsylvania, USA. Presented in part at the AAPOS annual meeting Washington D.C., March 31, 2004. Supported by Brandan’s Eye Research Fund. Submitted March 9, 2004. Revised May 31, 2005. Revision accepted May 31, 2005. Reprint requests: Alex V. Levin, MD, MHSc, FRCSC, Department of Ophthalmology M-158, The Hospital for Sick Children, 555 University Ave. Toronto, Ontario, Canada M5G 1X8 (e-mail: [email protected]). Copyright © 2005 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2005/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2005.05.010
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down.19,28 Other findings include congenital heart disease, cleft palate, hearing deficiency, poor verbal skills, and gastroesophageal reflux.1,5-8,12,15,17,20,24 However, other than the report by Levin and coworkers describing in detail the ophthalmic examination in 22 children,26 only 3 other publications address the ocular anomalies associated with this syndrome. These 3 articles describe case reports of small numbers of children with partial eye examinations.2-4 The present report of eye examinations of 120 patients with Cornelia de Lange syndrome (CdLS) is, to our knowledge, the largest series.
SUBJECTS AND METHODS We report the oculofacial findings in 120 children with CdLS that were examined by the senior author and 3 children that were examined by other pediatric ophthalmologists. The 22 patients previously reported26 are included herein. There are no established diagnostic criteria for CdLS. In each case enrolled in this study, the diagnosis was confirmed by a geneticist, with the majority being confirmed by one coauthor (L.G.J.), the founder of the CdLS Foundation, former Chair of their Scientific Advisory Committee, who has examined more children with CdLS than any other individual in the world (more than 2000 affected children). Fortunately, as described previously, in the majority of cases the classic phenotype is present and easily recognizable. We excluded all cases with uncertain diagnosis. Molecular genetic testing was not available at the time our subjects were enrolled. Each child underwent an ophthalmic evaluation as tolerated. Twenty-two children had their eye examinations conducted by one of the authors (A.V.L.) either at the Eye October 2005
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408 Wygnanski-Jaffe et al Clinic26 or at the Annual National or International meetings of the Cornelia de Lange Syndrome Foundation Inc. (held in the United States) or the Annual Medical Day of CdLS Canada. These conferences are run by the parentbased support associations as opportunities for family education and multidisciplinary medical consultation. The senior author attended these meetings and provided services ranging from full eye examinations (including a dilated fundus examination of both eyes) to an external pen light examination depending on the circumstance and the tolerance of the child. As a result, not all of the children had a complete eye examination. The minimum eye examination consisted of an external eye examination, assessment of visual fixation, penlight anterior segment examination, eye movement strabismus assessment, and pupil testing. Thirty-nine percent had a complete ophthalmic evaluation. Visual acuity was assessed by either observation of fixation or, with a projected Allen picture card (Richmond Products Boca Raton FL) in the one patient that could perform this test. Oculofacial measurements included direct measurement of outer and inner canthal distance (OCD and ICD, respectively, in mm). In girls between 1 and 4 years of age, the measured OCD was adjusted by adding a value of 0.2 cm as described by Feingold and Bossert.29 OCD, ICD, and interpupillary distance (IPD) were plotted against the normal standards of children 14 years of age or younger as developed by Feingold and Bossert.29 We are unaware of normal values in the literature for patients older than 14 years of age. IPD was calculated by the Feingold and Bossert method29 using the following formula: IPD ⫽ 0.7 ⫹ (0.59 ⫻ ICD) ⫹ (0.41 ⫻ OCD). A downslanting palpebral fissure was defined as one in which the lateral canthus was lower than the medial canthus. To distinguish hypertelorism from telecanthus, we used the Mustardé index,30 which refers to a relatively wide intercanthal distance in the presence of a normal interpupillary distance and defines telecanthus as a ratio of ICD/ IPD ⱖ0.55. We also calculated indices based on measured IPD, as did Mustardé, although it was difficult to measure IPD reliably in these children. Calculated palpebral fissure length (PFL) for 36 children was plotted for children aged 6 years or younger as defined by Chouke.31 The formula used to calculate the PFL was PFL ⫽ (OCD ⫺ ICD)/2. In children who had previous ptosis surgery, we recorded data from the unoperated affected eye but did not assess residual ptosis. At family conferences, children had either a hand-held portable slit-lamp examination or an examination by the magnification and illumination of a direct ophthalmoscope. Clinic examinations included slit-lamp examination as tolerated by the child. Corneal diameter was measured by either template rings or by ruler. If these objective measurements were not feasible, then corneal diameter was assessed grossly. Microcornea was defined as a corneal diameter smaller than
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10 mm or, in a newborn (up to age 4 months), smaller than 9 mm. Cycloplegic refraction using phenylephrine 2.5% and cycloplentolate 1% or 2% was obtained by retinoscopy and a sample of hand-held lenses to allow estimation to the nearest spherical equivalent. Cylinder values were not used for the purposes of this study because astigmatism was not found to be greater than 2.00 diopters (4 patients), with the exception of a single case of 3 diopters in whom the refraction was quite difficult and perhaps not accurate. Slit-lamp biomicroscopy and ophthalmoscopy also were performed when tolerated. Special attention was paid to the absence or presence of blepharitis. We considered blepharitis to be present when the patient demonstrated eyelid margin erythema, crusting on the lashes, collarettes, and madarosis. This assessment was made either by penlight examination, magnified view using the plus lens settings of a direct ophthalmoloscope, or by slit-lamp examination as tolerated. Developmental delay, skeletal anomalies, and stature also were noted and recorded. We used a subjective assessment based on parental report and examination. In some cases, we also had written or verbal assessments from other specialists, including geneticists, who had evaluated the patient. Four categories were used for each of these 3 variables independently: not affected (normal development, normal limbs, normal stature), mild (minimal behavior/learning difficulties, no limb abnormality other than small hands/feet or proximalized thumb, mildly small for age [3rd to 5th percentile]), moderate (moderate developmental delays or behavioral issues, obvious limb abnormalities not categorized as severe, moderate small stature [⬍3rd percentile]), and severe (severe developmental delay or behavioral issues requiring medication and/or constant care, severe characteristic limb reduction defects, extreme small stature). In addition, we had the opportunity to review the records of 3 children with CdLS provided to us by other pediatric ophthalmologists. Information specifically about children with CdLS and anterior segment anomalies, cataracts and glaucoma were reported and sent to us on 5 additional patients by other pediatric ophthalmologists. We have excluded all reports from other ophthalmologists from our statistical analysis but include comments regarding unique ophthalmic findings. Pearson correlation coefficients were computed for continuous variables (age ICD, OCD, IPD, PFL, corneal diameter, and spherical equivalent). Chi-square and Fisher’s exact tests were conducted for 2 ⫻ 2 and n ⫻ k contingency tables of categorical variables, as appropriate. T-tests were conducted to test for differences between groups (binary categorical variables) for each continuous variable. One-way analysis of variance was conducted to test for differences between groups (categorical variables with more than 2 levels) for each continuous variable.
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TABLE 1 Systemic findings Sample size
Frequency in %
106 108 104 117
100 76 78 99
Developmental delay Skeletal anomalies Small stature Typical facies
TABLE 2 Ophthalmologic manifestations Ocular finding Sample size Long lashes Synophrys Hypertrichosis Peripapillary pigment ring Telecanthus Myopia Ptosis Blepharitis Epiphora Microcornea Strabismus Nystagmus Down-slanting palpebral fissures
115 116 110 47 62 62 117 107 97 106 113 111 96
Prevalence in % 99 99 96 83 60 58 44 25 22 21 16 14 7
In light of the fact that this study is an hypothesisgenerating study and that multiple hypotheses were tested, the statistical problem of multiplicity must be addressed. Multiplicity in the statistical sense refers to the scenario in which multiple hypotheses are tested and requires some penalty to be applied to the nominal significance level to which computed P values are being compared. One typical approach for dealing with this problem is to apply the Bonferroni correction for multiple testing whereby, for any given number of hypotheses tested K, the nominal ␣ ⫽ 0.05 level against which computed P values usually are compared, is adjusted to ␣= ⫽ 0.05/K. For the purpose of defining and testing primary research hypotheses we chose 41 primary pairs (K), and 13 secondary pairs (not counted in K) tested for correlation (Tables 1 and 2). Pairs were designated as primary or secondary based on possible clinical significance should the correlations prove to be significantly correlated either positively or negatively. The secondary hypotheses are exploratory in nature, and we interpret them in a hypothesis-generating rather than in a hypothesis-testing context. The Bonferroni correction yields a new alpha level required for significance of 0.0012: only those P values ⬍0.0012 related to the primary pairs are considered significant. For the remaining 13 secondary pairs we considered the generated p values which were ⬍0.05 as potentially worthy of further investigation (ie, hypothesis generating). Primary pairs of clinical findings were those that, if related, would have a higher biologic significance in the opinion of the authors, for example, peripapillary pigment-refractive error as opposed to a secondary pair developmental delay and refractive error.
FIG 1. Affected boy with arched eyebrows, synophrys, long eyelashes, left ptosis, oval downturned mouth with thin lips, and anteverted nares.
RESULTS The clinical diagnosis of all patients was confirmed either by L.G.J., who is the Medical Director of the Cornelia de Lange Foundation Inc., or another clinical geneticist. Sixty-three patients were boys (male:female ratio 1.1:1.0). Mean patient age at the time of examination was 7.88 years (range, 3 months to 38 years). All children, except 2, were Caucasian. Many of the children exhibited abrupt and aggressive behavioral changes when their eyes were approached by light or by touch. This behavior limited the ability to obtain a complete examination in 61% of subjects. A subjective annotation regarding developmental status was made by the examining ophthalmologist in 106 children. Eighteen children were categorized as mildly (17%), 47 (44%) as moderately, and 41 (39%) as severely mentally disabled. An annotation regarding skeletal anomalies was made by the examining ophthalmologist in 108 children. Twenty-six were categorized as normal (24%), whereas 32 (30%) had mild, 27 (25%) had moderate, and 23 (21%) had severe skeletal anomalies. Mention of stature was
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FIG 2. Plot of outer canthal distance against normal standards for age.27
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FIG 4. Plot of calculated interpupillary distance, using method of Feingold and Bossert,27 against normal standards for age.
FIG 3. Plot of inner canthal distance against normal standards for age.27
noted in 104 children. Thirteen percent had mild, 40% moderate, and 25% severe small stature (Table 1). The frequencies of ocular findings are listed in Table 2. Oculofacial Features The typical CdLS facies was observed in 99% of the children (Figure 1). Only a single mildly affected child did not have this appearance. One hundred sixteen children were assessed for synophyrs. All but one (99%) had this finding. Almost all had a downsloping V-shaped configuration of the eyebrows as they met and extended onto the upper part of the nasal bridge. A small number of children were having the midportion of the eyebrows shaved or epilated by the parents for cosmesis. Long eye lashes were observed in 99% of patients. Brow hypertrichosis was seen in 96%. Downslanting of the palpebral fissures was observed in only 7 of 96 (7.3%) patients examined for this finding, unlike previous reports in the literature.6 We were able to obtain OCD values for 62 of the patients. Fifty-five of those measured were 14 years old
FIG 5. Plot of measured interpupillary distance against normal standards for age.27
and younger. Thirteen percent (7/55) fell below the third percentile (Figure 2).29 Mean OCD was 75.6mm ⫾ 6.8 (range, 56-95). ICD was measured for 68 children, of which 60 were younger than 14 years of age. Mean ICD was 26.3mm ⫾ 3.2 (range, 18-37). Forty-seven of the 60 (78%) were within the normal range, with 13 children less than or equal to the third percentile, which is suggestive of mild hypotelorism (Figure 3).29 As demonstrated in Figure 4, we did not find hypertelorism using the calculated IPD. It is difficult to accurately measure the IPD directly in these developmentally and behaviorally challenged individuals. However, when the 19 patients for whom the IPD was measured directly were plotted on the same curve of normal standards, there was a suggestion that there is no tendency toward hypertelorism (Figure 5). Of the 61 subjects who had both ICD and calculated IPD obtained, 37 (60%), had an increased Mustardè Index
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suggestive of telecanthus. Using measured IPD, 9 of 20 (45%) Mustardé values were abnormally high, we found 18 children to be over the 50th centile and 17 below the 50th centile. Lids Fifty-one of our 117 (44%) children had varying degrees of ptosis, ranging from mild cosmetic changes to functional obstruction of the visual axis. A compensatory chin lift was observed in 29 (57%) of those with ptosis. Brow lift was present in 36% of the children with ptosis. Twentyseven percent of the children had bilateral ptosis; in 16%, the ptosis was unilateral. In 75% of the children with ptosis, the levator function was limited or absent, indicated by no apparent upper lid fold or by weak levator function. Four patients underwent surgical repair of the ptosis prior to the examination. By history, 22% of patients suffered from epiphora, discharge, or red eyes. One hundred seven children of the 120 patients were assessed for blepharitis. Of these, 27 (25%) had active blepharitis. All children were checked for presence of a sty; however, only 5.8% (7 children) were positive for this finding. Nystagmus Fifteen of 111 (13.5%) children had nystagmus. The nystagmus was horizontal pendular in all cases. We found no correlation between nystagmus and other phenotypic characteristics, such as refractive error or developmental delay. Ocular Alignment One hundred thirteen children (94%) children had an assessment of ocular alignment. Ninety-four children (84%) were orthotropic, 11 (10%) were esotropic, 7 (6%) were exotropic, and 1 patient had undergone previous strabismus surgery for an unknown deviation. Refraction and Visual Acuity Forty-six (38%) of the 120 children underwent cycloplegic refraction of at least the right eye. The mean spherical equivalent in the right eye was minus 2.9 ⫾ 5.1 (range, ⫺20 to 7). Forty seven (39.2%) had cycloplegic refraction of the left eye. The mean spherical equivalent of the left eye was minus 3.3 ⫾ 5.4 (range, ⫺20 to 11.8). The refraction of each eye was analyzed separately to evaluate the presence or absence of anisometropia. Only 42% of the children who were refracted were not myopic. Eight eyes had a cycloplegic refraction of more than ⫺10.00 spherical equivalent. Forty-six (38%) had a spherical equivalent of greater than ⫺5.00 sphere. Only 3 eyes had a spherical equivalent of greater than ⫹ 3.50; one ⫹ 5.00, and one ⫹ 11.50 sphere. Visual acuity in 86 patients was equal in both eyes as assessed by a central steady and maintained fixation behav-
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ior at near. However, it is certainly possible (if not likely) that some patients (eg, those with cataract) would show reduced visual acuity if tested by a more objective method. Only one child was able to perform projected Allen picture visual acuity testing and had a visual acuity of 20/40 in each eye. Contrary to the findings of Cassidy and Allanson,27 in which half of their subjects had some verbal skills, it is our experience with our larger sample size that this degree of communication is less common and, in combination with other behavioral challenge, rendered no other children able to cooperate with quantitative visual acuity modes available in the examination settings.2-13 Nasolacrimal System Signs of nasolacrimal duct obstruction (epiphora, tearing, matting of lashes) were recorded in 97/120 (80%). By history, 39 (33%) children had such signs, and 22% specifically had epiphora alone or with discharge. Twenty-six of 95 (27%) had, by history, prior probing or intubation of the nasolacrimal duct system. Eleven of these children (11/26, 42%) still had epiphora despite prior nasolacrimal system draining procedures. Anterior Segment One hundred eight (90%) individuals had a slit-lamp examination or an examination by the magnification and illumination of a direct ophthalmoscope. No patients demonstrated blue sclera or corneal opacities as reported by others.6,7,22 Corneal diameter was assessed in 106 children: 24 children had a corneal diameter measured by either template rings or ruler, and in 82 the corneal diameter was grossly assessed. Microcornea was found in 22 of 106 (21%). One child had a mature nuclear unilateral cataract that was suspected to be secondary to self induced trauma. This child has an observed tendency to self abuse involving the periocular region, although the exact causative event was not observed. Three additional reports by other ophthalmologists noted one unilateral dense cataract and bilateral cataracts in 2 patients. In one case, the opacities were only peripheral. One patient had glaucoma by history but no signs of glaucoma were found on examination. He actually had microcornea. However, no refraction could be performed and he did not undergo a fundus examination. Posterior Segment A retina examination was performed in 40% of the patients and was considered to be normal in all patients except for 2. One child had bilateral pigmentary changes of the retina and the electroretinogram revealed widespread retinal dysfunction, there was no family history of retinal dysfunction. One child had slight disk pallor with temporal dragging of the macular vessels in both eyes, in a fashion that resembled retinopathy of prematurity, although the child was born at 38 weeks’ gestational age and a birth weight of 4.5 pounds. One patient had a posterior staphyloma and
412 Wygnanski-Jaffe et al another giant retinal breaks in one eye felt to be consistent with self abuse. The optic discs were examined in 47 children. Five patients (11%) were entirely normal. Thirty-nine (83%) showed a peripapillary pigment ring surrounding both nerve heads. One had optic nerve pallor. The child was referred back to their home eye care provider for further evaluation the results of which are not known to us. One had bilateral physiological optic nerve cupping. Correlations With the exception of those correlations that were biologically expected (eg, age vs corneal diameter, hypertrichosis vs synophyrs) and those which define the syndrome (eg, small stature vs limb abnormality), we found no statistically significant correlations between any individual ocular abnormality and a systemic feature of the syndrome. There were very weak correlations between microcornea and the presence of limb anomalies (P ⫽ 0.047), short palpebral fissure length and small stature (P ⫽ 0.029), short palpebral fissures and strabismus (P ⫽ 0.035), and myopia and small stature (P ⫽ 0.011). These correlations do not seem strong enough to allow for a conclusion that the paired features are likely to be related on a genetic or biologic basis. Likewise, there were no significant correlations when comparing one eye finding to another eye finding with the exceptions of those that would be biologically expected (eg blepharitis vs lid margin erythema). There was a significant correlation between the vision of the 2 eyes (P ⬍ 0.001). There was a weaker correlation between epiphora and blepharitis (P ⫽ 0.025) than epiphora and nasolacrimal duct obstruction (P ⬍ 0.001), suggesting that the latter is more likely to be a cause for epiphora. There was also a significant correlation between a history of prior nasolacrimal duct probing and persistent epiphora (P ⫽ 0.001), which suggests either that one must consider failed probing as the cause or that blepharitis is the true cause of the persistent epiphora only after nasolacrimal duct obstruction is ruled out. Prior probing and a diagnosis of nasolacrimal duct obstruction also were correlated with younger age (P ⬍ 0.001) which suggests that the older the patient, the less likely that epiphora is caused by nasolacrimal duct obstruction.
DISCUSSION We report the ophthalmic examinations of 120 patients with CdLS. We were able to confirm the findings in the previous report by Levin and coauthors and other previous reports and, as the result of our large sample size, provide more accurate frequency figures for brow hypertrichosis, synophrys, long eye lashes, ptosis, nystagmus, downslanting of the palpebral fissures, hypertelorism, arched eyebrows, telecanthus, myopia, strabismus, photophobia, blepharitis, and chronic conjunctival symptoms. In addition, we report peripapillary pigmentation and microcornea, which were reported only in single or rare case
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reports in other studies.2,4 We again examined various methods of measuring facial characteristics in these individuals and conclude that telecanthus rather than hypertelorism is common. All of the patients in our series exhibited features consistent with the diagnosis of CdLS including growth retardation of varying degrees (100%), developmental delay or mental retardation to a variable degree (100%), and limb anomalies (76%). Although in their series of more than 300 children Jackson and coauthors30 found limb abnormalities in only 27% of cases, limb abnormalities remain one of the most useful diagnostic characteristics. We examined all English and French (and other languages when translation available) literature reports and reviews of oculofacial abnormalities in CdLS. Most references in the literature do not include a complete ophthalmic examination.1-25 Synophrys is apparent in 85-100% of CdLS patients.1,2-8,13-17,19,21-25 In the present study, we found synophrys to be present in 99% of the children. Only 4 children did not have this finding. Many authors have been impressed by the long and curved eye lashes described in 7-100% of patients.1, 2-7,15-17,20-22,25-27 In the present series, we found long lashes were present in 99% of the children. Only one child was noted not to have this finding. Downslanting of palpebral fissures, in which the lateral canthus is positioned below the medial canthus of the eye, has been reported in 16-88% of patients with CdLS.3,9,19,22 We found this feature in only 7%, which may simply reflect our large sample size or specific attention paid to this detail. In several of the previous studies, patients with CdLS were noted to have telecanthus or hypertelorism.2,4,26 The previous review by Levin and coworkers26 indicated that both hypertelorism and telecanthus could be features of CdLS. In the present series using the same measurement techniques and the Mustardè index, we found that hypertelorism was uncommon. Using the calculated IPD, 60% of subjects had evidence of telecanthus. Using the measured IPD, 45% still had telecanthus. We believe there are errors inherent in using direct IPD measurement particularly in this population where patients may be combative, unable to fixate long enough for accurate measurement and resist instrumentation close to the face or converge on the near target. Therefore, according to our data including calculated IPD it appears that telecanthus (60%) and not hypertelorism (30%) is a feature more frequently associated with CdLS. Horizontally short palpebral fissures also have been reported by other authors to occur in as many as 100% of CdLS patients.2,6,23 In our study PFL was not measured directly in any of the patients, although direct measurement may be more desirable because it does not introduce an error that is obtained by using both the OCD and ICD in the formula. We are not aware of normal standards for Caucasians using direct or calculated PFL measurements.
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We were however able to document the occurrence of short PFL by calculation in 31% of our patients (Figure 6). Mild or visually significant ptosis, either unilateral or bilateral, occured in 44% of patients and appear to be mostly a consequence of poor levator function.3,4,6,8,24,25 In the present study, the incidence of ptosis was lower than that reported in the previous series by Levin and coworkers26 in which the rate of ptosis reached 67%. In our series, 51% of the patients with ptosis still had a lid crease. Once again, this result may simply reflect the increased accuracy inherent in a larger sample size. Surgical correction of ptosis, usually with a sling procedure particularly when there is poor levator function, may aid these children in attaining a clear visual axis and preventing the development of an abnormal head position (chin lift) and/or brow lift. In our experience, ptosis surgery may dramatically improve gross motor skills and ambulation in some patients. Blepharitis and chronic conjunctivitis also have been reported commonly with CdLS.5,11 In a previous series,26 59% of the patients in the group had blepharitis, chronic conjunctivitis, recurrent hordeolum, or nasolacrimal duct obstruction. In our current series, 25% of the patients examined suffered from blepharitis, 5.8% of the patients had a sty, 10% of the patients had a red lid margin, and 16% of the patients had history of nasolacrimal duct obstruction. It remains unclear whether recurrent external eye symptoms are caused by nasolacrimal duct obstruction or meibomian gland dysfunction. Because the latter may be ameliorated by simple lid hygiene as opposed to surgical intervention for the former, we recommend that each child with CdLS experiencing recurrent ocular discharge should first undergo treatment with simple lid hygiene for blepharitis. If symptoms persist, then nasolacrimal duct probing with or without silicone tube intubation should be undertaken. Many parents stated that treatment with lid hygiene alone has resulted in dramatic improvement in some children. Nevertheless, if only epiphora was found, it was most commonly correlated with nasolacrimal obstruction. Nystagmus also was found less commonly in our current report (14%) than in the previous reports.1,2-7,14,16,17,25 Levin and coworkers26 noticed nystagmus in 36% of their children, and previous reports noted nystagmus in as many as 67% of the individuals examined but with smaller sample sizes. The etiology is unknown. Horizontal strabismus has been previously reported in 20-50% of cases.1,2,4-7,15,16 We only found 16% of our patients to have strabismus. None had a vertical component. It is possible that a certain number of these cases are secondary to untreated refractive error especially those who are myopic and exotropic. Myopia is a well-recognized ocular feature of CdLS occurring in 60-73% of previously reported patients.2-7,8,16,17,22 In our study 60% of the children had myopia. It has not been determined if the myopia is due to corneal, lenticular,
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or axial elements. However, because one of our patients had a posterior staphyloma and a second patient had giant retinal breaks, axial myopia is suggested in at least these cases. Self-inflicted ocular trauma may also have played a role in at least one of our patients with myopia. No child was wearing glasses at the time of our examination and, in the previous study by Levin 3, children who had been prescribed glasses subsequently refused them. Nevertheless, we still advocate prescribing glasses to the children with high refractive errors, since this may change their quality of life. There was no correlation between the presence of microcornea and myopia or hyperopia suggesting that the nature of these refractive errors in this population is axial or lenticular. Although occlusion myopia is a well recognized phenomena, no correlation was found between myopia and ptosis (P ⫽ 0.05), suggesting that ptosis and refractive error may not be an association related to occlusion but rather to other genetic factors. Because myopia is very common in this group of children, early refraction is recommended to improve visual acuity and prevent amblyopia. Nevertheless, because of behavioral difficulties, it is our experience that not all of these children will be willing to wear glasses. At least one of our patients with myopia had a total retinal detachment, hyphema, and a vitreous hemorrhage as the result of selfinflicted injury. Another with cataract also may have experienced self-induced ocular injury. Although cataract and glaucoma also have been described in association with CdLS, the number of affected reported children remains small. We only found 2 cases of cataract among all 120 children examined and therefore feel that in this series we did not convincingly establish a correlation between CdLS and cataracts. Until further research is obtained to indicate otherwise, it is not certain if there is a true association between cataract and glaucoma with CdLS or if these are just coincidental findings. Microcornea was found to be present in 21% of our patients. Therefore, it is possible that microcornea is another feature of CdLS. The subjective assessment of corneal diameter by gross inspection in 12.5% of the patients examined suggests the true prevalence of microcornea may have been underestimated as gross examination would have detected only the more obvious. Peripapillary pigment was assessed in 47 patients has been previously described only in a single case report.2 In this series, it appeared in 83% of the examinees assessed for this anatomic variation and, hence, may be typical for this syndrome. Peripapillary pigmentation was not correlated with myopia or hyperopia, suggesting that this is a primary anatomic change rather than a change caused by an alteration in axial length. The pigmentary changes of the retina in a single child and the electroretinogram revealing wide retinal dysfunction is probably a coincidence, since it has not been reported in other children.
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Most patients with ptosis will require surgical correction. Self-abusive patients and those with combative behavior may require examination under anesthesia. The authors wish to thank the following for contributing information regarding CdLS patients they examined: M. Steele MD, Division of Pediatric Ophthalmology and Strabismus, New York University Medical Center; R. Bachman MD, Medical Geneticist, Walnut Creek, CA; M. Holmes MD, Ophthalmology, Pleasanton, CA; E. Ceisler MD, Pediatric Ophthalmology Consultants, NY; and A. Biglan MD, Pediatric Ophthalmology and Strabismus, Craneberry Township, PA. We are also grateful for the invaluable assistance of our research assistants Enza Perruzza and Erica Bell. FIG 6. Palpebral fissure length (PFL) in CdLS plotted against normal standards. Each dot represents a patient’s measured PFL.29
References
Although CdLS has been known for decades, the discovery of the mutated gene has been published only recently by 2 independent studies.31,32 The “Nipped B like” (NIPBL) gene, named after is counterpart in Drosophila fruit flies, encodes a key protein, delangin, which is involved with the development of many organs in the growing embryo. This gene is believed to have an architectural role in facilitating long distance interactions between enhancers and promoters of the homeobox regulatory elements. To date, all mutations identified appear to result in functional haploinsufficiency and an autosomal-dominant pattern of inheritance.31,33 Mutations in this gene are present in approximately half of the patients,34 suggesting that other genetic loci may be important or that there are genetic elements relevant to NIPBL (eg, intronic sequences, promoter) that have and that carry mutations yet to be discovered. The phenotypic similarity between CdLS and duplication 3q have been long recognized,16,31 which suggests a chromosomal localization of a contiguous gene.32 Ireland et al35 located the disorder to areas of chromosome 3q. They performed chromosome analysis and found a translocation with breakpoints at 3q26.3 and 17q23.1 and proposed that the gene for CdLS could be located at 3q26.3. Nevertheless Lopez-Rangel36 reported a case of a duplication in the 3q25.1-q26.1 that did not have a phenotype resembling CdLS or duplication 3q. It is possible that our sample suffered from a selection bias because CdLS children with ocular problems may be more likely to undergo an ophthalmic examination than those without ocular problems, particularly in the setting of the annual conferences, where families are given the option to chose which medical subspecialty consultation they desire. In conclusion, patients suffering from CdLS have many eye problems, some of which are readily treatable and demand early ophthalmic attention. On the basis of the our extensive experience, ophthalmologists examining patients with CdLS should look for myopic refractive errors and, once signs of blepharitis have been treated, consider probing and/or intubation of the nasolacrimal system.
1. 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 Brachmannde Lange syndrome. Neuropädiatrie 1971;3:46-66. 8. Hawley PD, Jackson LG, Kurnit DM. Sixty-four patients with Brachmann-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 de Lange syndrome. Pediatr Res 1976;10:843-50. 10. Cameroon TH, Kelly DP. Normal language skills and normal intelligence in a child with de Lange syndrome. J Speech Hear Disord. 1988;53:219-22. 11. Beck B. Psycho-social assessment of 36 de Lange patients. J Ment Defic Res 1987;31:251-7. 12. Opitz JM, Segal AT, Nadler HL. The etiology of the Brachmannde Lange syndrome. Birth Defects Reprint Series The National Foundation-March of Dimes 1965:22-33. 13. Beck B. Epidemiology of Cornelia de Lange syndrome. Acta Paediatr Scand 1976;65:631-8. 14. Schlesinger B, Clayton B, Bodian M, Jones KV. Typus degenerativus Amstelodamensis. Arch Dis Child 1963;38:349-57. 15. Hartz ZH, Jaslow RI, Gomez MR. The de Lange syndrome. Am J Dis Child. 1965;109:325-32. 16. Falek A, Schmidt R, Jervis GA. Familial de Lange syndrome with chromosome abnormalities. Pediatrics. 1966;37:92-101. 17. Ptacek LJ, Opitz J, Smith DW, Gerristen T, Waisman HA. The Cornelia de Lange syndrome. J Pediatr 1963;63:1000-20. 18. Beck B, Fenger K. Mortality, pathological findings and causes of death in the de Lange syndrome. Acta Pediatr Scand 1985;74:765-9. 19. De Lange C. Sur un type nouveau de degeneration (typus Amstelodamensis). Arch Med Enf 1933;36:713-9. 20. Opitz JM. The Brachmann-de Lange syndrome. Am J Med Genet 1985;22:89-102. 21. Lieber E, Glaser JH, Jhaveri R. Brachmann-de Lange syndrome. Am J Dis Child 1973;125:717-8. 22. Vilo-Coro AA, Arnoult JB, Robinson LK, Mazow ML. Lacrimal anomalies in Brachmann-de Lange syndrome. Am J Ophthalmol 1988;106:235-7.
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23. Preus M, Rex AP. Definition and diagnosis of the Brachmannde Lange syndrome. Am J Med Genet 1983;16:301-12. 24. Vorechovsky J, Podhradská O, Kasparková Z, Matusková D. Syndrome Brachmann-de Langeove u ctyr kojencu. Cesk Pediatr 1988; 43:81-4. 25. Bankier A, Haan E, Birrell R. Familial occurrence of Brachmannde Lange syndrome. Am J Med Genet 1986;25:163-5. 26. Levin AV, Seidman DJ, Nelson LB, Jackson LG. Ophthalmologic findings in the Cornelia de Lange syndrome. J Pediatr Ophthalmol Strabismus 1990;27:94-102. 27. Jackson L, Kline AD, Barr MA, Koch S. De Lange syndrome: a clinical review of 310 individuals. Am J Med Genet 1993;47:940-6. 28. Cassidy SB, Allanson JE. Management of genetic syndromes. New York: John Wiley and Sons; 2001. p. 86-88. 29. Feingold M, Bossert WH. Normal values for selected parameters: an aid to syndrome delineation. Birth Defects: Original Article Series. The National Foundation-March of Dimes. 1974;10:1-15. 30. Mustardé J. Epicanthal folds and the problem of telecanthus. Trans Ophthalmol Soc UK 1963;83:397-411. 31. Krantz ID, McCallum J, DeScipio C, et al. Cornelia de Lange syndrome is caused by mutations in the NIPBL, the human
32.
33.
34.
35.
36.
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homolog of Drosphilia melanogaster Nipped-B. Nat Genet 2004;36:631-5. Tonkin ET, Wang TJ, Lisgo S, et al. NIPBL, encoding a homolog of fungal Scc2-type sister cromatid cohesion proteins and fly Nipped –B, is mutated in Cornelia de Lange syndrome. Nat Genet 2004;36:636-41. Robinson LK, Wolfsburg E, Jones KL. Brachmann-de Lange syndrome: evidence for autosomal dominant inheritance. Am J Med Genet 1985;22:109-15. Gillis LA, McCallum J, Kaur M, DeScipio C, Yaeger D, Mariani A, Kline AD, LI HH, Devoto M, Jackson LG, Kranz ID. NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. Am J Hum Genet 2004;74:610-23. Ireland M, English C, Cross I, et al. A de novo translocation t(3;17)(q26.3;q23.1) in a child with Cornelia de Lange syndrome. Am J Med Genet 1991;28:639-40. Lopez-Rangel E, Dill FJ, Hrynchak, et al. Partial duplication of 3q(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, and erecting those statues? Of course we don’t know for sure, because no European ever saw it being done to write about it. But we can make informed guesses from oral traditions of the islanders themselves (especially about erecting statues), from statues in the quarries at successive stages of completion, and from recent experimental tests of different transport methods. In Rano Raraku quarry one can see incomplete statues still in the rock face and surrounded by narrow carving canals only about two feet wide. The hand-held basalt picks with which the carvers worked are still at the quarry. The most incomplete statues are nothing more than a block of stone roughly carved out of the rock with the eventual face upwards, and with the back still attached to the underlying cliff below by a long keel of rock. Next to be carved were the head, nose, and ears, followed by the arms, hands, and loincloth. At that stage the keel connecting the statue’s back to the cliff was chipped through, and transport of the statue out of its niche began. All statues in the process of being transported still lack the eye sockets, which were evidently not carved until the statue had been transported to the ahu and erected there. One of the most remarkable recent discoveries about the statues was made in 1979 by Sonia Haoa and Sergio Rapu Haoa, who found 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 inserted into a statue, they create a penetrating, blinding gaze that is awesome to look at. The fact that so few eyes have been recovered suggests that few actually were made, to remain under guard 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)
C
From the aDepartment of Ophthalmology The Hospital for Sick Children University of Toronto, Toronto, Canada, bPublic Health Sciences The Hospital for Sick Children University of Toronto, Toronto, Canada, cPopulation Health Sciences The Hospital for Sick Children University of Toronto, Toronto, Canada, dDivision of Medical Genetics Drexel University Medical School, Philadelphia, Pennsylvania, USA. Presented in part at the AAPOS annual meeting Washington D.C., March 31, 2004. Supported by Brandan’s Eye Research Fund. Submitted March 9, 2004. Revised May 31, 2005. Revision accepted May 31, 2005. Reprint requests: Alex V. Levin, MD, MHSc, FRCSC, Department of Ophthalmology M-158, The Hospital for Sick Children, 555 University Ave. Toronto, Ontario, Canada M5G 1X8 (e-mail: [email protected]). Copyright © 2005 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2005/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2005.05.010
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down.19,28 Other findings include congenital heart disease, cleft palate, hearing deficiency, poor verbal skills, and gastroesophageal reflux.1,5-8,12,15,17,20,24 However, other than the report by Levin and coworkers describing in detail the ophthalmic examination in 22 children,26 only 3 other publications address the ocular anomalies associated with this syndrome. These 3 articles describe case reports of small numbers of children with partial eye examinations.2-4 The present report of eye examinations of 120 patients with Cornelia de Lange syndrome (CdLS) is, to our knowledge, the largest series.
SUBJECTS AND METHODS We report the oculofacial findings in 120 children with CdLS that were examined by the senior author and 3 children that were examined by other pediatric ophthalmologists. The 22 patients previously reported26 are included herein. There are no established diagnostic criteria for CdLS. In each case enrolled in this study, the diagnosis was confirmed by a geneticist, with the majority being confirmed by one coauthor (L.G.J.), the founder of the CdLS Foundation, former Chair of their Scientific Advisory Committee, who has examined more children with CdLS than any other individual in the world (more than 2000 affected children). Fortunately, as described previously, in the majority of cases the classic phenotype is present and easily recognizable. We excluded all cases with uncertain diagnosis. Molecular genetic testing was not available at the time our subjects were enrolled. Each child underwent an ophthalmic evaluation as tolerated. Twenty-two children had their eye examinations conducted by one of the authors (A.V.L.) either at the Eye October 2005
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408 Wygnanski-Jaffe et al Clinic26 or at the Annual National or International meetings of the Cornelia de Lange Syndrome Foundation Inc. (held in the United States) or the Annual Medical Day of CdLS Canada. These conferences are run by the parentbased support associations as opportunities for family education and multidisciplinary medical consultation. The senior author attended these meetings and provided services ranging from full eye examinations (including a dilated fundus examination of both eyes) to an external pen light examination depending on the circumstance and the tolerance of the child. As a result, not all of the children had a complete eye examination. The minimum eye examination consisted of an external eye examination, assessment of visual fixation, penlight anterior segment examination, eye movement strabismus assessment, and pupil testing. Thirty-nine percent had a complete ophthalmic evaluation. Visual acuity was assessed by either observation of fixation or, with a projected Allen picture card (Richmond Products Boca Raton FL) in the one patient that could perform this test. Oculofacial measurements included direct measurement of outer and inner canthal distance (OCD and ICD, respectively, in mm). In girls between 1 and 4 years of age, the measured OCD was adjusted by adding a value of 0.2 cm as described by Feingold and Bossert.29 OCD, ICD, and interpupillary distance (IPD) were plotted against the normal standards of children 14 years of age or younger as developed by Feingold and Bossert.29 We are unaware of normal values in the literature for patients older than 14 years of age. IPD was calculated by the Feingold and Bossert method29 using the following formula: IPD ⫽ 0.7 ⫹ (0.59 ⫻ ICD) ⫹ (0.41 ⫻ OCD). A downslanting palpebral fissure was defined as one in which the lateral canthus was lower than the medial canthus. To distinguish hypertelorism from telecanthus, we used the Mustardé index,30 which refers to a relatively wide intercanthal distance in the presence of a normal interpupillary distance and defines telecanthus as a ratio of ICD/ IPD ⱖ0.55. We also calculated indices based on measured IPD, as did Mustardé, although it was difficult to measure IPD reliably in these children. Calculated palpebral fissure length (PFL) for 36 children was plotted for children aged 6 years or younger as defined by Chouke.31 The formula used to calculate the PFL was PFL ⫽ (OCD ⫺ ICD)/2. In children who had previous ptosis surgery, we recorded data from the unoperated affected eye but did not assess residual ptosis. At family conferences, children had either a hand-held portable slit-lamp examination or an examination by the magnification and illumination of a direct ophthalmoscope. Clinic examinations included slit-lamp examination as tolerated by the child. Corneal diameter was measured by either template rings or by ruler. If these objective measurements were not feasible, then corneal diameter was assessed grossly. Microcornea was defined as a corneal diameter smaller than
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10 mm or, in a newborn (up to age 4 months), smaller than 9 mm. Cycloplegic refraction using phenylephrine 2.5% and cycloplentolate 1% or 2% was obtained by retinoscopy and a sample of hand-held lenses to allow estimation to the nearest spherical equivalent. Cylinder values were not used for the purposes of this study because astigmatism was not found to be greater than 2.00 diopters (4 patients), with the exception of a single case of 3 diopters in whom the refraction was quite difficult and perhaps not accurate. Slit-lamp biomicroscopy and ophthalmoscopy also were performed when tolerated. Special attention was paid to the absence or presence of blepharitis. We considered blepharitis to be present when the patient demonstrated eyelid margin erythema, crusting on the lashes, collarettes, and madarosis. This assessment was made either by penlight examination, magnified view using the plus lens settings of a direct ophthalmoloscope, or by slit-lamp examination as tolerated. Developmental delay, skeletal anomalies, and stature also were noted and recorded. We used a subjective assessment based on parental report and examination. In some cases, we also had written or verbal assessments from other specialists, including geneticists, who had evaluated the patient. Four categories were used for each of these 3 variables independently: not affected (normal development, normal limbs, normal stature), mild (minimal behavior/learning difficulties, no limb abnormality other than small hands/feet or proximalized thumb, mildly small for age [3rd to 5th percentile]), moderate (moderate developmental delays or behavioral issues, obvious limb abnormalities not categorized as severe, moderate small stature [⬍3rd percentile]), and severe (severe developmental delay or behavioral issues requiring medication and/or constant care, severe characteristic limb reduction defects, extreme small stature). In addition, we had the opportunity to review the records of 3 children with CdLS provided to us by other pediatric ophthalmologists. Information specifically about children with CdLS and anterior segment anomalies, cataracts and glaucoma were reported and sent to us on 5 additional patients by other pediatric ophthalmologists. We have excluded all reports from other ophthalmologists from our statistical analysis but include comments regarding unique ophthalmic findings. Pearson correlation coefficients were computed for continuous variables (age ICD, OCD, IPD, PFL, corneal diameter, and spherical equivalent). Chi-square and Fisher’s exact tests were conducted for 2 ⫻ 2 and n ⫻ k contingency tables of categorical variables, as appropriate. T-tests were conducted to test for differences between groups (binary categorical variables) for each continuous variable. One-way analysis of variance was conducted to test for differences between groups (categorical variables with more than 2 levels) for each continuous variable.
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TABLE 1 Systemic findings Sample size
Frequency in %
106 108 104 117
100 76 78 99
Developmental delay Skeletal anomalies Small stature Typical facies
TABLE 2 Ophthalmologic manifestations Ocular finding Sample size Long lashes Synophrys Hypertrichosis Peripapillary pigment ring Telecanthus Myopia Ptosis Blepharitis Epiphora Microcornea Strabismus Nystagmus Down-slanting palpebral fissures
115 116 110 47 62 62 117 107 97 106 113 111 96
Prevalence in % 99 99 96 83 60 58 44 25 22 21 16 14 7
In light of the fact that this study is an hypothesisgenerating study and that multiple hypotheses were tested, the statistical problem of multiplicity must be addressed. Multiplicity in the statistical sense refers to the scenario in which multiple hypotheses are tested and requires some penalty to be applied to the nominal significance level to which computed P values are being compared. One typical approach for dealing with this problem is to apply the Bonferroni correction for multiple testing whereby, for any given number of hypotheses tested K, the nominal ␣ ⫽ 0.05 level against which computed P values usually are compared, is adjusted to ␣= ⫽ 0.05/K. For the purpose of defining and testing primary research hypotheses we chose 41 primary pairs (K), and 13 secondary pairs (not counted in K) tested for correlation (Tables 1 and 2). Pairs were designated as primary or secondary based on possible clinical significance should the correlations prove to be significantly correlated either positively or negatively. The secondary hypotheses are exploratory in nature, and we interpret them in a hypothesis-generating rather than in a hypothesis-testing context. The Bonferroni correction yields a new alpha level required for significance of 0.0012: only those P values ⬍0.0012 related to the primary pairs are considered significant. For the remaining 13 secondary pairs we considered the generated p values which were ⬍0.05 as potentially worthy of further investigation (ie, hypothesis generating). Primary pairs of clinical findings were those that, if related, would have a higher biologic significance in the opinion of the authors, for example, peripapillary pigment-refractive error as opposed to a secondary pair developmental delay and refractive error.
FIG 1. Affected boy with arched eyebrows, synophrys, long eyelashes, left ptosis, oval downturned mouth with thin lips, and anteverted nares.
RESULTS The clinical diagnosis of all patients was confirmed either by L.G.J., who is the Medical Director of the Cornelia de Lange Foundation Inc., or another clinical geneticist. Sixty-three patients were boys (male:female ratio 1.1:1.0). Mean patient age at the time of examination was 7.88 years (range, 3 months to 38 years). All children, except 2, were Caucasian. Many of the children exhibited abrupt and aggressive behavioral changes when their eyes were approached by light or by touch. This behavior limited the ability to obtain a complete examination in 61% of subjects. A subjective annotation regarding developmental status was made by the examining ophthalmologist in 106 children. Eighteen children were categorized as mildly (17%), 47 (44%) as moderately, and 41 (39%) as severely mentally disabled. An annotation regarding skeletal anomalies was made by the examining ophthalmologist in 108 children. Twenty-six were categorized as normal (24%), whereas 32 (30%) had mild, 27 (25%) had moderate, and 23 (21%) had severe skeletal anomalies. Mention of stature was
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FIG 2. Plot of outer canthal distance against normal standards for age.27
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FIG 4. Plot of calculated interpupillary distance, using method of Feingold and Bossert,27 against normal standards for age.
FIG 3. Plot of inner canthal distance against normal standards for age.27
noted in 104 children. Thirteen percent had mild, 40% moderate, and 25% severe small stature (Table 1). The frequencies of ocular findings are listed in Table 2. Oculofacial Features The typical CdLS facies was observed in 99% of the children (Figure 1). Only a single mildly affected child did not have this appearance. One hundred sixteen children were assessed for synophyrs. All but one (99%) had this finding. Almost all had a downsloping V-shaped configuration of the eyebrows as they met and extended onto the upper part of the nasal bridge. A small number of children were having the midportion of the eyebrows shaved or epilated by the parents for cosmesis. Long eye lashes were observed in 99% of patients. Brow hypertrichosis was seen in 96%. Downslanting of the palpebral fissures was observed in only 7 of 96 (7.3%) patients examined for this finding, unlike previous reports in the literature.6 We were able to obtain OCD values for 62 of the patients. Fifty-five of those measured were 14 years old
FIG 5. Plot of measured interpupillary distance against normal standards for age.27
and younger. Thirteen percent (7/55) fell below the third percentile (Figure 2).29 Mean OCD was 75.6mm ⫾ 6.8 (range, 56-95). ICD was measured for 68 children, of which 60 were younger than 14 years of age. Mean ICD was 26.3mm ⫾ 3.2 (range, 18-37). Forty-seven of the 60 (78%) were within the normal range, with 13 children less than or equal to the third percentile, which is suggestive of mild hypotelorism (Figure 3).29 As demonstrated in Figure 4, we did not find hypertelorism using the calculated IPD. It is difficult to accurately measure the IPD directly in these developmentally and behaviorally challenged individuals. However, when the 19 patients for whom the IPD was measured directly were plotted on the same curve of normal standards, there was a suggestion that there is no tendency toward hypertelorism (Figure 5). Of the 61 subjects who had both ICD and calculated IPD obtained, 37 (60%), had an increased Mustardè Index
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suggestive of telecanthus. Using measured IPD, 9 of 20 (45%) Mustardé values were abnormally high, we found 18 children to be over the 50th centile and 17 below the 50th centile. Lids Fifty-one of our 117 (44%) children had varying degrees of ptosis, ranging from mild cosmetic changes to functional obstruction of the visual axis. A compensatory chin lift was observed in 29 (57%) of those with ptosis. Brow lift was present in 36% of the children with ptosis. Twentyseven percent of the children had bilateral ptosis; in 16%, the ptosis was unilateral. In 75% of the children with ptosis, the levator function was limited or absent, indicated by no apparent upper lid fold or by weak levator function. Four patients underwent surgical repair of the ptosis prior to the examination. By history, 22% of patients suffered from epiphora, discharge, or red eyes. One hundred seven children of the 120 patients were assessed for blepharitis. Of these, 27 (25%) had active blepharitis. All children were checked for presence of a sty; however, only 5.8% (7 children) were positive for this finding. Nystagmus Fifteen of 111 (13.5%) children had nystagmus. The nystagmus was horizontal pendular in all cases. We found no correlation between nystagmus and other phenotypic characteristics, such as refractive error or developmental delay. Ocular Alignment One hundred thirteen children (94%) children had an assessment of ocular alignment. Ninety-four children (84%) were orthotropic, 11 (10%) were esotropic, 7 (6%) were exotropic, and 1 patient had undergone previous strabismus surgery for an unknown deviation. Refraction and Visual Acuity Forty-six (38%) of the 120 children underwent cycloplegic refraction of at least the right eye. The mean spherical equivalent in the right eye was minus 2.9 ⫾ 5.1 (range, ⫺20 to 7). Forty seven (39.2%) had cycloplegic refraction of the left eye. The mean spherical equivalent of the left eye was minus 3.3 ⫾ 5.4 (range, ⫺20 to 11.8). The refraction of each eye was analyzed separately to evaluate the presence or absence of anisometropia. Only 42% of the children who were refracted were not myopic. Eight eyes had a cycloplegic refraction of more than ⫺10.00 spherical equivalent. Forty-six (38%) had a spherical equivalent of greater than ⫺5.00 sphere. Only 3 eyes had a spherical equivalent of greater than ⫹ 3.50; one ⫹ 5.00, and one ⫹ 11.50 sphere. Visual acuity in 86 patients was equal in both eyes as assessed by a central steady and maintained fixation behav-
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ior at near. However, it is certainly possible (if not likely) that some patients (eg, those with cataract) would show reduced visual acuity if tested by a more objective method. Only one child was able to perform projected Allen picture visual acuity testing and had a visual acuity of 20/40 in each eye. Contrary to the findings of Cassidy and Allanson,27 in which half of their subjects had some verbal skills, it is our experience with our larger sample size that this degree of communication is less common and, in combination with other behavioral challenge, rendered no other children able to cooperate with quantitative visual acuity modes available in the examination settings.2-13 Nasolacrimal System Signs of nasolacrimal duct obstruction (epiphora, tearing, matting of lashes) were recorded in 97/120 (80%). By history, 39 (33%) children had such signs, and 22% specifically had epiphora alone or with discharge. Twenty-six of 95 (27%) had, by history, prior probing or intubation of the nasolacrimal duct system. Eleven of these children (11/26, 42%) still had epiphora despite prior nasolacrimal system draining procedures. Anterior Segment One hundred eight (90%) individuals had a slit-lamp examination or an examination by the magnification and illumination of a direct ophthalmoscope. No patients demonstrated blue sclera or corneal opacities as reported by others.6,7,22 Corneal diameter was assessed in 106 children: 24 children had a corneal diameter measured by either template rings or ruler, and in 82 the corneal diameter was grossly assessed. Microcornea was found in 22 of 106 (21%). One child had a mature nuclear unilateral cataract that was suspected to be secondary to self induced trauma. This child has an observed tendency to self abuse involving the periocular region, although the exact causative event was not observed. Three additional reports by other ophthalmologists noted one unilateral dense cataract and bilateral cataracts in 2 patients. In one case, the opacities were only peripheral. One patient had glaucoma by history but no signs of glaucoma were found on examination. He actually had microcornea. However, no refraction could be performed and he did not undergo a fundus examination. Posterior Segment A retina examination was performed in 40% of the patients and was considered to be normal in all patients except for 2. One child had bilateral pigmentary changes of the retina and the electroretinogram revealed widespread retinal dysfunction, there was no family history of retinal dysfunction. One child had slight disk pallor with temporal dragging of the macular vessels in both eyes, in a fashion that resembled retinopathy of prematurity, although the child was born at 38 weeks’ gestational age and a birth weight of 4.5 pounds. One patient had a posterior staphyloma and
412 Wygnanski-Jaffe et al another giant retinal breaks in one eye felt to be consistent with self abuse. The optic discs were examined in 47 children. Five patients (11%) were entirely normal. Thirty-nine (83%) showed a peripapillary pigment ring surrounding both nerve heads. One had optic nerve pallor. The child was referred back to their home eye care provider for further evaluation the results of which are not known to us. One had bilateral physiological optic nerve cupping. Correlations With the exception of those correlations that were biologically expected (eg, age vs corneal diameter, hypertrichosis vs synophyrs) and those which define the syndrome (eg, small stature vs limb abnormality), we found no statistically significant correlations between any individual ocular abnormality and a systemic feature of the syndrome. There were very weak correlations between microcornea and the presence of limb anomalies (P ⫽ 0.047), short palpebral fissure length and small stature (P ⫽ 0.029), short palpebral fissures and strabismus (P ⫽ 0.035), and myopia and small stature (P ⫽ 0.011). These correlations do not seem strong enough to allow for a conclusion that the paired features are likely to be related on a genetic or biologic basis. Likewise, there were no significant correlations when comparing one eye finding to another eye finding with the exceptions of those that would be biologically expected (eg blepharitis vs lid margin erythema). There was a significant correlation between the vision of the 2 eyes (P ⬍ 0.001). There was a weaker correlation between epiphora and blepharitis (P ⫽ 0.025) than epiphora and nasolacrimal duct obstruction (P ⬍ 0.001), suggesting that the latter is more likely to be a cause for epiphora. There was also a significant correlation between a history of prior nasolacrimal duct probing and persistent epiphora (P ⫽ 0.001), which suggests either that one must consider failed probing as the cause or that blepharitis is the true cause of the persistent epiphora only after nasolacrimal duct obstruction is ruled out. Prior probing and a diagnosis of nasolacrimal duct obstruction also were correlated with younger age (P ⬍ 0.001) which suggests that the older the patient, the less likely that epiphora is caused by nasolacrimal duct obstruction.
DISCUSSION We report the ophthalmic examinations of 120 patients with CdLS. We were able to confirm the findings in the previous report by Levin and coauthors and other previous reports and, as the result of our large sample size, provide more accurate frequency figures for brow hypertrichosis, synophrys, long eye lashes, ptosis, nystagmus, downslanting of the palpebral fissures, hypertelorism, arched eyebrows, telecanthus, myopia, strabismus, photophobia, blepharitis, and chronic conjunctival symptoms. In addition, we report peripapillary pigmentation and microcornea, which were reported only in single or rare case
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reports in other studies.2,4 We again examined various methods of measuring facial characteristics in these individuals and conclude that telecanthus rather than hypertelorism is common. All of the patients in our series exhibited features consistent with the diagnosis of CdLS including growth retardation of varying degrees (100%), developmental delay or mental retardation to a variable degree (100%), and limb anomalies (76%). Although in their series of more than 300 children Jackson and coauthors30 found limb abnormalities in only 27% of cases, limb abnormalities remain one of the most useful diagnostic characteristics. We examined all English and French (and other languages when translation available) literature reports and reviews of oculofacial abnormalities in CdLS. Most references in the literature do not include a complete ophthalmic examination.1-25 Synophrys is apparent in 85-100% of CdLS patients.1,2-8,13-17,19,21-25 In the present study, we found synophrys to be present in 99% of the children. Only 4 children did not have this finding. Many authors have been impressed by the long and curved eye lashes described in 7-100% of patients.1, 2-7,15-17,20-22,25-27 In the present series, we found long lashes were present in 99% of the children. Only one child was noted not to have this finding. Downslanting of palpebral fissures, in which the lateral canthus is positioned below the medial canthus of the eye, has been reported in 16-88% of patients with CdLS.3,9,19,22 We found this feature in only 7%, which may simply reflect our large sample size or specific attention paid to this detail. In several of the previous studies, patients with CdLS were noted to have telecanthus or hypertelorism.2,4,26 The previous review by Levin and coworkers26 indicated that both hypertelorism and telecanthus could be features of CdLS. In the present series using the same measurement techniques and the Mustardè index, we found that hypertelorism was uncommon. Using the calculated IPD, 60% of subjects had evidence of telecanthus. Using the measured IPD, 45% still had telecanthus. We believe there are errors inherent in using direct IPD measurement particularly in this population where patients may be combative, unable to fixate long enough for accurate measurement and resist instrumentation close to the face or converge on the near target. Therefore, according to our data including calculated IPD it appears that telecanthus (60%) and not hypertelorism (30%) is a feature more frequently associated with CdLS. Horizontally short palpebral fissures also have been reported by other authors to occur in as many as 100% of CdLS patients.2,6,23 In our study PFL was not measured directly in any of the patients, although direct measurement may be more desirable because it does not introduce an error that is obtained by using both the OCD and ICD in the formula. We are not aware of normal standards for Caucasians using direct or calculated PFL measurements.
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We were however able to document the occurrence of short PFL by calculation in 31% of our patients (Figure 6). Mild or visually significant ptosis, either unilateral or bilateral, occured in 44% of patients and appear to be mostly a consequence of poor levator function.3,4,6,8,24,25 In the present study, the incidence of ptosis was lower than that reported in the previous series by Levin and coworkers26 in which the rate of ptosis reached 67%. In our series, 51% of the patients with ptosis still had a lid crease. Once again, this result may simply reflect the increased accuracy inherent in a larger sample size. Surgical correction of ptosis, usually with a sling procedure particularly when there is poor levator function, may aid these children in attaining a clear visual axis and preventing the development of an abnormal head position (chin lift) and/or brow lift. In our experience, ptosis surgery may dramatically improve gross motor skills and ambulation in some patients. Blepharitis and chronic conjunctivitis also have been reported commonly with CdLS.5,11 In a previous series,26 59% of the patients in the group had blepharitis, chronic conjunctivitis, recurrent hordeolum, or nasolacrimal duct obstruction. In our current series, 25% of the patients examined suffered from blepharitis, 5.8% of the patients had a sty, 10% of the patients had a red lid margin, and 16% of the patients had history of nasolacrimal duct obstruction. It remains unclear whether recurrent external eye symptoms are caused by nasolacrimal duct obstruction or meibomian gland dysfunction. Because the latter may be ameliorated by simple lid hygiene as opposed to surgical intervention for the former, we recommend that each child with CdLS experiencing recurrent ocular discharge should first undergo treatment with simple lid hygiene for blepharitis. If symptoms persist, then nasolacrimal duct probing with or without silicone tube intubation should be undertaken. Many parents stated that treatment with lid hygiene alone has resulted in dramatic improvement in some children. Nevertheless, if only epiphora was found, it was most commonly correlated with nasolacrimal obstruction. Nystagmus also was found less commonly in our current report (14%) than in the previous reports.1,2-7,14,16,17,25 Levin and coworkers26 noticed nystagmus in 36% of their children, and previous reports noted nystagmus in as many as 67% of the individuals examined but with smaller sample sizes. The etiology is unknown. Horizontal strabismus has been previously reported in 20-50% of cases.1,2,4-7,15,16 We only found 16% of our patients to have strabismus. None had a vertical component. It is possible that a certain number of these cases are secondary to untreated refractive error especially those who are myopic and exotropic. Myopia is a well-recognized ocular feature of CdLS occurring in 60-73% of previously reported patients.2-7,8,16,17,22 In our study 60% of the children had myopia. It has not been determined if the myopia is due to corneal, lenticular,
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or axial elements. However, because one of our patients had a posterior staphyloma and a second patient had giant retinal breaks, axial myopia is suggested in at least these cases. Self-inflicted ocular trauma may also have played a role in at least one of our patients with myopia. No child was wearing glasses at the time of our examination and, in the previous study by Levin 3, children who had been prescribed glasses subsequently refused them. Nevertheless, we still advocate prescribing glasses to the children with high refractive errors, since this may change their quality of life. There was no correlation between the presence of microcornea and myopia or hyperopia suggesting that the nature of these refractive errors in this population is axial or lenticular. Although occlusion myopia is a well recognized phenomena, no correlation was found between myopia and ptosis (P ⫽ 0.05), suggesting that ptosis and refractive error may not be an association related to occlusion but rather to other genetic factors. Because myopia is very common in this group of children, early refraction is recommended to improve visual acuity and prevent amblyopia. Nevertheless, because of behavioral difficulties, it is our experience that not all of these children will be willing to wear glasses. At least one of our patients with myopia had a total retinal detachment, hyphema, and a vitreous hemorrhage as the result of selfinflicted injury. Another with cataract also may have experienced self-induced ocular injury. Although cataract and glaucoma also have been described in association with CdLS, the number of affected reported children remains small. We only found 2 cases of cataract among all 120 children examined and therefore feel that in this series we did not convincingly establish a correlation between CdLS and cataracts. Until further research is obtained to indicate otherwise, it is not certain if there is a true association between cataract and glaucoma with CdLS or if these are just coincidental findings. Microcornea was found to be present in 21% of our patients. Therefore, it is possible that microcornea is another feature of CdLS. The subjective assessment of corneal diameter by gross inspection in 12.5% of the patients examined suggests the true prevalence of microcornea may have been underestimated as gross examination would have detected only the more obvious. Peripapillary pigment was assessed in 47 patients has been previously described only in a single case report.2 In this series, it appeared in 83% of the examinees assessed for this anatomic variation and, hence, may be typical for this syndrome. Peripapillary pigmentation was not correlated with myopia or hyperopia, suggesting that this is a primary anatomic change rather than a change caused by an alteration in axial length. The pigmentary changes of the retina in a single child and the electroretinogram revealing wide retinal dysfunction is probably a coincidence, since it has not been reported in other children.
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Most patients with ptosis will require surgical correction. Self-abusive patients and those with combative behavior may require examination under anesthesia. The authors wish to thank the following for contributing information regarding CdLS patients they examined: M. Steele MD, Division of Pediatric Ophthalmology and Strabismus, New York University Medical Center; R. Bachman MD, Medical Geneticist, Walnut Creek, CA; M. Holmes MD, Ophthalmology, Pleasanton, CA; E. Ceisler MD, Pediatric Ophthalmology Consultants, NY; and A. Biglan MD, Pediatric Ophthalmology and Strabismus, Craneberry Township, PA. We are also grateful for the invaluable assistance of our research assistants Enza Perruzza and Erica Bell. FIG 6. Palpebral fissure length (PFL) in CdLS plotted against normal standards. Each dot represents a patient’s measured PFL.29
References
Although CdLS has been known for decades, the discovery of the mutated gene has been published only recently by 2 independent studies.31,32 The “Nipped B like” (NIPBL) gene, named after is counterpart in Drosophila fruit flies, encodes a key protein, delangin, which is involved with the development of many organs in the growing embryo. This gene is believed to have an architectural role in facilitating long distance interactions between enhancers and promoters of the homeobox regulatory elements. To date, all mutations identified appear to result in functional haploinsufficiency and an autosomal-dominant pattern of inheritance.31,33 Mutations in this gene are present in approximately half of the patients,34 suggesting that other genetic loci may be important or that there are genetic elements relevant to NIPBL (eg, intronic sequences, promoter) that have and that carry mutations yet to be discovered. The phenotypic similarity between CdLS and duplication 3q have been long recognized,16,31 which suggests a chromosomal localization of a contiguous gene.32 Ireland et al35 located the disorder to areas of chromosome 3q. They performed chromosome analysis and found a translocation with breakpoints at 3q26.3 and 17q23.1 and proposed that the gene for CdLS could be located at 3q26.3. Nevertheless Lopez-Rangel36 reported a case of a duplication in the 3q25.1-q26.1 that did not have a phenotype resembling CdLS or duplication 3q. It is possible that our sample suffered from a selection bias because CdLS children with ocular problems may be more likely to undergo an ophthalmic examination than those without ocular problems, particularly in the setting of the annual conferences, where families are given the option to chose which medical subspecialty consultation they desire. In conclusion, patients suffering from CdLS have many eye problems, some of which are readily treatable and demand early ophthalmic attention. On the basis of the our extensive experience, ophthalmologists examining patients with CdLS should look for myopic refractive errors and, once signs of blepharitis have been treated, consider probing and/or intubation of the nasolacrimal system.
1. 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 Brachmannde Lange syndrome. Neuropädiatrie 1971;3:46-66. 8. Hawley PD, Jackson LG, Kurnit DM. Sixty-four patients with Brachmann-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 de Lange syndrome. Pediatr Res 1976;10:843-50. 10. Cameroon TH, Kelly DP. Normal language skills and normal intelligence in a child with de Lange syndrome. J Speech Hear Disord. 1988;53:219-22. 11. Beck B. Psycho-social assessment of 36 de Lange patients. J Ment Defic Res 1987;31:251-7. 12. Opitz JM, Segal AT, Nadler HL. The etiology of the Brachmannde Lange syndrome. Birth Defects Reprint Series The National Foundation-March of Dimes 1965:22-33. 13. Beck B. Epidemiology of Cornelia de Lange syndrome. Acta Paediatr Scand 1976;65:631-8. 14. Schlesinger B, Clayton B, Bodian M, Jones KV. Typus degenerativus Amstelodamensis. Arch Dis Child 1963;38:349-57. 15. Hartz ZH, Jaslow RI, Gomez MR. The de Lange syndrome. Am J Dis Child. 1965;109:325-32. 16. Falek A, Schmidt R, Jervis GA. Familial de Lange syndrome with chromosome abnormalities. Pediatrics. 1966;37:92-101. 17. Ptacek LJ, Opitz J, Smith DW, Gerristen T, Waisman HA. The Cornelia de Lange syndrome. J Pediatr 1963;63:1000-20. 18. Beck B, Fenger K. Mortality, pathological findings and causes of death in the de Lange syndrome. Acta Pediatr Scand 1985;74:765-9. 19. De Lange C. Sur un type nouveau de degeneration (typus Amstelodamensis). Arch Med Enf 1933;36:713-9. 20. Opitz JM. The Brachmann-de Lange syndrome. Am J Med Genet 1985;22:89-102. 21. Lieber E, Glaser JH, Jhaveri R. Brachmann-de Lange syndrome. Am J Dis Child 1973;125:717-8. 22. Vilo-Coro AA, Arnoult JB, Robinson LK, Mazow ML. Lacrimal anomalies in Brachmann-de Lange syndrome. Am J Ophthalmol 1988;106:235-7.
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23. Preus M, Rex AP. Definition and diagnosis of the Brachmannde Lange syndrome. Am J Med Genet 1983;16:301-12. 24. Vorechovsky J, Podhradská O, Kasparková Z, Matusková D. Syndrome Brachmann-de Langeove u ctyr kojencu. Cesk Pediatr 1988; 43:81-4. 25. Bankier A, Haan E, Birrell R. Familial occurrence of Brachmannde Lange syndrome. Am J Med Genet 1986;25:163-5. 26. Levin AV, Seidman DJ, Nelson LB, Jackson LG. Ophthalmologic findings in the Cornelia de Lange syndrome. J Pediatr Ophthalmol Strabismus 1990;27:94-102. 27. Jackson L, Kline AD, Barr MA, Koch S. De Lange syndrome: a clinical review of 310 individuals. Am J Med Genet 1993;47:940-6. 28. Cassidy SB, Allanson JE. Management of genetic syndromes. New York: John Wiley and Sons; 2001. p. 86-88. 29. Feingold M, Bossert WH. Normal values for selected parameters: an aid to syndrome delineation. Birth Defects: Original Article Series. The National Foundation-March of Dimes. 1974;10:1-15. 30. Mustardé J. Epicanthal folds and the problem of telecanthus. Trans Ophthalmol Soc UK 1963;83:397-411. 31. Krantz ID, McCallum J, DeScipio C, et al. Cornelia de Lange syndrome is caused by mutations in the NIPBL, the human
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homolog of Drosphilia melanogaster Nipped-B. Nat Genet 2004;36:631-5. Tonkin ET, Wang TJ, Lisgo S, et al. NIPBL, encoding a homolog of fungal Scc2-type sister cromatid cohesion proteins and fly Nipped –B, is mutated in Cornelia de Lange syndrome. Nat Genet 2004;36:636-41. Robinson LK, Wolfsburg E, Jones KL. Brachmann-de Lange syndrome: evidence for autosomal dominant inheritance. Am J Med Genet 1985;22:109-15. Gillis LA, McCallum J, Kaur M, DeScipio C, Yaeger D, Mariani A, Kline AD, LI HH, Devoto M, Jackson LG, Kranz ID. NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. Am J Hum Genet 2004;74:610-23. Ireland M, English C, Cross I, et al. A de novo translocation t(3;17)(q26.3;q23.1) in a child with Cornelia de Lange syndrome. Am J Med Genet 1991;28:639-40. Lopez-Rangel E, Dill FJ, Hrynchak, et al. Partial duplication of 3q(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, and erecting those statues? Of course we don’t know for sure, because no European ever saw it being done to write about it. But we can make informed guesses from oral traditions of the islanders themselves (especially about erecting statues), from statues in the quarries at successive stages of completion, and from recent experimental tests of different transport methods. In Rano Raraku quarry one can see incomplete statues still in the rock face and surrounded by narrow carving canals only about two feet wide. The hand-held basalt picks with which the carvers worked are still at the quarry. The most incomplete statues are nothing more than a block of stone roughly carved out of the rock with the eventual face upwards, and with the back still attached to the underlying cliff below by a long keel of rock. Next to be carved were the head, nose, and ears, followed by the arms, hands, and loincloth. At that stage the keel connecting the statue’s back to the cliff was chipped through, and transport of the statue out of its niche began. All statues in the process of being transported still lack the eye sockets, which were evidently not carved until the statue had been transported to the ahu and erected there. One of the most remarkable recent discoveries about the statues was made in 1979 by Sonia Haoa and Sergio Rapu Haoa, who found 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 inserted into a statue, they create a penetrating, blinding gaze that is awesome to look at. The fact that so few eyes have been recovered suggests that few actually were made, to remain under guard 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)