Sd Cohen

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Mechanisms of Myopia in Cohen Syndrome Mapped toChromosome 8q22

Paula Summanen, 1 Satu Kivitie-Kallio, 2 Reijo Norio, 3 Christina Raitta, 1,4 and Tero Kivela 1

P URPOSE. To analyze the mechanisms of myopia in Cohensyndrome (Mendelian Inheritance in Man [MIM] no. 216550).METHODS . A cross-sectional study of 22 Finnish patients (agerange, 2–57 years) with Cohen syndrome, which maps tochromosome 8q22, was undertaken to record cycloplegic re-fraction, keratometry (corneal power and radius of curvature),biometry (anterior chamber depth [ACD], lens thickness [LT],axial [AL] and vitreal length [VL]), and Hoffer Q-modeled lenspower. These components of refraction were correlated to ageand spherical equivalent (SE) at the corneal plane. Contribu-tion to total myopia of refractive (corneal and lenticular) andaxial components was modeled by multiple linear regressionand by estimating the effect of deviation from population mean values.R ESULTS. The mean SE in patients with Cohen syndrome older than 10 years was –9.35 D; the mean cylinder power, 1.70 D;and the mean anisometropia, 0.53 D. Relative to the em-metropic eye of a young adult, the AL and VL (mean, 23.9 and16.6 mm, respectively) and lens power (mean, 30.30 D) werehigher in 74% and 93% of patients, respectively, and the ACD(mean, 2.5 mm) was smaller and the LT (mean, 4.9 mm) andcorneal power (mean, 45.63 D) higher than average in allpatients. Corneal power ( r 0.513, P 0.021) increased with age, but AL and VL ( P 0.46 and 0.54, respectively) and lenspower ( P 0.89) did not correlate with age. The lens power decreased with AL ( r 0.564, P 0.029) and tended toincrease with corneal power ( r 0.475, P 0.074). Multiplelinear regression identied AL and corneal power as indepen-dent predictors of SE. Based on deviation from populationmeans, the lens power explained 55%, corneal power 23%, and

AL 22% of total myopia. ACD decreased and LT increasedmarkedly with age, rendering angle-closure glaucoma a possi-bility.CONCLUSIONS . Myopia in Cohen syndrome is mainly refractive intype and is due to high corneal and lenticular power, which isotherwise rare in young patients. It may be superimposed onaxial myopia, probably related to polygenic factors that deter-mine myopia in the general population. The refractive myopiain Cohen syndrome may result from dysgenesis and atrophy of the cornea, ciliary body, and iris, which in turn cause iridial

and zonular laxity and spherophakia. ( Invest Ophthalmol VisSci. 2002;43:1686–1693)

The Cohen syndrome (Mendelian Inheritance in Man [MIM]No. 216550) described by Cohen et al. in 1973, 1 is an

autosomal recessive disease that maps to chromosome 8q22. 2,3

It is characterized by nonprogressive mental and motor retar-dation; a sociable and cheerful disposition; microcephaly; 4

hypotony; dysmorphic features, including wave-shaped, oftendown-slanting, lid openings; thick eyebrows and eyelashes; ashort philtrum with an inability to cover the upper teeth 5 ;granulocytopenia 5–7 ; and retinochoroidal dystrophy. 5,6,8–11

Myopia is another frequent hallmark of Cohen syndrome,and it is variously considered to be either a major or a minor diagnostic criterion (for a review, see Refs. 11,12). Of 22Finnish patients with Cohen syndrome, all but one 5-year-old

girl had myopia at the median age of 33 years. The myopia wasoften of high grade with a median spherical equivalent of –11D.12 In other reports, myopia has mostly been moderate, but infour it was of high grade. 5,9,10,13 The myopia in Finnish pa-tients was progressive, with a median increase of –6.5 Dduring an average follow-up of 15 years. 12

Myopia in general can be predominantly corneal, lenticular,or axial, or it may represent a more complex imbalance be-tween the total refractive power and the axial length of theeye. 14 Preliminary observations suggest that myopia in somepatients with Cohen syndrome may be predominantly cornealand lenticular, rather than axial. 12 Because this would be arelatively unusual combination in young-adult–onset myopia, we analyzed in detail the components of refraction with kera-tometry and biometry in patients of various ages with Cohen

syndrome and searched for secondary changes related to axialmyopia to better understand the mechanisms of myopia inCohen syndrome.

P ATIENTS AND METHODS

Inclusion Criteria A nationwide survey of Cohen syndrome in Finland, organized be-tween 1994 and 1996 by the Department of Pediatrics, Helsinki Uni- versity Central Hospital, ascertained from hospitals, pediatricians, andclinical geneticists 29 patients who fullled the diagnostic criteria. 5,15

Patients in this population-based cohort were eligible for participationin the present study. Informed consent was obtained from the guard-ians of 22 patients (inclusion ratio, 76%). The median age of the 10enrolled male and 12 female patients was 31 years (range, 2–57). TheCohen syndrome gene ( COH1 ) had been localized by linkage disequi-librium and haplotype analysis to chromosome 8q22 in all the patientsexcept one, who did not undergo genetic analysis. 3 The study followedthe tenets of the Helsinki Declaration and was approved by the insti-tutional review board.

Ophthalmologic Examination The patients underwent manual refraction with streak retinoscopy while under cycloplegia induced by 0.5% cyclopentolate drops. Mediaopacities precluded adequate refraction in three patients (ages, 34, 50,and 57 years), including the two oldest ones. The corneal radius of

From the 1Department of Ophthalmology and 2 Division of ChildNeurology, Department of Pediatrics, Helsinki University Central Hos-pital, Helsinki, Finland; the 3 Department of Medical Genetics, TheFinnish Family Federation, Helsinki, Finland; 4Deceased.

Supported by grants from The Eye Foundation of Finland; The UllaHjelt Foundation, Finland; and the Helsinki University Central HospitalResearch Grant.

Submitted for publication May 31, 2001; revised November 9,2001; accepted November 27, 2001.

Commercial relationships policy: N.The publication costs of this article were defrayed in part by page

charge payment. This article must therefore be marked “ advertise- ment ” in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Paula Summanen, Department of Ophthal-mology, Helsinki University Central Hospital, Haartmaninkatu 4 C, PL220, FIN-00029 HUS, Helsinki, Finland; paula.summanen@hus..

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curvature and corneal power in the two main meridians were mea-sured by automated keratometry (RK; Canon Inc., Tokyo, Japan, 17patients; and KM-500; Nidek Co., Gamagori, Japan, 3 patients). A-scanbiometry was performed in supine patients under cycloplegia to de-termine the axial length, anterior chamber depth, and lens thickness(Ultrasonic Biometer 810; Humphrey Instruments, San Leandro, CA, 18patients; CompuScan L; Storz, St. Louis, MO, 2 patients). The mean of two keratometry and ve biometry readings was used in statisticalanalysis. No biometry (ages, 2 and 21 years) and keratometry readings(ages 39 years) were obtained from two subjects, respectively, becauseof fear of equipment and dif culty in xation. A complete data set wasavailable for 15 patients.

Fundus changes related to axial myopia were determined in all eyes with binocular indirect ophthalmoscopy. 14,16,17 A Goldmann three-mirror contact lens examination was possible in 10 patients (age range,15– 46 years). The presence or absence of myopic spectacle correctionbefore the age of 30 was determined in all parents who could becontacted.

Statistical MethodsComputations were performed by computer (SPSS, ver 9.0.1; SPSS Inc,Chicago, IL; Prism 3; GraphPad Software, San Diego, CA; and Stat- Xact-3; Cytel Software, Cambridge, MA). Mean SD and median with range are reported as summary statistics, which were calculated inpatients who were more than 10 years of age.

The age of the patient and all refractive components analyzedfullled the assumption of normal distribution, as assessed by the

Kolmogorov-Smirnov test (Table 1).18

Consequently, intereye correla -tions and interrelationships between the age and refractive compo-nents were analyzed with the parametric Pearson product momentcorrelation and linear regression. 19 The intereye correlation was high for all variables (Table 1), and one eye of each patient (except one whohad unilateral phthisis) was randomly chosen for statistical analysis onthe basis of random number tables.

Because many refractive errors were high, the refraction data wereconverted to the cross-cylinder notation and vertexed to the cornealplane. 20 The spherical equivalent and average keratometry reading were calculated as the mean of the power in the two main meridiansand the cylinder power as the difference between powers in thesemeridians. To obtain the mean cylinder power and axis, the cylinder data were converted to the Cartesian coordinate system and a double-angle, plus-cylinder axis plot was used to display the aggregate astig-matism data. 20

The relative lens (center) position was calculated as the sum of theanterior chamber depth and half of lens thickness, and the vitreouslength as the difference between the axial length and the sum of anterior chamber depth and lens thickness. The ratio of axial length tocorneal radius of curvature was calculated. Lens power was modeledby calculating the predicted power of an intraocular lens that wouldproduce the observed spherical equivalent of refraction by the Hoffer Q theoretical formula. 21,22

The contribution to total myopia of refractive and axial compo-nents was analyzed by two methods. The spherical equivalent waspredicted by multiple linear regression based on keratometry andbiometry readings. 19 The predicted change in spherical equivalentcaused by deviation of the corneal power and axial length from thepopulation means of 42.8 D and 23.5 mm, respectively, was calculated(assuming that 0.45 mm corresponds to 1.0 D of axial myopia 14 ). Any deviation of predicted from observed spherical equivalent was attrib-uted to lens power.

R ESULTS

Cycloplegic Refraction Of 19 patients who underwent refraction, 18 had myopia and14 had at least 1 D of astigmatism (the latest known refractionof the three patients with media opacities ranged from 8.5 to

13 D). The mean spherical equivalent at the corneal plane was 9.35 3.35 D; Table 1, and the mean cylinder power and axes of the right and left eyes were 1.71 D 107°and 1.70 D 81°, respectively, vertexed to the cornealplane (Fig. 1). The median anisometropia was 0.53 0.57 D;Table 1.

The spherical equivalent tended to decrease (myopiatended to increase) with age (Fig. 2A; r 0.443, P 0.057Pearson product moment correlation), whereas the cylinder power did not correlate with age ( r 0.250, P 0.30).

Biometry and Keratometry Related to AgeThe axial and vitreous lengths (Table 1) were longer than themean for the emmetropic eye of a young adult (23.5 and 16.2mm, respectively) 23 in 14 of the 19 patients (74%; 95% con -dence interval [CI], 49 –91) who underwent biometry and were older than 10 years. The axial length (Fig. 2B; r 0.176, P 0.46) and vitreous length ( r 0.151, P 0.54) did not

T ABLE 1. Age, Refraction, Biometry, and Keratometry in 20 Patients with Cohen Syndrome Mapped to 8q22 ‘

Descriptive StatisticsIntereye

Correlation r ( P )*Normality Test

Statistic ( P )†Mean SD Median (Range)

Age (y) 33 12.6 34 (14 –57) — 0.14 (0.76)Vertexed refraction (D)

Spherical equivalent 9.35 3.35 11.08 ( 2.65 to 15.92) 0.98 ( 0.001) 0.15 (0.78) Anisometropia 0.53 0.57 0.36 (0.0 –1.89) — 0.23 (0.06)

Biometry (mm) Axial length 23.9 1.38 24.0 (21.4 –26.0) 0.82 ( 0.001) 0.14 (0.80) Anterior chamber depth 2.5 0.46 2.4 (1.8 –3.4) 0.89 ( 0.001) 0.15 (0.73)Lens thickness 4.9 0.63 4.9 (4.2 –6.0) 0.51 (0.036) 0.22 (0.29)Relative lens position 4.9 0.32 4.9 (4.4 –5.5) 0.65 (0.005) 0.15 (0.75) Vitreous length 16.6 1.18 16.7 (14.5 –18.4) 0.66 (0.004) 0.14 (0.84)

KeratometryMean corneal radius (mm) 7.3 0.27 7.3 (6.9 –7.7) 0.71 (0.001) 0.15 (0.72)Mean corneal power (D) 45.63 1.66 45.73 (43.12 –48.52) 0.72 (0.001) 0.15 (0.75) Axial length/corneal radius (ratio) 3.28 0.20 3.35 (2.83 –3.60) 0.88 ( 0.001) 0.15 (0.77)

Modeled lens power (D)Hoffer Q power 30.30 4.60 28.62 (22.75 –37.00) 0.91 ( 0.001) 0.20 (0.54)

Patients were 10 years old or older. Data are for one randomly chosen eye.*Pearson product moment correlation, two-sided.

†Kolmogorov-Smirnov test, two-sided.

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correlate with age. The anterior chamber depth was less andthe lens thickness more than the mean for the young adult eye(3.6 and 3.6 mm, respectively) 23 in all 19 patients (95% CI,82–100). The anterior chamber depth decreased (Fig. 2C; r

0.727, P 0.001) and the lens thickness increased (Fig. 2D;r 0.789, P 0.001) signi cantly with age. The relative lensposition (Table 1) did not correlate with age ( r 0.236, P 0.33).

The mean corneal power was higher and the radius of curvature smaller (Table 1) than the average for the em-metropic eye of a young adult (42.8 D and 7.79 mm, respec-tively) 23 in all 18 patients who underwent keratometry and were older than 10 years (100%; 95% CI, 81 –100). The cornealpower increased (radius decreased) with age (Fig. 2E; r

0.513, P 0.021). The ratio of axial length to corneal radius was higher than 3.0 in all but one of 17 patients in whom itcould be calculated, and all but one of 20 patients who underwent keratometry had more than 1.0 D of corneal cylinder (Table 1), the mean power and axis of which were 2.57 D93° and 3.09 D 92° in the right and left eyes, respectively (Fig. 1). The corneal cylinder power did not correlate with age( r 0.030, P 0.90).

The lens power modeled by the Hoffer Q formula rangedfrom 22.75 to 37.0 D (Table 1). It was higher than the meanpower for the emmetropic young adult lens (23.1 D) 23 in allbut one of the 14 patients in whom it could be calculated and who were older than 10 years (93%; 95% CI, 66 –100). Lenspower was unrelated to age (Fig. 2F; r 0.038, P 0.89).

FIGURE 1. A double-angle, plus-cylinder plot of total ( A , B ) and cor-neal ( C, D ) astigmatism in the right ( A , C ) and left ( B, D ) eyes of 19Finnish patients with Cohen syndrome mapped to chromosome 8q22.The open circle (centroid) shows the mean cylinder power and axis.

FIGURE 2. Correlation between ageand ( A ) vertexed spherical equiva-lent, ( B ) axial length, ( C ) anterior chamber depth, ( D ) lens thickness,( E ) average corneal power, and ( F )modeled lens power in 22 Finnish patients with Cohen syndromemapped to chromosome 8q22 (two-sided Pearson product moment cor-relation). Lines are linear regressions with 95% CIs. Age correlated inversely with anterior chamber depth and correlated directly with lensthickness and corneal power.

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Correlation between Spherical Equivalent and Refractive ComponentsThe spherical equivalent decreased (myopia increased) with increasing axial length (Fig. 3A; r 0.513, P 0.035), vitreous length ( r 0.592, P 0.016), and corneal power (Fig. 3B; r 0.508, P 0.037). It did not correlate with corneal cylinder power ( r 0.042, P 0.86), anisometropia( r 0.207, P 0.42), anterior chamber depth ( r 0.273, P 0.29), lens thickness ( r 0.232, P 0.39), relative lensposition ( r 0.158, P 0.56), and modeled lens power ( r

0.329, P 0.23).

Correlation between Refractive ComponentsThe axial length did not correlate with corneal power (Fig. 3C;r 0.104, P 0.68), whereas the modeled lens power

decreased with increasing axial length (Fig. 3D; r 0.564, P 0.029). The anterior chamber depth ( r 0.155, P 0.51)and the lens thickness ( r 0.266, P 0.27) were also unre-lated to the axial length. The anterior chamber depth de-creased with increasing lens thickness (Fig. 3E; r 0.746, P 0.001) and with decreasing corneal radius of curvature(Fig. 3F; r 0.694, P 0.001), but it did not correlate with theother variables studied. The lens thickness correlated inversely with the corneal radius of curvature (Fig. 3G; r 0.542, P 0.025). The modeled lens power increased with decreasingrelative lens position (anterior shift of the lens center; r

0.621, P 0.018), and it also tended to increase with cornealpower (Fig. 3H, r 0.475; P 0.074). It did not correlate with lens thickness ( r 0.224, P 0.44).

A graph of the contribution of anterior chamber depth, lensthickness, and vitreal-to-axial length in patients of increasing

FIGURE 3. Correlation between re-fractive components in 22 Finnish patients with Cohen syndromemapped to chromosome 8q22. ( A ) Axial length and ( B ) average cornealpower against spherical equivalent;axial length against ( C ) average cor-neal power and ( D ) modeled lenspower; ( E ) lens thickness and ( F ) av-erage corneal radius of curvatureagainst anterior chamber depth; ( G )lens thickness against average cor-neal radius of curvature; and ( H )modeled lens power against averagecorneal power (two-sided Pearsonproduct moment correlation). Linesare linear regressions with 95% CIs.Spherical equivalent correlated inversely with axial length and cornealpower, axial length with lens power,and anterior chamber depth with lens thickness, whereas corneal ra-dius of curvature correlated directly with anterior chamber depth and inversely with lens thickness.


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age with Cohen syndrome (Fig. 4) emphasizes that age-relatedchange took place in the anterior segment, in which lensthickness increased at the expense of decreasing anterior chamber depth, without systematic change in axial or vitreouslength.

Multiple Linear Regression of Spherical Equivalent Multiple linear regression indicated that axial length ( P

0.001) and corneal power ( P 0.001) were strong indepen-dent predictors of the spherical equivalent (Table 2). A multi- variate model including these two variables was estimated toexplain 72% of observed spherical equivalent ( R2 0.724; Fig.5A). The lens thickness ( P 0.23), anterior chamber depth

( P

0.72), and relative lens position ( P

0.25) did notimprove prediction signi cantly ( R2 0.727 – 0.785). Modeledlens power could not be legitimately entered into the model,because it was a derivative of the axial length and cornealpower.

Analysis of Refractive versus Axial Myopia Analysis of deviation from the mean of normal young adultssuggested that among patients with Cohen syndrome with alow-to-moderate grade myopia of 1 to 10 D, a short or relatively normal axial length is associated with a disproportionately high corneal and lens power, making the myopia mainly refractive(Figs. 5B–D). In high-grade myopia of more than 10 D, the axiallength is often moderately increased but is never compensated

for by decreased corneal and lens power. Thus, myopia waspredicted by a refractive and an axial component in this sub-group (Figs. 5B –D).

The quantitative contribution to total myopia of corneal andlens power and axial length was modeled by calculating thepredicted change in refraction caused by deviation from mean values for the young adult human eye (Fig. 6). In this analysis,the mean proportion of total myopia explained by dispropor-tionately high lens power was 55% (95% CI, 44 – 65), whereasdisproportionately high corneal power and axial length ex-plained 23% (95% CI, 16 –30) and 22% (95% CI, 11 –34) of totalmyopia, respectively. Thus, a mean of 78% (95% CI, 66 – 89) of total myopia was refractive. Whereas lens and corneal power always contributed to myopia, a short axial length decreased itin three patients and the contribution of axial length to totalmyopia was negligible ( 10%) in three other patients (Fig. 6).

Increased axial length accounted for a major proportion( 40%) of total myopia in four eyes (Fig. 6).

Family History of Early-Onset Myopia Presence or absence of juvenile and young-adult – onset myopia was known in parents of 13 patients (59%) from 10 families.The mother in one family and both parents in two families hadhad myopia of 2.0 to 6.0 D since the ages of 18 to 20 years.

Of their offspring, one was estimated to have 46% axial myopia(Fig. 6; patient 3), one had a negligible axial component (pa-tient 4), and the axial length of the third patient could not bereliably measured (patient 1).

Retinal Changes Related to Axial Myopia None of the patients had any central (myopic crescent, lacquer cracks, Fuchs spots, posterior staphyloma) or peripheral retinaldisease (lattice degeneration, white without pressure, retinalbreaks, retinal dialysis) associated with myopia. One patienthad a blind eye due to long-standing retinal detachment, attrib-uted to injury.

DISCUSSION

Finnish patients with Cohen syndrome mapped to chromo-some 8q22, who had had moderate to high myopia fromchildhood, had eyes that showed a higher corneal and lentic-ular power, a shallower anterior chamber, and a thicker lensthan the average eye of a young adult, but their axial length differed little from that of an emmetrope of similar age. 14,23

Closer analysis indicated that three quarters of the myopia wasrefractive, especially lenticular. Correlation between refractionand age in cross-sectional analysis suggested that the myopia was progressive, which has been con rmed by longitudinalanalysis. 12 Progression was mainly due to age-related increasein corneal power. This is contrary to the rule that juvenile andearly-onset adult myopia are axial in type. 14,22 In juvenilemyopia, the corneal power is greater than average, but axiallength and anterior chamber depth should also be higher, andthe lens power should not differ from that of emmetropes. 23 Incontrast, late-adult – onset myopia often is refractive. 14 Cohensyndrome represents an unusual combination of refractive my-opia and young age.

Frequent anterior segment abnormalities in patients with Cohen syndrome point to the possibility that, in them, myopiamay result from dysgenesis or degeneration of the iris, ciliary body, zonules, and lens. Iridodonesis, 12 together with in-creased thickness, apparent spherophakia, and anterior shift of the lens, suggests that zonular laxity and lens subluxation may act as mediators. This may be due to generalized atrophy of theuvea or a speci c molecular defect of the zonules. In Marfansyndrome, zonular laxity is caused by abnormal brillin, a 350kDa glycoprotein that is a major constituent of the lens capsuleand zonules. 24 This leads to stunted lens growth, spheropha-kia, iridodonesis, and cataracts, 24,25 which seem to be part of Cohen syndrome as well. However, in Marfan syndrome the

T ABLE 2. Multiple Linear Regression of the Spherical Equivalent inCohen Syndrome

Coefcient (SE) 95% CI t P

Constant 107.81 (21.75) 60.42 to 155.20 4.96 0.001 Axial length 1.54 (0.37) 2.36 to 0.72 4.10 0.001Mean corneal

power 1.77 (0.42) 2.68 to 0.87 4.27 0.001

R2 0.724.

FIGURE 4. Contribution of anterior chamber depth, lens thickness,and vitreous length to axial length in 19 Finnish patients with Cohensyndrome mapped to chromosome 8q22. Lens thickness increased with age at the expense of decreasing anterior chamber depth.


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cornea attens rather than steepens, and frank luxation of the

lens is typical, unlike in Cohen syndrome.12,25

Iris atrophy, which had been observed in eight of our patients, 5,12 possibly contributes to the increased lens thick-ness and the anterior shift of the lens diaphragm. Experiments

with surgically aniridic rhesus monkeys show that the nonac-

commodated lens becomes thicker and is shifted anteriorly if the iris is removed and no longer in contact with the lens. 26

The investigators speculated that an intact iris diaphragm isnecessary to keep the lens in position and to atten it.

The corneal radius of curvature, which was always smaller than average, decreased with age, and the anterior chamber paradoxically became progressively shallower with decreasingcorneal radius. The anterior chamber depth should correlate with the axial length, 14 but this was not true in Cohen syn-drome. Perhaps a concomitant decrease in relative diameter of the ciliary ring took place, which may have added to zonular laxity and anterior shift of the lens. 27 A notable age-relatedchange was an increase in lens thickness, which added todecreasing anterior chamber depth. In myopia, the anterior

chamber is usually deep,14

but Cohen syndrome has the po-tential to cause primary angle-closure glaucoma in high myo-pia, as happened in both eyes of one of our patients, a 42-year-old woman with myopia of 12.0 D. 12

Cohen syndrome shares these features with retinopathy of prematurity (ROP), another condition characterized by fre-quent myopia. Several studies agree that an anterior chamber that is more shallow and a lens that is thicker than averagecharacterize ROP, especially if it has advanced to stage 3. 28,29

Presumably, scarring related in part to treatment causes ante-rior shift of the lens diaphragm and relaxation of thezonules. 29,30 However, in contrast to Cohen syndrome, noconsistent abnormality of corneal power has been docu-mented, 29 and progression of myopia usually ends before 3 years of age. 30,31

FIGURE 5. Refractive and axial com-ponents of myopia in 15 Finnish pa-tients with Cohen syndrome mappedto chromosome 8q22. ( A ) Observedspherical equivalent versus that pre-dicted by multiple linear regressionof average corneal power and axiallength. ( B ) Axial length and averagecorneal power, ( C ) axial length andmodeled lens power ( D ), and aver-age corneal power and modeled lenspower relative to mean values in a young-adult emmetropic eye, dividedby grade of myopia. Corneal and lenspower were always higher than aver-age, whereas axial length varied fromshort to long.

FIGURE 6. Estimated contribution of corneal power, lens power andaxial length to the spherical equivalent in 14 Finnish patients with Cohen syndrome mapped to chromosome 8q22. Observed sphericalequivalent is the arithmetic sum of the three elements; when all threecomponents contribute to myopia, the observed spherical equivalentcan be read directly.


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Some patients with Cohen syndrome have had microcor-nea, 1,5,32,33 suggesting corneal dysgenesis, and microphthal-mia. 1,32,34 In one patient described by Cohen himself, themicrophthalmia was associated with a coloboma that involvedthe anterior and posterior uvea, 1 and one patient in another series had bilateral colobomatous microphthalmia. 32 None of the Finnish patients had either typical microphthalmia or acoloboma, even if they had small anterior segments. 12 It is

possible that different mutations of COH1 will be found toaccount for different phenotypes of Cohen syndrome, 9,11 or that microphthalmia is a secondary defect in Cohen syndrome.

Modeled lens power tended to be lower when axial length was longer, suggesting some degree of emmetropization. Ap-parently, the lens also compensated for approximately one half of corneal astigmatism. Biomicroscopy and lens opacitometry showed frequent incidence of early nuclear sclerosis in our patients with Cohen syndrome. 12 The lens thickness did notpredict myopia by multiple linear regression, and lenticular myopia in Cohen syndrome probably is related more to anincrease in the lens radius of curvature and the refractiveindex. 14 Unexpectedly, lens power was unrelated to age in our series.

By comparing components of refraction to population av-erages, we could conclude that increased axial length wasclinically signi cant in the myopia of Cohen syndrome in only 4 of 14 patients. When axial length was long, the myopia wasalways high. Notwithstanding the predominance of refractivemyopia, axial length correlated with spherical equivalent, andthe axial length in addition to the corneal power was a strongindependent predictor of the spherical equivalent by multiplelinear regression. Possibly as evidence of attempted em-metropization, shorter than average axial length compensatedfor increased corneal and lenticular power in three eyes. Inmost patients, the cornea was steep in relation to the axiallength, however, and caused increased myopia.

Long axial lengths can be induced in animals subjected to visual deprivation. 35 In Cohen syndrome, vision usually re-

mains normal until the age of 10, and even when visual eldsconstrict and impair distance vision, reasonable reading visionis retained until the age of 30 to 40 years. 12 Visual deprivationis not likely to explain the myopia of Cohen syndrome. Tape-toretinal degeneration and chorioretinopathy associate with axial myopia in many syndromes, such as gyrate atrophy, 36

progressive bifocal chorioretinal atrophy, 37 long-chain 3-hy-droxyacyl-CoA-dehydrogenase de ciency, 38 and several typesof retinitis pigmentosa. 39 The retinal pigment epithelial mot-tling, choroidal atrophy, narrow retinal arterioles, and an iso-electric electroretinogram in Cohen syndrome bear resem-blance to symptoms in retinitis pigmentosa. 12 However, noneof our patients had retinal changes associated with axial myo-pia, thought to be the only reliable method of distinguishing

eyes in which the posterior segment has expanded beyond thatof normal growth. 14,16

The fairly normal range of axial lengths in our series sug-gests that elongation of the eye is probably independent of mutated COH1 and is determined by other factors. Similarly, itis postulated that axial myopia in premature infants with ROPmay be unrelated to retinopathy. Presumably, the refractiveerror of parents in uences the axial component. This ndssome support in the fact that many siblings with Cohen syn-drome have similar refractions. 1,10,34,40 – 48 In our series, theparents of two siblings who had myopia of 11 to 12 D hadmyopia of 2.0 to 6.0 D, and one of the siblings had notableaxial myopia. The refraction of the parents of other children who had notable axial myopia remained unknown. A family has been reported in which the child had myopia of 14.0 Dand the parents of 5.0 and 7.0 D. 13 Intuitively, parental

hyperopia may lead conversely to a shorter than average axiallength and may counterbalance myopia in Cohen syndrome.

Hypermobility of joints, skeletal and postural anomaliessuch as long and slender hands and ngers, cubitus valgus,genu valgum, pes planovalgus, scoliosis, and kyphoscoliosis arecommon in Cohen syndrome, and mitral valve prolapse anddecreased left ventricular function are occasionally ob-served. 15,34 These features hint that there is a generalized

disorder of connective tissue in Cohen syndrome.34,49,50

Myo-pia and cataract are common to several collagen mutations,such as Stickler syndrome, Wagner disease, and Kniest dyspla-sia.51,52 However, the myopia in these connective tissue syn-dromes is axial in type and is often associated with an in-creased risk of retinal detachment, 53 which is not the case inCohen syndrome. 12

All evidence taken together, the myopia in Finnish patients with Cohen syndrome mapped to chromosome 8q22 is pre-dominantly refractive and due to a disproportionately high power of the cornea and the lens, but it may be modulated by an axial component that is independent of COH1 , the Cohensyndrome gene. The refractive components in Cohen syn-drome resemble those in late-adult – onset myopia, 14 a fact thatmay be related to dysgenesis, degeneration, and prematureaging of the anterior segment of the eye in this syndrome.Future identi cation of the COH1 gene is likely to reveal aspeci c molecular defect that can lead to nonaxial high myo-pia. Regardless of its exact pathogenesis, correction of myopiais indicated in Cohen syndrome. Our patients enjoyed wearingspectacles as a rule, and correction of myopia and astigmatismaffected their development positively. 12,15

Acknowledgments

The authors thank the patients and their parents and guardians for their collaboration in making this study possible and the Department of Ophthalmology, University of Oulu, for providing the facility for ex-amination of three of the patients.

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