Clinical Section

Autosomal recessive plana. A clinical and genetic study of 78 cases in Finland Henrik Forsius1, Margareta Damsten1, Aldur W.Eriksson1, Johan Fellman1, Sinikka Lindh1 and Esa Tahvanainen2

1The Folkha¨lsan Institute of Genetics, Helsinki, 2Department of Biochemistry, National Institute of Public Health, Helsinki, Finland

ABSTRACT. Purpose: To review the literature of autosomal recessive cornea plana (RCP) and ing in different parts of the world (Sigler- to perform a clinical and genetic study on this disorder in Finland. The 78 Finnish Villanueva et al. 1997). RCP patients represent the majority of RCP cases worldwide; outside Finland only Cornea plana with autosomal recessive 35 cases have been reported. inheritance (RCP) is a more severe anom- Methods: Families with RCP, particularly in northern Finland, have been followed aly than the dominant form. The most up by the senior author since the 1950s and extensive genealogical studies have been typical symptoms are refractive corneal made. power strongly reduced to about 25–35 D, slight microcornea, a widened limbus Results: The most typical symptoms are greatly reduced corneal refraction, 25–35 zone, strong hyperopia, a shallow an- dioptres, causing strong hyperopia, slight microcornea, an extended limbus zone, a terior chamber and a deep central cor- central, deep and a marked , seen even before the age neal opacity. Broekema (1909) was the of 20. We present a pedigree comprising 33 affected persons with cornea plana. We first to describe RCP in a single case and have mapped the two genes for the dominantly and the recessively inherited type of Ru¨bel (1912) was the first to note its fam- cornea plana to the same region on the long arm of chromosome 12, (12q21). ilial character. Conclusions: In northern Finland RCP has a higher frequency than elsewhere, prob- We have found in the literature only 18 ably as a result of a strong founder effect in the population that arrived in these articles, (not including those from Fin- regions approx. 400 years ago. The strong accumulation of this rare disease in these land, which will be discussed separately) isolated areas and the strong genealogical connections between different families describing a total of 19 single cases of the with RCP, suggest that probably all the Finnish RCP cases are caused by the same recessive type of cornea plana in which mutation. the patients were not apparently related to each other (Berg 1931; Broekema Key words: anomaly of cornea – cornea plana, autosomal recessive and dominant heredity – 1909; Dada et al. 1988; Ferdinando 1941; – Finland, population structure. Cockburn 1944; Fishman et al. 1982; Focosi 1967; Friede 1921; Granstro¨m Acta Ophthalmol. Scand. 1998: 76: 196–203 1951; Henry 1962; Malik et al. 1965; Copyright c Acta Ophthalmol Scand 1998. ISSN 1395-3907 Nath et al. 1964; Razemon et al. 1971 (two cases); Rizzini & Scialdone 1966; Sharkey et al. 1992; Shorb 1972, Swett ornea plana is a rare hereditary an- 1992). Some authors (Bloch 1965, Elliot 1924; and Velicky & Vrabec 1951). C omaly with both autosomal domi- et al. 1985) have used the term sclerocor- In the solitary cases which Berg (1931) nant (CNA1,MIM 121400) and auto- nea for both primary and secondary cor- and Dada et al. (1988) described, the par- somal recessive (CNA2,217300) inherit- nea plana. ents were consanguineous. Many of the ance (McKusick 1994). Our team has In autosomal dominantly inherited articles listed above mention that no mapped the gene for both types of cornea cornea plana, visual acuity is normal, the other case of cornea plana had been plana to the same region on the long arm corneal parenchyma is clear, the limbus found in the family. of chromosome 12, (12q21) (Tahvanainen zone is abnormally broad, and the cor- In addition to Ru¨bel (1912) familial et al. 1996). A flat cornea has also been neal refraction is only about 3–7 dioptres cases of recessive cornea plana have described to occur as a consequence of (D) weaker than the normal corneal re- been presented by Felix (1925), Pur other malformations of the eye or to be fraction, which is about 43 D, (a cornea (1956), Itin (1966) (the same patients part of syndromes with a different her- with a radius of 7.5 mm has a refractive were also in greater detail described the edity, such as Ehlers-Danlos disease type power of 45 D). Autosomal dominant same year by Bloch (1965)), Justa et al. VI (Cameron 1993) and posterior amor- cornea plana in two or more generations (1984) and Grimm et al. (1995), a total phous (Roth et al. has been described in only 9 families liv- of 16 cases.

196 thologically low corneal refraction, this with certainty (Broekema 1909; Pur 1956; would have been aboutπ13 D, because Velicky and Vrabec 1951; Cockburn the normal corneal refraction is about 43 1944; Dada et al. 1988). D and in recessive cornea plana about 30 The thickness of the cornea was meas- D. One reason why the total refraction is ured by Justa et al. (1984), Dada et al. smaller than theoretically expected could (1988), Shorb (1972) and Sharkey et al. be that the axial length of the bulb is (1992) in altogether 14 eyes (range 0.53– greater than normal. This, however, had 1.12 mm). In normal eyes the cornea is been measured in only seven eyes among thinnest in the centre, but in the cases of the solitary cases, mean 22.9 mm, varying cornea plana with a central disc it is thin- between 21.5 and 25 mm (Dada et al. nest at the border of the central corneal 1988 for whose case the corneal refrac- opacity. tion values are missing; Fishman 1982; In cornea plana the anterior chamber Shorb 1972, Sharkey et al. 1992). The is shallow. Dada et al. (1988) and Sharkey mean axial length for the familial cases et al. (1992) measured 0.8 mm in the eyes was 24.0 mm in the 12 eyes investigated, that they described. Itin (1965) gives the varying between 22.0 and 30.9 mm (Itin values 1.9, 2.0 and 2.1 mm for the three 1965; Justa et al. 1984). The highest my- eyes measured by him. The values include opic value, ª8.5 D, was noted in the eye the cornea. Justa et al. (1984) measured with the greatest axial length (Itin 1966). 9 eyes for which the value was between For 25 eyes in the solitary cases, the 1.0 and 1.4 mm. mean refraction was π8.08 D (range ª4.5- In RCP the corneal diameter is, as a 16 D). In 10 eyes the hyperopia was 10 rule, smaller than normal or at least gives Fig. 1. Map of Finland in 1900 containing the π π locations of birth of the grandparents of our D or more. The mean refraction of the 29 that impression, because the superficial patients. eyes in the familial cases was π9.35 D scleral tissue encroaches 1–2 mm upon (range ª8.5 ... π14.25 D); 18 eyes had a the cornea. It is difficult to give a mean, total refraction of π10 D or more. Among because often it is not clearly stated in the solitary cases, was seen in the literature whether the measurement Ru¨bel (1912) described three brothers 14 eyes (0.5 to 4 D). Of these, two were given is of the breath of the clear zone or with cornea plana. The healthy parents against the rule. In 22 eyes among the fam- of the total corneal diameter. had altogether 10 children. Pur (1956) de- ilial cases, astigmatism was noted (range anomalies in the form of iris hy- scribed two brothers whose parents were 0.5 to 4 D). In eight eyes the astigmatism poplasia, displacement of the and healthy. Felix (1925) and Itin (1966) also was against the rule. peripheral or anterior iris synechiae described two affected brothers. In both The visual acuity ranged between 0 and were mentioned by Henry (1962), Raz- families the parents were related. Justa et 1.0, the mean being 0.32 for the 32 eyes of emon et al. (1971), Fishman (1982) and al. (1984) found cornea plana in a woman the solitary cases and 0.29 for the 26 eyes Granstro¨m (1951) in their reports of and her four children. The authors list among the familial cases. One eye was solitary cases, and Ru¨bel (1912) (two their cases as recessively inherited be- completely blind among the solitary cases cases), Pur (1956) and Itin (1966) (one cause all those affected have findings and two eyes among the familial cases. case) among their familial cases. A typical of recessive cornea plana. The central corneal opacity that is marked arcus senilis, already apparent Two sisters, 2 and 10 years old, with typical of recessive cornea plana was ob- at an early age, is a typical sign of cor- posterior amorphous corneal dysgenesis, served in 10 of the 13 familial cases pub- nea plana, both in the dominantly and presented by Grimm et al. (1995), also lished by Itin (1966), Felix (1925), Justa in the recessively inherited form. This meet the criteria for RCP. The corneal re- et al. (1984) and Grimm et al. (1995). In has been described or can be evaluated fraction in these patients varied between the solitary cases the central corneal opa- from photographs in at least 14 articles 24.2 and 36.0 D. The parents had normal city was rarely described: only in six cases referred to above. eyes. The most significant sign of RCP is the low corneal refractive power. In publi- Table 1. The incidence of diagnosed cases with autosomal recessive cornea plana in different cations describing solitary cases this has regions of Finland. Province number 1 in Figure 1 is the province of Lapland and number 2 is been noted by 14 authors, describing al- the province of Oulu. In this table the numbers for provinces 3, 4, 5 and 6 are pooled to SW together 15 cases. For one eye, which is Finland and for provinces 7, 8 and 9 to SE Finland. The incidence is measured as the number of not included in our statistics, Henry grandparents per 100 000 inhabitants. The population data and the areas were recorded in 1900, (1962) gives the figure ‘‘less than 30’’. The this date being close to the average time of the births of the grandparents. mean corneal refraction in the 28 eyes of Subregions Number of Inhabitants Incidence Area (km2) Inhabitants the above-mentioned authors was 32.0 D of Finland grandparents in 1900 of CP in 1900 per km2 horizontally and 33.6 D vertically and in the 28 eyes of the six articles concerning SW Finland 24 1506642 1.59 90535 16.64 familial cases it was 26.6 D horizontally SE Finland 34 925021 3.68 84430 10.96 and 26.7 D vertically. Province of Oulu 71 221666 32.03 65091 3.41 Prov. of Lapland 34 59233 57.40 91888 0.64 If the only part of the eye responsible Total Finland 163 2712562 6.01 331944 8.17 for the total refraction had been the pa-

197 tries. Finland, however, forms an excep- mented that this part of Finland was per- tion. Our team has found the majority of manently populated as recently as the last all cases and the largest pedigrees that four centuries by Finns who, having large have been published (Forsius 1961; For- families, rapidly increased in number. sius & Lehmann 1962; Eriksson et al. Probably, also most of the cases of cor- 1973; Tahvanainen et al. (1995a,b, 1996). nea plana diagnosed in other parts of The reason why cornea plana is relatively Finland are included in this material, be- common particularly in northern Fin- cause the density of ophthalmologists in land, is that the Finnish population is of Finland is high, 1:12000, and our interest recent origin. Finland was populated in anomalies of this type is well known. about 2000 years ago by small groups of We did not always have the opportunity settlers who interbred rapidly, and their for a thorough investigation of the pa- disease genes, among them cornea plana, tients, and the data reported by different multiplied also. As a result more than 30 ophthalmologists differ markedly. The hereditary diseases which are elsewhere consequence of this can be seen in Table rare, among them cornea plana, are rela- 2. Also, some of the old hospital reports tively common in Finland (Nevanlinna could not be found. 1972, 1980; Norio et al. 1973; de la The diagnosis of RCP in solitary cases Chapelle 1993). Probably all Finnish necessitates a flat cornea (∞36 D) with- cases of recessive cornea plana are caused out blood vessels centrally and an ex- by the same mutation. tended limbus zone. If additional symp- This article presents data of 78 cases toms also indicated RCP, a value for cor- Fig. 2. The cornea is thin and the anterior of recessively inherited cornea plana neal refraction higher than 36 D was chamber is shallow in the eye of this six-year- found in Finland. One of us (Forsius) allowed for familial cases. In non-familial old girl. has personally studied 65 of the cases borderline cases chromosome analysis and the reports of the rest have been was performed. The geographical distri- sent to us. bution of cornea plana in Finland can be Congenital ptosis is often mentioned in In 1961 we described 19 affected mem- seen in Fig. 1 and Table 1. The majority patients with cornea plana. The cause is bers of 9 families (Forsius 1961). Later of our cases are familial or were born in probably the missing corneal protrusion. on new cases and pedigrees have been isolated regions where other patients with A convergent squint is also a commonly published (Forsius & Lehmann 1962; cornea plana lived. noted secondary sign. Forsius & von Fieandt 1963; Eriksson et The incidences of cornea plana in dif- al. 1973). In this article we have included ferent regions of Finland are presented in all these cases. Table 1. The incidence is measured as the The majority of the cases have been Patients in Finland found in the northern half of Finland, Autosomal recessive cornea plana is as where we have worked (Oulu University shown above a rare disease in most coun- Eye Hospital). It is historically docu-

Fig. 4. Profile photo of the same eye as in Fig. Fig. 3. An arcus senilis (juvenilis) is already seen in the eye of this 9-year-old girl. The central 3. The cornea has the same curvature as the corneal opacity and the extended limbus zone are also typical of recessive cornea plana. .

198 fraction in normals and in patients with cornea plana is around 13 D. This should theoretically result in a correspondingly strong hyperopia. In fact, the hyperopia is considerably less, on average between 7 and 8 D (Table 2). Therefore, it was inter- esting to include the bulb length in the study. The bulb length was measured in 22 cases and was between 18.4 and 28.0 mm. The flat cornea makes the bulb shorter. If the corneal refraction in CRP is very low, the patient usually also has abnormally high hyperopia but exceptions occur, de- pending mostly on the bulb length. The largest bulb length, 27.4 mm, was meas- ured in a patient with a total refraction of ª5.0 D and a corneal refraction of 38.8 D, and the shortest axial length, 18.4 mm, was seen in an eye with a total refraction of π11.0 D and a mean corneal refraction of Fig. 5. Microcornea, extended limbus zone and large iris synechiae in a 12-year-old boy. 30.67 D. In Fig. 8 we observe statistically significant negative correlations (p∞0.01) between the mean total refraction and the number of grandparents per 100 000 in- autosomal recessive cornea plana. The mean corneal refraction (right eye: nΩ41, habitants. The population data and the normal protrusion of the cornea is lacking rΩª0.372 and left eye: nΩ38, rΩª0.485). areas were recorded in 1900, this date and the limbus zone is abnormally broad Weobserved a nonsignificant negative cor- being close to the average time of the (Fig. 5–7). The cornea is thin (Fig. 2) and relation between the mean total refraction births of the grandparents. After that a it is thinnest outside the central corneal and the bulb length (Fig. 9). In Fig. 8 and strong internal migration started in Fin- opacity (Fig. 6). A central corneal disc was Fig. 9 the numbers of individuals for land. noted in at least 51 patients and, when ob- whom both eyes are included are 36 and served, was usually bilateral. 17, respectively. In spite of the statistically A summary of the statistics of our significant correlations in Figure 8, we ob- series is given in Table 2. serve in both Fig. 8 and Fig. 9 large intra- Results The most prominent sign of cornea and inter-individual variations in the oph- Cornea plana affects the sexes in the plana is the extremely low corneal refrac- thalmological measurements. same proportion. Of the 78 persons tion, the mean being 30.61 D. Visual acuity was rarely normal. This affected in Finland, 38 were males and 40 The difference between the corneal re- was due to the corneal opacities, mostly females. Age at diagnosis varied between 4 weeks and 78 years, with a mean of 23 years. Fig. 2–7 illustrate the signs typical of

Fig. 6. Slit photo of a 16-year-old boy with re- cessive cornea plana. The cornea is thinner outside the central corneal opacity. Extended Fig. 7. Left eye of a 49-year-old male with cornea plana. Extended limbus zone. The 4,5¿4.5 mm limbus zone and marked arcus senilis. central disc forms a plus . Marked arcus senilis.

199 Table 2. Summary statistics of our series. All refraction values are given in dioptres (D). Negative with other anomalies outside the eye. In cylinder values mean astigmatism against the rule. one case, a girl, osteochondritis disse- cans was observed and in a boy a brain Variable n Mean SD Range has been diagnosed. We regard Corneal refraction, horiz. Dx 47 30.21 4.67 19.50 ... 40.50 these findings as coincidental. Corneal refraction, vert. 45 30.94 3.89 15.00 ... 39.00 The pedigree in Fig. 10 shows the Corneal refraction, horiz. Sin 46 30.54 5.05 18.50 ... 44.00 genealogical connections between the Corneal refraction, vert. 43 30.76 4.68 21.00 ... 44.75 sibships with cornea plana from the re- Total refraction, horiz. Dx 71 7.60 4.22 ª3.00 ... 16.00 gion of the Kemijoki river in Lapland Cylinder 68 ª0.13 1.38 ª4.50 ... 2.50 and the sibships from the regions Total refraction, horiz. Sin 70 7.27 4.89 ª6.50 ... 18.00 around the Oulujoki river in the prov- Cylinder 68 ª0.10 1.59 ª7.00 ... 3.00 ince of Oulu (Uleåborg). The genealogi- Corneal diameter, horiz. Dx 35 9.79 0.76 8.00 ... 11.00 cal studies have shown that at least the Corneal diameter, vert. 34 9.91 0.79 8.00 ... 11.50 cornea plana families in the two north- Corneal diameter, horiz. Sin 33 9.86 1.03 7.00 ... 13.00 Corneal diameter, vert. 32 9.98 1.08 7.00 ... 13.00 ernmost provinces, Lapland and Oulu, Visual Acuity Dx 59 0.45 0.29 0.00 ... 1.30 have intermarried for many generations Visual Acuity Sin 58 0.41 0.28 0.00 ... 1.00 and have many common ancestors de- Axial bulb length (mm) Dx 21 23.35 2.32 18.80 ... 26.80 spite the fact that the distance between Axial bulb length (mm) Sin 22 23.53 2.61 18.40 ... 28.00 the two cornea plana clusters is more than 200 km. The parental consanguin- ity is rather remote in some cases, e.g. many of the earliest common ancestors noted as a central disc 4–6 mm in diam- terior synechiae in 14. In a few cases, cen- were born in the 17th century in the eter attached to Descemet’s membrane. tral synechiae have been seen or small same parish and had even the same sur- Some eyes were blind at birth and in three white or dark spots on the corneal endo- name. Many of the ancestors were obvi- eyes the cause was closed-angle glau- thelium, resembling old precipitates. ously related, although we have not coma. The mean visual acuity for 117 They are probably remnants of earlier sy- been able to confirm the kinships be- eyes was 0.43. nechiae. (Fig. 5). tween all of them. In cornea plana, arcus senilis develops In a patient in whom the iris almost One affected female, XI/5 in the pedi- early. The first sign, a partial arcus juven- totally occluded the pupil, a central iri- gree, has given birth to two affected ilis, we have seen at as early an age as dectomy resulted in improved vision. children and one healthy boy. In her own nine years (Fig. 3). In old people a strong Congenital ptosis and convergent sibship of 16 children, four are affected. arcus senilis is often the most prominent squint are often, but not regularly, seen. Among the relatives of the father of the sign of cornea plana. We noted squint in 23 out of 78 cases and two affected children, two cases of cornea Iris anomalies have been observed in notable ptosis in nine cases. plana were also found. They are included 26 cases and, among these, peripheral an- RCP does not seem to be combined in the large pedigree, which when pub- lished in 1973 (Eriksson et al.), included 26 affected persons. Now the pedigree has been enlarged and includes 33 cases; part is published here (Fig. 10).

Discussion From the number presented above, 78 Finnish cases of recessively inherited cor- nea plana compared with the 35 affected found in all other countries together, it is evident that the disease is concentrated in Finland. The sexes are equally affected. The main cause of the inbreeding and consequent accumulation of CRP seems to have been the low density of the popu- lation in northern Finland, still observ- able in 1900 (Table 1). The Finnish cases of cornea plana and the familial cases described in the litera- ture show very typical and similar signs. Fig. 8. There is a statistically significant negative correlation (p∞0.01) between the mean total refraction and the mean corneal refraction (right eye: P nΩ41, rΩª0.372 and left eye: g nΩ38, They include a flat cornea with a corneal rΩª0.485). The number of individuals for whom both eyes are included is 36. In spite of the refractive power of only 25–35 D, causing statistically significant correlations, we observe large intra- and inter-individual variations in the extreme hyperopia of up to 17 D, a ophthalmological measurements. widened limbus zone, a limited diameter

200 eye as dry as possible. Surprisingly, in gonioscopy the chamber angle is mostly found to be clearly open. The lens and the posterior part of the eye are in most cases normal. In the worst case we have seen (Fig. 7 in For- sius 1961), only some remnant of the lens could be found. In this eye a deep horizontal was seen extending across the whole cornea. The same type of keratopathy, but less ad- vanced and not combined with lens anomalies, was seen in both eyes of a boy (XII/3 in Fig. 10). He was nearly blind and attended a school for the visually handicapped. All the severely affected patients we have studied are members of families that include other Fig. 9. There is a non-significant negative correlation between the mean total refraction and the affected persons. bulb length (right eye: P nΩ18, rΩª0.345 and left eye: g nΩ18, rΩª0.39). The number of Often the appearance of the cornea is individuals for whom both eyes are included is 17. We observe large intra- and inter-individual an oval, i.e. when the arcus senilis is ex- variations in the ophthalmological measurements. tremely strong and the limbal vessels from above extend further over the cor- neal surface from above (Fig. 7). When of the cornea, i.e. of the clear zone, and coma in four eyes. In three of them this measuring, however, you see a longer cor- a central deep corneal opacity around resulted in blindness. It is difficult to neal diameter as often vertically as hori- which the cornea is thinnest. obtain reliable values for the tension, zontally. Corneal astigmatism is as often The anterior chamber is flat (Fig. 2) because tonometers are not constructed with the rule as against the rule. The cor- and the risk of closed is for cornea plana. We prefer to use the neal axis is only exceptionally quite verti- greater than normal. We found glau- applanation tonometer and to keep the cal or horizontal. The corneal epithelium

Fig. 10. Pedigree of patients with recessively inherited cornea plana showing genealogical connections between the two concentrations of patients around the rivers Kemijoki and Oulujoki. The consanguinity of the parents X/7 and X/8, and of X/3 and X/12 is not shown in this pedigree.

201 is often uneven and it is not always poss- found, diagnostic problems can occur. congenita in 12 Familien in Finnland. Acta ible to obtain exact measurements of the Chromosomal analysis can be useful for Genet 12: 230–241. corneal refraction. the differential diagnosis of cornea plana. ForsiusH&vonFieandt O (1963). Photokera- Keratometers are not constructed to We were able to exclude four atypical tometry and refraction analysis in congenital cornea plana. Acta Ophthalmol (Copenh) measure a refraction of less than 30 di- solitary cases because they were not as- 41: 609–620. signed to the long arm of chromosome optres and only a few authors, Friede Friede R (1921): Ueber kongenitale ‘‘Cornea (1921), Berg (1931) and Forsius & von 12. plana’’ und ihr Verha¨ltnis zur Mikrokornea. Fieandt (1963), have developed special Klin Monatsbl Augenheilkd 192–203. equipment for this purpose. The best way Granstro¨m KO (1951): A case of cornea plana. is to place a weak plus lens in front of the Acta Ophthalmol (Copenh) 32: 488–489. keratometer, after which you can Acknowledgements Grimm BB, Waring III GO, & Grimm SB measure low corneal refractions. The authors express their grateful appreci- (1995). Posterior amorphous corneal dys- During retinoscopy, it is often noted ations to the cornea plana patients, and to An- genesis. Am J Ophthalmol 120: 448–455. that the refraction from the central cor- ita Tuurala for her excellent genealogical Henry P (1962): A case of congenital cornea plana. Ophthalmologica 143: 141–142, 1962. neal opacity is several dioptres weaker studies and to the foundation Stiftelsen Liv och Ha¨lsa for financial support. Itin W (1966): Longueur axiale de l’oeil chez than that from the area outside this, be- deux fre´res atteints de scle´ro-corne´epe´r- cause the cornea is thinnest at its border iphe´rique avec cornea plana. Ophthalmo- and the disc thus forms a plus lens. The logica 152: 369–377. first authors to discuss the refraction References Justa V, Reis FJP & Juacaba RC (1984): Cor- caused by the central disc were Velicky & nea plana. Rev Bras Ophthalmol 43: 109– Berg F (1931): U¨ ber Variabilita¨t und Korrel- 112. Vrabec (1951). We calculated that theor- ation bei den verschiedenen Abmessungen Malik SRK, Sood GC,Gupta DK & Seth RK etically the disc weakened the refraction des Auges. Graefes Arch Exp Ophthalmol by 1.87 D (Forsius & von Fieandt 1963), 127: 606–639. (1965): Sclero-cornea. Brit J Ophthalmol 49: but we found a difference of up to 7 D in Bloch N (1965): Les differents types de sclero- 60: 602. McKusick VA (1994): Mendelian Inheritance refraction using retinoscopy. When pre- cornee, leurs modes d’he´re´dite´, et les malfor- in Man. Baltimore, Johns Hopkins Univer- scribing spectacles, we prefer to base mations congenitales concomitantes. J Genet Hum 14: 133–172. sity Press, 11th edn. them on the subjective refraction when- Nath K, Nema HV & Shukla BR (1964): Evol- ever possible, but suggest that children Broekema JC (1909): Bijdrage tot de Kennis der Hypermetropie, Dissertation, s-Gravenhage, ution of certain corneal malformations should be given lenses which are 3–4 D Amsterdam. (Studies on a case of microcornea plana con- weaker than the objective values obtained Cameron JA (1993): Corneal abnormalities in genita with atrophy of iris and glaucoma). with cyclophlegica from the area outside Ehlers-Danlos syndrome type VI. Cornea Acta Ophthalmol (Copenh) 42: 78–83. the disc. Contact lenses have been tried 12(1): 54–59. Nevanlinna HR (1972). The Finnish popula- in many cases, but have usually been de la Chapelle A (1993) Disease gene mapping tion structure. A genetic and genealogical abandoned. They cause marked irritation in isolated human populations: the example study. Hereditas 71: 195–236. or do not stay in place. 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Cor- herited cornea plana does not cause ipertensione endocranica. Boll.d‘Oc. 14: nea 11(2): 163–172. problems, but it has to be remembered 465–474. Ru¨bel B (1912): Kongenitale familia¨re that in the same family the severity of the Fishman AJ, Ackerman J, Kanarek I, Novets- Flachheit der Kornea. Klin Monatsbl Aug- disease may vary greatly and so may the ky A, Ackerman E & Schiowitz S: (1982): enheilkd 50: 427–433. difference between the eyes of the same Cornea plana: A case report. Annals of Sharkey JA, Kervick GN, Jackson AJ & Johnston PB (1992). Cornea plana and patient. In solitary and atypical cases of Ophthalmol 14: 47–48. Focosi F (1967): Cornea plana e sclerocornea. sclerocornea in assoiation with recessive sclerocornea where the central part of the Annal di Ottalm 43: 1299–1304. epidermolysis bullosa dystrophica. 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202 Sigler-Villanueva A, Tahvanainen E, Lindh S, Eerola A, Weissenbach J, Sistonen P & de la Diegues-Lucena J & Forsius H (1997): Chapelle A (1995b): Cornea plana congenita Received on June 5th, 1997. Autosomal dominant cornea plana: Clinical gene assigned to the long arm of chromo- Accepted August 27th, 1997. findings and a review of the literature. Oph- some 12 by linkage analysis. Genomics 26: Corresponding author: thalmic Genet 18: 2: 000–000. 290–293. Henrik Forsius, MD, Prof. Swett WE (1924). Congenital cornea plana. Tahvanainen E, Sigler-Villanueva A, Forsius The Folkha¨lsan Institute of Genetics Am J Ophthalmol 7: 437–439. H, Salo P & de la Chapelle A. (1996): Domi- Mannerheimva¨gen 97 Tahvanainen E, Forsius H, Damsten M, Karila nantly and recessively inherited cornea SF-00280 Helsinki E, Kolehmainen J, Weissenbach J, Sistonen plana congenita map to the same small re- Finland P & de la Chapelle A (1995a): Linkage dis- gion of chromosome 12. Genome Res 6: FAX: 358-9-61585519 equilibrium mapping of the cornea plana 249–254. congenita gene. Genomics 30: 409–414, 1995. Velicky J & Vrabec F. Cornea plana congenita. Tahvanainen E, Forsius H, Karila E, Ranta S, Annal D o´culistique 184: 707–713, 1951.

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