Clinical Genetics 1913: 4: 301-310

Congenital plana in Finland

A. W. ERIKSSON,W. LEHMANN,AND H. FORSIUS Folkhalsan Institute of Genetics, Population Genetics Unit, Helsinki; Institute of Human Genetics, University of Kiel, Kiel; University of Oulu Eye Hospital, Oulu, Finland

Two different hereditary forms of congenital cornea plana are described: an autosomal dominant form with relatively mild symptoms, and an autosomal recessive form (CPCR) with more severe symptoms, such as decreased visual acuity, extreme hyperopia (total refraction usually 10 D or more), hazy limbus corneae, more or less pronounced opacities in the corneal parenchyma, and marked arcus senilk, often detectable at an early age. As far as can be judged from the number of cases hitherto published, cornea plana is a rare disease. In Finland, 49 caw of the recessive and seven of the dominant form of cornea plana congenita have been discovered to date, which is about twice the number of cases of recessively inherited cornea plana reported elsewhere in the world. In Finnish Lapland, the gene frequency of cornea plana congenita recessiva is estimated to be 1.3 (about 16 patients per 100,000 inhabi- tants), or about four times as high as in Finland as a whole. Around the lower reaches of the River Kemijoki there is a relatively high prevalence of the recessive form of the disease. The Kemijoki pedigree includes 25 patients related to each other through their ancestors.

Accepted for publication 31 Junuury 1973

The descriptive name cornea plana does not Rudiments of a appear at the quite correspond to the ocular findings in end of the second month (fetal length 25-30 the disease in question. The cornea is not mm), but a difference in curvature between flat, but its radius is larger than normal and the cornea and only becomes discern- involves a continuation of the curved sur- ible during the third month (fetal length face of the sclera over the area of the 45-50 mm), and the borderline between cornea. these two tissues is not distinct until the end Congenital cornea plana seems to be a of the third month (fetal length 65 mm). The rare anomaly. Only one to three cases are development of the angle of the anterior described in most reports. If more or less chamber is considerably slower. This struc- the same phenotype can be caused by ture does not attain its final shape until after both a recessive and a dominant gene, the birth. It can thus be concluded that the phenotype caused by the dominant gene is gene causing cornea plana influences devel- generally manifested by milder symptoms. opment in the 12th embryonic week, when This applies also to cornea plana. the bulb is attaining its final shape. In this disease, the corneal anlage deviates from the normal, as is also proved by the thinness of Pathogenesis the cornea and the differences in thickness The first rudiments of a cornea can be dis- between its various portions. In many in- tinguished in the fourth to fifth embryonic stances fibers run from the into the cen- weeks, when the embryo measures 7-9 mm. tral portion of the cornea. By contrast, the 3 02 ERIKSSON, LEHMANN, AND FORSIUS iridocorneal angle is usually normal, in spite of a low anterior chamber, and increased intraocular pressure is not typically asso-> ciated with cornea plana, although it does occur. The corneal tissue is derived from both the mesoderm and the ectoderm. Hence, pathological changes in the limbus and cornea may theoretically originate in both of these structures. Abnormal flatness of the cornea also occurs in connection with devel- opmental disturbances of a different genesis. A lengthened sclerocorneal zone and slight flatness of the cornea are often seen in cases of , for instance. In patients with uveae the cornea is sometimes not only unusually small, but also flat. Corneal flatness has been reported in Hurler’s dis- ease, Lobstein’s syndrome and DI trisomy (FranGois 1965). The mode of inheritance varies. Severe of the cornea and sclera may also cause flattening of the cornea.

Clinical Picture As a rule, cornea plana congenita recessiva (CPCR) is readily identified by the following typical signs: Fig. lb. Slit lamp photograph of the anterior portion of one eye of the patient shown in Fig. 1. The ante- rior chamber is extremely flat and the is dis- located.

I) The sclerocorneal zone is lengthened, which results in superficial haziness of a broad area in the limbus. The borderline between the sclera and cornea is indistinct. The cornea is either seemingly or actually unusually small (Figs. 1 a and 2). often occurs at an early age. 2) A round grey area, about 5 mm broad, is seen centrally in the cornea (Figs. la and 2). The cornea is thin at the margin of this area and thicker at the middle (Figs. lb and FIg. la. Left eye of an 11-year-old boy wlth recessive 2). The parenchyma of this disc-shaped cen- congenital cornea plana (case 18). His mother (case 13) also has cornea plana. tral area is more opaque than in other sites. CONGENITAL CORNEA PLANA IN FINLAND 303

Fig. 2. Extreme arcus senilis in the left eye of a 67-year-old female (case 30) with congenital cornea plana.

3) The corneal radius is larger than nor- 4) The cornea is thinner than normal. mal. The anterior portion of the eye (cor- 5) The often droops slightly (Fig. nea) is therefore less prominent or forward 3). bulging than normal when seen from the Minor differences in the clinical picture side (Figs. lb and 2). occur between the two eyes of the same subject and between different members of the same family. In mild cases, visual acuity is 0.6-0.8. In severe cases other anomalies of the bulb are also present, such as mal- formations of the iris, a slit-like pupil, or adhesions between the iris and cornea. Ab- sence of the has been described, and blindness sometimes occurs. In our series of 49 cases of recessive cornea plana, three patients were blind.

Material and Results Forsius discovered the first cases of cornea plana in Finland in 1953, when practicing Fig. 3. Slight palpebrae congenita is often as- sociated with cornea plana. as an ophthalmologist at Kemi in Finnish 3 04 ERIKSSON, LEHMANN, AND FORSIUS

I tected in two families. Patients with the el709 milder, dominant form do not exhibit the central opacity of the cornea which is typical ep of patients with the recessive form. Corneal refraction deviates from the normal by only 5-8 D. Both of the above-mentioned fami- lies have many ancestors traceable to the rural community of Jalasjarvi, in the west of central Finland, and we have recently suc- ceeded in proving that the two families have some common ancestors (Fig. 4). Families showing the dominant form of cornea plana have previously been described by Waarden- burg (1930), Barkan & Borley (1936), Ga- CORNEA PLANA (DOMINANT) steiger (1945) and Larsen & Eriksen (1949). Recessive form. Recessively inherited cor- nea plana has been observed by us in a B50 BLIND AT 50 total of 49 subjects in 32 sibships. Corneal refraction varies widely. The lowest reading for corneal refraction is 23 D, and values under 34 D predominate. A few members of these families have a nearly normal corneal refraction. These subjects are marked in the pedigrees as cases of CPCR if the cornea shows other typical signs. Although patients with cornea plana were sought in Helsinki in 1953-63 just as actively as in Oulu from

Fig. 4. Pedigree of two families with the dominant 1964 onwards, only eight patients with form of cornea plana. CPCR, belonging to seven different families, have been found south of the County of Lapland. Since then, he has systematically Oulu; the remaining 41 patients trace their recorded such cases when they occurred origin to north Finland. The geographical among his private patients at the Ophthal- distribution of the cases and their parents mological Department of Helsinki Univer- suggests that the frequency of the CPCR sity Central Hospital and, later, at the Eye gene is much higher in north Finland than Department of Oulu University. Through the in the south (Fig. 5). courtesy of colleagues we have obtained No symptoms or signs have been ob- data on additional families affected with this served in the parents of our patients with disease. Our results have been published in CPCR. An exception to this rule is the a number of reports (Forsius 1961, Forsius second family from the left in the pedigree & Lehmann 1962, Forsius & von Fieandt in Fig. 6 (Family Meh.), which includes two 1963, Forsius & Eriksson 1972). At present cases (17 and 18) in which CPCR is present our material consists of 34 sibships com- in the mother and two children. It seems prising 56 cases of cornea plana. probable, however, that the father also has Dominant form. Seven cases of the domi- the CPCR allele. The father comes from nant form of cornea plana have been de- another community than the mother, but CONGENITAL CORNEA PLANA IN FINLAND 3 05

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his paternal grandfather had the same sur- JACOB name and came from the same village as I 4'.-1698 -1702 one of the ancestors of family Hei. (cases 27 I I and 28). The family Pitkan., shown in the Kemi- joki pedigree in Fig. 6, has maternal con- nections with the Oulujarvi pedigree in Fig. 7, in which it can be seen that remote con- sanguineous marriages have been rather common. According to previous reports, only the patients described by Felix (1925) and Bloch (1965) had closely related par- ents. These authors reported on two cases each of recessively inherited cornea plana. In one of our cases of cornea plana the d (5 L3 b I I flatness of the cornea corresponds to the criteria for the recessive form of the dis- ease, but the posterior portion of the cornea exhibits a pit, or posterior. In a monograph on various sclerocorneal anom- Fig. 7. Pedigree of cornea plana congenita recessiva patients from the region north of Lake Oulujarvi in alies, Bloch (1965) pointed out that cor- the County of Oulu (Ulelborg). nea plana very much resembles the above- mentioned malformation, which in typical cases is known under the name of Peters' syndrome (Peters 1906). This malformation such as church registers, also appear in Fig. is considered to be due to a disturbance of 6. It is likely that at least some of the ances- the development of Descemet's membrane. tors who were blind or had poor vision Two investigations on this anomaly have had, in fact, cornea plana. But it should been published in Finland (Forsius &L Met- be borne in mind that at the time in ques- sala 1963, Krause et al. 1969). tion, was not infrequent in Lap- The 26 patients in the eight families from land. On the other hand, according to Nuu- the area of the River Kemijoki in the south- tila (1968) the dystrophia retinae pigmentosa western part of the County of Lapland have et dysacusis syndrome was not particularly many common ancestors; these families have common around the lower reaches of the intermarried for many generations (Fig. 6). River Kemijoki, and this is confirmed by The parental consanguinity is rather remote. the fact that for the subjects included in Many of the earliest known ancestors, born our pedigrees we have found no notes on in the communities of Simo and Tervola and poor hearing in connection with the nota- the rural community of Rovaniemi, have the tions of poor vision or blindness. same surname (Ruikk.). All these ancestors were obviously related, although we have Refraction not been able to confirm the kinships (marked by broken lines in the pedigree in About two thirds of the total refraction of Fig. 6). The occurrence of poor vision and the eye, corresponding to about 43 D, oc- blindness, and the ages at which poor vision curs in the cornea and anterior chamber. In was first mentioned in official documents cases of cornea plana, refraction in the 308 ERIKSSON, LEHMANN, AND FORSIUS anterior part of the eye is generally only the small number of people who colonized 30-35 D. There is thus a decrease in refrac- Lapland. Over half the cases of CPCR tion by 8-13 D, which suggests the occur- known in Finland were found among Finns rence of a corresponding degree of hyper- in Lapland. If the prevalence of CPCR in opia. In reality, hyperopia is uaually slighter the whole country were the same as in Lap- and may even be lacking, because re- land, the total number of cases would fraction is increased by the greater thickness amount to over 600. On the presumption of the central portion of the cornea, among that panmixia prevails in Lapland, a fre- other things. In 34 cornea plana eyes the quency of 1.25 % is obtained for the CPCR length of the bulb, measured ultrasonically, gene (Table 1). According to this, 2.5 % of was almost normal, 24.1 mm (21.4-27.4 the population of Lapland would be hetero- mm). When the bulb is longer than normal zygous for this recessive gene. About 90 % (> 24 mm), refraction may even be on the of the cornea plana patients in Lapland myopic side. In 24 normal members of have their domiciles around the lower reaches cornea plana families the mean length of the of the River Kemijoki, where about 40 % of bulb was 23.9 mm (22.3-26.8 mm) (Vuo- the population of Lapland lives. Hence, this pala, unpublished observations). The pheno- region can be considered a kind of genetic typic expression of the CPCR gene is highly isolate, in which panmixia does not neces- variable. As can be seen in Fig. 8, in the sarily prevail, and the gene frequencies given same family the corneal refraction of the in Table 1 must be regarded as approximate. patients varies considerably. With regard to the manifestation of the gene for CPCR it should be borne in mind that families are generally smaller in south Dlscusslon Finland than they are in the north, and the Lapland was still rather sparsely inhabited risk of manifestation of the disease is there- in the sixteenth and seventeenth centuries. fore much smaller. Among families with one The majority of the population around the child, a recessive feature remains unob- River Kemijoki probably originates from served in 75 %, of those families where both

Flg. 8. Rounded values in diopters for corneal refraction in a family with recessive cornea plana congenita. The values indicate the nearest horizontal: vertical values (right eye upper row, left eye lower row), Corneal refraction varies between 20 and 34 D in the probands and is quite normal in the heterozygote parents and the non-affected sibs. Note: Corneal refraction is expressed in diopters. The radial length of the cornea can be calculated by the 1wO formula d = ~ r/(n-1) where n = 1.3375. A radius of 7.5 mm corresponds to 45 D. CONGENITAL CORNEA PLANA IN FINLAND 309

Table 1 Distribution of recorded cornea plana congenita reccssiva (CPCR) cases in Finland according to the birthplaces of thcir mothers

Size of CPCR CPCR patients CPCR Qene County population patients per 100,000 frequency 1950 1972 inhabitants

Lapland 167,143 26 15.56 0.0125 Oulu (Ulehborg) 359,821 15 4.17 0.0065 Other counties 3,502,839 0' 0.23 0.0015 Total Finland 4,029,803 49 1.22 0.0035

* This number includes four patients from the region ceded to the U.S.S.R.,where the number of inhabitants is calculated to have been 310,000. parents are heterozygotes. In families with The concentration of the rare CPCR five children the corresponding figure is gene in certain parts of Finland constitutes only 24 %. However, the difference in prev- further evidence of the rather unique pat- alence of CPCR between south and north tern of the Finnish gene pool. Finland is not explained by the difference in size of the sibships. Acknowledgments No fewer than 41 (more than 80 %) of our CPCR patients come from the Counties This work was supported by grants from of Lapland and Oulu, although only 4 and Fight for Sight, Inc., New York, and the 9 %, respectively, of the total Finnish popu- Sigrid JusClius Foundation, Helsinki. The lation live in these areas. Only a few of the authors are indebted to Mrs. Anita Tuurala, families with affected children live in towns, Helsinki, for skilful assistance with the although about half the Finnish population genealogical details. today is urbanized. It is evident that the ac- cumulation of CPCR cases demonstrated in References Fig. 5 is a consequence of isolation by dis- Barkan, H. & W. E. Borley (1936). Familial tance and sparsity of population. In the cornea plana complicated by cataracta nigra 1940's the population density in the Counties and . Amer. J. Ophthal. 19, 307- of Lapland and Oulu was only 1.2 and 5.2 310. inhabitants per sq.km. land area, whereas Bloch, N. (1965). Les differents types de sclkro- the corresponding figure for the whole cornee, leurs modes d'hCrkdit6 et les malfor- mations congenitales concomitantes. J. Ge'nPt. country was 10.6. hum. 15, 213, 133-172. According to the literature, over half the Felix, C. H. (1925). Kongenitale familiare cases of cornea plana known in the whole Cornea plana. Klin. Mbl. Augenheilk. 74, world have been discovered in Finland; 710-716. Forsius, H. (1961). Studien uber Cornea plana still, there are certainly many patients in congenita bei 19 Kranken in 9 Familien. this country who have escaped our atten- Acta ophthal. (Kbh.) 39, 203-221. tion. It is obvious that founder effect, and Forsius, H. & A. W. Eriksson (1972). Cornea perhaps genetic drift, have produced a con- plana congenita. Duodecim 88, 52-59. centration of the disorder in the counties of Forsius, H. & 0. von Fieandt (1963). Photo- keratometry and refraction analysis in con- Oulu and Lapland, particularly around the genital cornea plana. Acta ophthal. (Kbh.) lower reaches of the River Kemijoki. 41. 609-620. 3 10 ERIKSSON, LEHMANN, AND FORSIUS

Forsius, H. & W. Lehmann (1962). Cornea Nuutila, A. (1968). Neuropsychiatric and ge- plana congenita in 12 Families in Finland. netic aspects of the dystrophia retinae pig- Acta genet. (Basel) 12, 230-241. mentosa - dysacusis syndrome. Diss. Helsinki. Forsius, H. & P. Metsala (1963). Keratoconus pp. 1-67. posticus. Acra ophfhal. (Kbh.) 41, 768-776. Peters, A. (1906). Ueber angeborene Defect- Franqois, J. (1965). Coloboma of the iris and bildung der Descemetschen Membran. Klin. of the . Genetics in . Mbl. Amyenheilk. 44, 27-40. Congress in Brno 1965. Acta Fnc. nied. Brun. Waardenburg, P. J. (1930). Hornhautrefraktion 25, 29-51. und Hornhautscheibengrosse. Klin. Mbl. Au- Gasteiger, H. (1945). Ueber eigenartige Ver- genheilk. 85, 169 185. Lnderungen des vorderen Augenabschnittes bei Mutter und Tochter (Cornea plana, blaue Sklera und Bindehautxerose). Klin. Mbl. Au- genheilk. 111, 247-254. Address: Krause, U., M. Koivisto & P. Rantakallio Aldur W. Erikssori (1969). A case of Peters’ syndrome with Institufe of Humeri Genetics spontaneous corneal perforation. J. pediar. Free Ilniversity of Arnsterdnrn Ophthal. 6, 145- 149. Van der Boechorststruat 7 Larsen, V. & A. Eriksen (1949). Cornea plana. Amsterdam, The Netherlnnds Acra ophthal. (Kbh.) 27, 275-286.