Clinical Section Autosomal recessive cornea 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 corneal opacity and a marked arcus senilis, 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; sclerocornea – 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 corneal dystrophy (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, astigmatism 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 Iris 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 pupil 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.