Documenta Ophthalmologica 73: 81-92, 1989. �9 1990 Kluwer Academic Publishers. Printed in the Netherlands.

Prevalence of tapeto-retinal dystrophies among Danish children

THOMAS ROSENBERG National Eye Clinic for the Visually Impaired, Hellerup, Denmark

Received 9 June 1989; accepted 15 October 1989

Key words: epidemiology, paediatric ophthalmology, pigmentary retinal dystrophy, retinitis pigmentosa, tapeto-retinal dystrophy, visual impairment

Abstract. Age specific prevalence rates are presented based on 110 cases of pigmentary retinopathy (RP) recorded in the Danish child population of a little over one million in- dividuals on January 1, 1988.

A steady and steep rise in age specific prevalences of notified RP throughout infancy and childhood was found. The material consisted in 52 non-systemic and 58 systemic cases. 35 of the systemic cases could be nosologically identified, leaving 23 cases unidentified with respect to known diseases or syndromes.

Among the genetic types autosomal recessive inheritance was the most common with 60 cases (55%). Parental consanguinity was less frequent than hitherto reported. On the other hand undetected carrier state for X-linked tapeto-retinal dystrophy played a more significant role than expected. A clear excess of males among the simplex cases indicated that some X-linked cases may still be unrecognized.

A significant proportion of non-systemic, early infantile RP with an autosomal recessive or simplex mode of inheritance are clinically and electrophysiologically characterised as cone-rod dystrophies.

Introduction

Diffuse and peripheral tapeto-retinal dystrophies, pigmentary retinopathy, or retinitis pigmentosa (RP) are among the leading causes of visual impair- ment in children in a number of industrialised countries [1-3].

Nevertheless epidemiological data on childhood RP are few, mainly because most statistics are based on materials from schools for the blind and other institutions without a well defined population of recruitment. In a study on 515 visually impaired Swedish children Lindstedt [4] calculated prevalences of tapeto-retinal degenerations as 1.5:100.000 in age group 0-7 years and 3.4:100.000 in age group 8-20. Population studies including all age groups have reached figures between 5.0:100.000 and 21.0:100.000 [5-8].

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The aim of this study was to provide epidemiological data on tapeto-reti- nal dystrophies in the Danish child population of a little more than 1 million individuals.

Material

January 1, 1988 was chosen as cut-off day. At this time the Danish popula- tion aged 0-17 years counted 1.123.714 children [11].

In the corresponding years 1970-1987 the number of live born children was 1.116.627.

1437 (1.3 per thousand) were registered as visually impaired and 110 (7.7 per cent) of the visually impaired children were diagnosed as suffering from a diffuse or peripheral tape to-retinal dystrophy (RP). The latter group was the basis of the present analysis.

Methods

Registration. In Denmark the notification of visually handicapped children is compulsory. This fact in addition to accurate annual population surveys are the prerequisites for analyzing the prevalence of visual impairment due to any ocular condition in the Danish child population between 0 and 18 years of age.

The Register for the Blind and Partially Sighted Children is kept at the National Eye Clinic. The database is currently updated according to reports from practising ophthalmologists, hospital departments, assessment teams etc. Information on 33 variables are registered on each child including ophthalmological and paediatrical diagnoses, etiology, birth weight, visual acuity group, etc. In addition a paper file is kept with full copies of medical information from practising specialists and hospitals involved in the care of the child. The formal and real inclusion criteria for registration were discussed in a separate paper along with the registrational efficiency [9].

Terminology and delineations. The terms pigmentary retinopathy, retinitis pigmentosa (RP), and diffuse or peripheral tapeto-retinal dystrophy are used alternatively and synonymously to coin an assembly of clinically defined pathological retinal and choroidoretinal conditions.

The following diagnostic criteria were used: Ophthalmoscopical evidence of narrow retinal arterioles, diffuse and widespread atrophy of retinal pigment epithelium and/or choroidal layers, spicule or granular

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hyperpigmentations, abnormality of fundus reflexes and retinal atrophy of the optic discs were considered facultative objective signs of RP.

Anamnestic or psycho-physically ascertained night blindness, visual field defects, photophobia and progressive visual loss would imply suspicion of being symptoms of a pigmentary retinopathy.

Unless the signs and symptoms or family history were typical and convincing for a diagnosis, severe reduction or extinction of the dark adapted electroretinogram (ERG) was considered obligate for the diagnosis of a diffuse or peripheral tapeto-retinal dystrophy.

This delineation implies that "pure" cone dystrophies, whether stationary or progressive, were excluded from the material, while retinopathies characterised electrophysiologically as cone-rod dystrophies were included. Juvenile macular dystrophies of Stargardt type and fundus flavimaculatus were excluded for the same reasons.

Vitreoretinal dystrophies, diagnosed as X-linked juvenile retinoschisis, were excluded. So were cases of retinal dysplasia with partial persistence of foetal vitreous structures as found in some cases of eye-muscle-brain syndromes. No case of vitreo-retinal dystrophy of Goldmann-Favre type was registered.

From a practical point of view only very few cases presented difficulties with respect to inclusion into the material. The material was divided into two main groups, systemic and non-systemic RP, based on the presence of extraocular symptoms. Systemic RP, consequently, includes both RP associated with metabolic disorders and syndromic cases.

Assessment. The assessment of RP in a Danish child most often involves a practitioning ophthalmologist, the local eye department and one of the following institutions in Copenhagen: University Eye Department at Rigshospitalet, Eye Clinic for the Mentally Retarded or the National Eye Clinic for the Visually Impaired.

In multiply handicapped children the assessment is interdisciplinary, most often coordinated by local paediatric departments with support from national centers, mainly Section of Clinical Genetics, Department of Paediatrics, Rigshospitalet (metabolical and molecular biological service) and The John F. Kennedy Institute (cytogenetical and metabolical service).

A substantial number of the multiply handicapped ,children were diagnosed and reported by Mette Warburg, MD, at the Hospital for Mentally Retarded Children in Vangede, Copenhagen.

Classifications. Grouping with respect to diagnostic category was made by the author on the basis of available retrospective clinical evidence. Most of

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the children in question have been controlled by ophthalmologists for years with the consequence that diagnostical decisions on grouping and typing were mostly based on several successive reports. In addition the majority of the children (91 out of 110) were referred to the National Eye Clinic for supplementary diagnostic and counselling reasons. With regard to the multiply handicapped children extensive metabolical, neurological and cytogenetical examinations had been performed in most cases.

Genetic classification was mainly based on family history. With positive information on parental consanguinity the case was categorised as autosomal recessive. The same categorisation was made with affected sisters or brothers with no evidence of other affected family members. Most of the X-linked cases belonged to families known for generations. In other instances observations of carrier signs in the mother or the presence of pigmentary dystrophy in maternal cousins or half-brothers were decisive. The term "simplex" was used to characterize a sporadic case without positive information on parental consanguinity.

Results

Prevalence. The 110 cases correspond with a prevalence rate in the age group 0-17 years of 9.8 : 100.000 or close to 1 in 10.000. Expressed in fraction of the liveborn (including 6 children who died before cut off-day) the cumulated incidence of RP notified before the age of 18 years was 1 per 9.600.

The numbers of children in each birth year cohorte from 1970 through 1987 varied roughly between 75.000 and 50.000 with a declining tendency throughout the period. Table 1 presents the background population as well as the number of recorded affected children with reference to the year of birth. The corresponding prevalence rates (Py) are seen to vary between 0 and 23.8 per 100.000. Despite large fluctuations from one birth year group to the neighbouring groups, the tendency for a steady and rapid incline of age specific prevalence rates with increasing age seems obvious. The presentation of Py with one decimal in the nominator may be misleading. It should be pointed out that the notification of one child more or less in the respective birth year cohortes corresponds with a change in Py value between 1, 3 and 1, 9 per 100.000. A Py value of23.8:100.000 in the 17-year- old expresses a risk for a child of this specific age of being affected by a notified tapeto-retinal dystrophy.

Figure 1 depicts the cumulated age specific prevalence rates (ZP) year by year. ZP expresses the prevalence rates in the whole child population up to

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Table 1. Numbers of affected children (Ny) compared to liveborn (Lb) and total birth year population (Ty). Age specific prevalences are listed in 5. column (Py). Cumulated population size according to birth year and the corresponding cumulated age specific prevalences are listed in 6. and 7.

year Lb Ny Ty Py ZTy EPy

1987 56.300 0 56.190 0 5.6.190 0 1986 55.312 1 55.704 1.8 111.894 0.9 1985 53.749 1 54.399 1.8 16,6.293 1.2 1984 51.800 4 52.479 7.6 218.772 2.7 1983 50.822 3 51.512 5.8 2710.284 3.3 1982 52.658 2 53.407 3.7 323.691 3.4 1981 53.089 3 53.688 5.6 377.379 3.7 1980 57.293 3 57.805 5.2 435.184 3.9 1979 59.564 7 59.805 11.7 494.989 4.8 1978 62.036 8 62.524 12.8 557.513 5.7 1977 61.878 7 62.395 11.2 619.908 6.3 1976 65.267 2 65.795 3.0 685.703 6.0 1975 72.071 11 72.356 15.2 758.059 6.9 1974 71.327 7 71.439 9.8 829.498 7.1 1973 71.895 8 71.786 11.1 901.284 7.4 1972 75.505 8 75.463 10.6 97,6.747 7.7 1971 75.359 18 75.402 23.9 1.052.149 8.8 1970 70.802 17 71.565 23.8 1.123.714 9.0

Cumulated age-specific Prevalence rates (registrated RP per 100.000)

10.0"

9.0-

8.0-

7.0-

6.0"

5 .0 -

4.0-

3 .0 -

2 .0 -

1 ,0-

I I I Ii 5 10 15 A g e ( y e a r s )

Fig. 1. Ordinate: Cumulated age-specific Prevalences (EPy) of registrated RP (per 100.000 children in the population (ZTy)). Abscissa: Age per January 1st, 1988.

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a given age. The random fluctuations of EP due to small numbers are gradually decreasing with increasing age and background population.

Types. Each case was classified according to clinical criteria, i.e. involvement of other organ systems than the eye, age of onset, hereditary pattern, morphology, symptomatology etc. Figure 2 presents an outline of the composition of the material with respect to this standard classification.

Non-systemic RP. A little less than half of the children, of which 45 were examined at the National Eye Clinic once or repeatedly, did not show any other sign of disease or dysmorphology.

19 cases were classified as congenital of which 17 exhibited a rather uniform clinical picture allowing for a diagnosis of Leber's congenital amaurosis (LCA) [12].

The familial occurrence was solitary in the 15 Leber cases, the remaining two were brother and sister born 1977 and 1973. The Leber cases were distributed at random over the 18 year period in question.

The overall frequency of non-systemic LCA was 1 : 66.000. Expressed as a fraction of liveborn in 1970-1987 the figure turned up to be the same.

The remaining two patients with a presumed congenital tapeto-retinal dystrophy were two maternal cousins with congenital nystagmus and a moderate-severe reduction in their dark adapted single flash as well as flicker mediated ERG's. The boys have been followed for 8 years and their visual and electrophysiological functions in this period have been stationary. The condition is provisionally labelled Congenital stationary retinal dysfunction syndrome (CSRD). A clinical and genetical study of this X-linked condition in a large Danish family is in progress.

33 children were diagnosed as having an aquired non-systemic RP, the youngest being 6 years old. One additional child aged 3 most certainly was affected by X-linked RP as determined by restriction fragment length polymorphism-technique. So far he has not been clinically examined and the case was not included in this material. Thirteen boys from 10 families were affected by X-linked retinitis pigmentosa (XRP), 4 patients supposedly were affected by an autosomal dominant type (AD), 6 were typed as autosomal recessive (AR), and the remaining 10 as simplex. Most of the X-linked cases were typical with respect to symptoms, morphology and myopia. In contrast the majority of the 16 simplex or AR cases debuted early with a squint, followed by a reduced visual acuity or night blindness. The refraction in most of the cases was medium to high hypermetropia. The retinal affection in several cases was initially mistaken for a juvenile macular dystrophy.

In 4 cases in which differentiation between cone and rod function of the

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110

Non-systemic R ~ ~ Systemic RP 52 (47%) 58 (53%)

.don..,oo 0,seas Congenital Aquired and syndromes Unidentified

19 33 35 23

• / \ ~i.,,>..>, ~ / \ ~ e ~ Congen 'al I Uncertain

17 2 6 4 8 10 9 LCA CSRD AR AD SV BB Aquired

Fig. 2. Pigmentary retinal dystrophies in 110 children < 18 years. The number of cases in each subgroup is indicated. Abbreviations: LCA, Lebers congenital amaurosis. CSRD, Congenital stationary retinal dysfunction (see text). AR, Autosomal recessive. AD, Autosomal dominant. SV, Spielmeyer-Vogt's disease. BB, Bardet-Biedl's syndrome. Systemic RP includes associated and syndromic RP. Simplex means sporadic cases without parental consanguinity.

residual ERG was possible, a cone-rod dystrophy was found. In most cases the diagnosis was postponed for years after the initial ophthalmological examinations and was nearly always the result of an electrophysiological examination.

Systemic retinitis pigmentosa (RP § Thirty-five out of 58 cases could be referred to well defined clinical entities among which Usher's syndrome accounted for 12 cases, Bardet-Biedl' syndrome for 10 cases and juvenile ceroid lipofuscinosis, Spielmeyer-Vogt's disease for 8 cases (Fig. 2).

The youngest Usher patient was born 1984, the rest of the children being born in the 70's. The corresponding frequency expressed in relation to live- born is 1 per 75.000. No attempt was made to differentiate between the subtypes Usher I and Usher II. Half of the Usher cases had familial evidence of autosomal recessive inheritance. The rest were sporadic without information on parental consanguinity.

Nine of the Bardet-Biedl patients were born into familes without any other known occurrence of RP or parental consanguinity. The remaining patient was an adopted child from Sri Lanka about whom no familial information was available. Despite the significant signs and symptoms of this syndrome the correct diagnosis was in most cases achievecl at a very late stage, i.e. when the children were aged 6-10 years.

The 8 children with Spielmeyer-Vogt's disease were all born in the period 1970-1984 and in addition no child from this period with the disease had died. Assuming that all cases born in this period were diagnosed by the end of 1987 a frequency of the homozygeos state of 1:112.000 is calculated.

Five patients were diagnosed as having more rare, butt well-known hereditary diseases; 2 brothers suffered from autosomal dominant

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microcephaly with lacunar atrophy of the retina and choroid [13], 2 un- related, mentally retarded boys with choroideremia had X chromosomal deletions [14, 15]. Finally a 14 year old boy with a progressive hearing disorder and ataxia in addition to RP had a diagnosis of infantile Refsum disease confirmed by high blood concentration of phytanic acid.

Five multihandicapped children with specified diagnosis were excluded from this prevalence study because they died before the cut-off day of this investigation. The clinical diagnoses of these children were as follows: Infantile ceroid lipofuscinosis, Santavuori type, Late infantile ceroid lipofuscinosis, Bielchowsky type (2 cases), AlaGille's syndrome and myxo- neuro-mitochondriopathy.

Nearly half of the syndromic cases (cf. Fig. 2) has not so far been categorized despite the most extensive clinical, biochemical, and cytogeneti- cal examinations.

In 12 patients of this group the pigmentary retinopathy was classified as congenital, and in further 2 cases this was uncertain but considered prob- able. This group is by some authors considered under the heading of Leber's congenital amaurosis. All the cases were solitary with respect to familial occurrence, parental consanguinity being present in 3 out of 10 elucidated instances. Mental retardation (MR) was present in all 14 cases belonging to the group of congenital RP +. In addition a variety of congenital malforma- tions and dysfunctions were present, as microcephaly in 2, hydrocephaly in 2, clefting of the lip and palate in 1, cirrhosis of the liver in 1, reduced resistence to infections in 2, deafness in 2, and paraplegia in 1.

Haematological and biochemical findings in this group were haemolytical anemia, hypoglobulinaemia, hypobetalipoproteinaemia, and reduction as well as elevation in lysozymal hexosaminidase A and hexosaminidase B- activity. One child had a chromosomal rearrangement: 45xy,t(13:14) (pl 1:ql 1), likewise of questionable relevance to the condition.

Only one child, a boy with anal atresia, hypospadia, palatoschisis, poly- and syndactylia and hydrocephaly which could not be diagnosed with respect to a known syndrome, had died before the day of this study.

Finally a group of 9 patients with aquired tapeto-retinal dystrophies displayed a variety of signs expressing a considerable clinical heterogeneity. Four of these children were intellectually normally developed. One was born with clefting of the lip and gum as well as hypospadia. Three children had truncal obesity, and one of these had congenital malformation of the anus. Five patients were characterised as mentally retarded, two of them had severe hearing deficiency. Another suffered from obesity and still another from ataxia.

Laboratory tests revealed cystathioninuria in a boy with ataxia and

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muscular weakness in addition to mental retardation and RP. In further two patient an immunodeficiency was demonstrated.

Familial and hereditary pattern. The 110 registrated children were offsprings of 101 couples. Seven couples had two children registered, two pairs being twins. One couple had three children registered with a diagnosis of Usher's syndrome. Eight more children had affected sibs older than the age limit for registration. This means that 16 of the 101 couples (or women) had two or more affected children. X-linked heredity accounted for 6 of the 16 cases with more than one affected child.

The distribution of hereditary patterns with reference to familial occurr- ence only was: 6 dominant, 24 recessive, and 17 X-linked while 62 cases were the only known cases in their respective families. In one case., any informa- tion on familial occurence was missing.

After correcting for diseases with established recessive transmission (i.e. monosymptomatic congenital amaurosis of Leber, Usher and Bardet-Biedl syndromes, Spielmeyer-Vogt and Refsum disease) the relative distribution with respect to mode of inheritance was: 6 dominant (5%), 17 X-linked (15%), 60 autosomal recessive (55%), and 27 simplex (25%) cases.

Seventy-two of the 110 children were males. After withdrawal of the above mentioned 17 known or presumed X-linked cases a significant male dominance of 55:38 (63%) still remained.

In 70 out of 79 cases parental consanguinity could be excluded, leaving 11% with positive information of consanguinity. In the 16 instances of affected brothers and sisters consanguinity was was ruled out in 10 cases being not cleared up in the remaining 6.

Discussion

The Danish population is well registered permitting detailed statistics of population dynamics. In general the population is considered rather station- ary as well as homogeneous with respect to ethnic composition. This state- ment surely needs modification as illustrated by the number of" children born 1970-1987 which due to net immigration has grown with over 7.000 in the corresponding age groups by the date of investigation (Danmarks Statistik, personal communication 1988).

The presented figures are believed to represent more than 90% of the diagnosed cases in Denmark. This is due to a tradition for referral to virtually only three diagnostic centers in Denmark of which the National Eye Clinic receives a larger proportion. Another important factor is a well

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developed cooperation between medical and educational professions taking care of children. The numbers, therefore, simply reflect "the state of art" with respect to diagnostical awareness and efficiency among ophthalmolo- gists in general.

Unfortunately, the records of the registered cases in many instances show considerable delay in achieving correct ophthalmological diagnoses, sometimes for several years. This may even be so in cases with early and repeated ophthalmological examinations. Therefore, it must be concluded that the presented figures with certainty are underestimating the real preva- lence of several types of RP.

The age specific prevalence rates for each birth year cohorte apart from year to year fluctuations demonstrate a very rapid increase up to a maximum of more than 20 per 100.000. There is no tendency towards deflection of this curve which is in accordance with the general clinical impression of an increasing number of newly diagnosed cases up to the mid twenties. The cumulated prevalence rates demonstrate a slower, nearly rectilinear rise with a doubling in rate for every fourth year. The prevalence rate for the whole group is still half the magnitude as reported from population studies includ- ing all age groups. [7, 8]. This means that age specific prevalence rates for a single birth year cohorte is supposed to rise considerably over 20:100.000 during the third decade of life.

The 0-5 year prevalence rate of 1.5:100.000 in Sweden as estimated by Lindstedt [4] seems to be comparable to the cumulated value 3.7:100.000 in the present material (Table 1). The difference between the figures may be ascribed to a growing interest in diagnosing these conditions during the last decades. The availability of appropriate electrophysiological service seems to be the most critical determining factor for early diagnosis of retinitis pigmentosa in children when morphological retinal signs may be slight or even absent.

Most cases of tapeto-retinal dystrophies could not be classified with respect to mode of segregation on the basis of familial occurrence alone. This is partly due to a rather low reproduction rate among Danish women and a frequent breaking up of marriages. It should be noted that parental consanguinity was far less important for the occurrence of two affected or more sibs with RP than the carrier state for X-linked tapeto-retinal dystrophies. Most of the latter women were unaware of their condition as carriers pointing to an important area of intensified medical information with a perspective of prevention. The rather common occurrence of X- linked conditions should be brought into mind every time one is dealing with only affected boys in a sibship.

The preponderence of the male sex in this material exceeding that of the

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background population points to the possibility that some of the simplex cases may in fact be X-linked. The majority of the simplex cases, indeed, is still believed to be due to autosomal recessive conditions or submicroscopi- cal chromosomal deletions.

Besides early extinguished or nearly extinct ERG the criteria for classify- ing a case as congenital were the abscence of fixation before 6 months of age and the presence of nystagmus [16]. In a few cases with moderately preserved visual acuity and/or only slight or intermittent nystagmus the differentiation between congenital and early infantile RP offered some difficulty. No at- tempt was made to subdivide further into categories according to age of debut. In opposition to Foxman et al. [16] the author in many cases found this criterion of limited value for categorisation.

The substantial number of undetermined, syndromic RP is noteworthy. Some signs as e.g. mental retardation seem to be shared by most of these cases, while e.g. hearing deficiency, obesity, clefting of the lips and gums, hypospadia and immunodeficiencies seem to occur in a significant number of cases, yet without pointing towards definite syndromes or presumed chromosomal locations.

Acknowledgements

The author is indepted to most Danish ophthalmologists, paediatricians and low vision teachers for their contributions to the National Register for the Blind and Partially Sighted Children. For their diagnostic help in com- plicated cases I wish to thank Niels Jacob Brandt, MD, head of the Section of Clinical Genetics, Department of Paediatrics, Rigshospitalet, Margaretha Mikkelsen, head of The John F Kennedy Institute, Deptartment of Cytogenetic. I am indepted also to Ernst Christensen, PhD and Marianne Schwartz, PhD for their enthusiastic collaboration in biochemical and DNA studies respectively.

Mette Warburg, MD, head of the Eye Clinic for Mentally Retarded in Copenhagen who takes a unique position in Danish ophthalmopaediatrics has been of invaluable help in this study. John Heckenlively, MD and Mette Warburg gave constructive critical remarks to the manuscript.

The study was supported by a grant from Landsforeningen til Forebyg- gelse of Ojensygdomme og Blindhed.

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11. Danmarks Statistik. Befolkningen pr. 1. Januar 1988. Nyt Fra Danmarks Statistik, 1988; Nr. 58.

12. Keast-Butler, J. 1983. Congenital Retinal Blindness. In: Wybar, K., Taylor, D. eds. Pediatric ophthalmology. New York: Marcel Dekker. 209-17.

13. Warburg, M., Heuer, H.E. 1983. Autosomal dominant microcephaly with lacunar retinal hypopigmentations. In: Henkind P. ed. Acta: XXIV Int. Congr. Ophthalmol. Philadelp- hia: JB Lippincott.

14. Rosenberg, T., Schwartz, M., Niebuhr, E., Sardemann, H., Andersen, O., Lundsteen, C. 1986. Choroideremia in interstitial deletion of the X chromosome. Ophthal Paed Genet (Amsterdam) 7: 205-10.

15. Rosenberg, T., Niebuhr, E., Yang, H-M, Parving, A., Schwartz, M. 1987. Choroideremia, congenital deafness and mental retardation in a family with an X chromosomal deletion. Ophthal Paed. Genet. (Amsterdam) 8: 139-43.

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Address for offprints: Thomas Rosenberg, MD, National Eye Clinic for the Visually Impaired. 1 Rymarksvej, DK-2900 Hellerup, Denmark.