Uveitis? Discordance in Monozygotic Twins

22 BritishJoumnalofOphthalmology, 1992,76,22-24

Is there a genetic basis for Fuchs' heterochromic Br J Ophthalmol: first published as 10.1136/bjo.76.1.22 on 1 January 1992. Downloaded from uveitis? Discordance in monozygotic twins

N P Jones, A P Read

Abstract relatives) 84 (93-3%) had no family history of One pair, and probably two pairs, of mono- heterochromia or ocular disease. Six patients zygotic twins are reported with discordance for (6 7%), however, each thought that one other Fuchs' heterochromic uveitis (FHU). Regular family member had heterochromia. For geo- Mendelian inheritance of this disease is now graphical and other reasons it was possible to proved to be impossible. The heritability of examine only two ofthese six suggested cases. In FHU is low and may be zero. The possibility of both instances there was unilateral sector hyper- any genetic predisposition to the disease and pigmentation, no sign of past or present intra- its association with 'simple' heterochromia are ocular inflammation, and otherwise normal discussed. ocular examination. This cohort of 103 patients included two who had a monozygotic twin, but no dizygotic twins. Both are reported below. Fuchs' heterochromic uveitis (FHU) is a chronic, indolent uveitis of unknown aetiology first described comprehensively by Ernst Fuchs Case reports in 1906.' The occasional concurrence of FHU in more than one member of the same family has CASE 1 been reported2`5 and the possibility of a genetic The patient, a 51-year-old woman, presented aetiology, usually described as an autosomal 'with a history of gradual loss ofvision on the left dominant trait with low penetrance, has been side. She was aware of heterochromia affecting discussed on several occasions. In 1955, the left side which had been present since birth. Franceschetti,6 having reported a large series of This eye was known to be amblyopic but further 62 patients with FHU and established the visual loss had occurred. modern criteria for diagnosis, concluded that 'If On examination of the left eye there were one day we have the good fortune to find numerous stellate keratic precipitates scattered identical twins with Fuchs' syndrome, we hope evenly over the whole posterior surface of the it will then be easier to answer the difficult cornea, with fine interconnecting fibrillary question of the role of a genetic factor in compli- deposits. There were few cells in the anterior http://bjo.bmj.com/ cated heterochromia'. Almost immediately, chamber and barely detectable flare. The right FHU coexisting in a pair of monozygotic twins iris had a normal architecture and was light was described,7 and the possibility of a genetic brown (Fig 1). The left iris was macroscopically factor was further strengthened. Family studies blue, the anterior border layer pigment had on a cohort of 103 patients with FHU are entirely disappeared, and this layer was grossly reported here, including case reports of discord- atrophic (Fig 2). The iris stroma was also ance ofFHU in monozygotic twins. The implica- markedly atrophic with obvious thinning and on September 29, 2021 by guest. Protected copyright. tions of these findings on a genetic theory for some visibility of pigment epithelium from the FHU are discussed. anterior aspect. The iris pigment epithelium was clearly abnormal and there were large scattered transillumination defects, mainly peripheral but Patients and methods also involving the pigment ruff. The pupil on From 1987 all new and old patients attending the this side was slightly irregular, but there were no outpatient department at Manchester Royal Eye posterior synechiae. A posterior subcapsular Hospital with a definite or suggested diagnosis of cataract was present, and vitreous cellular FHU were referred to one of us (NPJ). Of these, activity and condensations were visible. There 103 patients were considered to fulfil the diag- were no fundal lesions. The diagnosis of FHU nostic criteria for FHU. As part of a comprehen- was made. sive history and examination these patients were The patient was one of triplets. There was no Department of questioned on their family history and a family history of maternal illness in pregnancy, and the Ophthalmology, tree was was delivered at term without University of Manchester constructed. Any history of possible patient vaginally N P Jones heterochromia or inflammatory eye disease was complications. One further child, a girl, was noted. Where possible allegedly affected family delivered without mishap but a third female was Department of Medical members were DNA on a stillborn and small. Genetics, University of examined. analysis Manchester pair of monozygotic twins was performed. The surviving twin was examined. The eyes A P Read were completely normal. The irides were a very Correspondence to: similar colour to the normal right iris of the Mr N P Jones, FRCS, University Department of Results patient; stromal architecture and pigmentation Ophthalmology, Manchester In 13 cases the family history was incomplete or were symmetrical and normal. There was no Royal Eye Hospital, Oxford Road, Manchester M13 9WH. unknown due to lack ofknowledge on the part of evidence ofpast or present intraocular inflamma- Accepted for publication the patient (two being adopted). Of the remain- tion and the lenses were clear. There was there- 30 May 1991 ing 90 patients (who had a total of601 first degree fore no evidence of FHU (Figs 3 and 4). Is there agenetic basisforFuchs' heterochromic uveitis? Discordance in monozygotic twins 23 Br J Ophthalmol: first published as 10.1136/bjo.76.1.22 on 1 January 1992. Downloaded from - '' ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.~~~~~~~....

_RE ...... f` Figure I Case 1. The twin with Fuchs' heterochromic Figure 2 Case 1. The twin with Fuchs' heterochromic uveitis, normal right eye. uveitis, affected left eye.

's'. Figure 3 Case 1. The unaffected twin, right eye. Figure 4 Case 1. The unaffected twin, left eye.

The twins were facially very similar even at 51 familial, or from evidence of a relationship to years of age, and in fact the patient's hetero- more clearly defined genetic conditions. chromia had been a useful distinguishing feature in childhood. DNA analysis was performed by means of the minisatellite probe 33-6, which TWIN STUDIES showed that each twin had 25 clearly visible Makley7 found a pair of presumed monozygotic bands, which were in identical positions. twins in 1956 who were concordant for FHU. http://bjo.bmj.com/ The possibility of a non-genetic aetiology still existed of course, as the twins had occupied the CASE 2 same uterus simultaneously. However, our find- This female patient presented at the age of 69 ing ofone, and probably two, pairs ofdiscordant with a history of floaters. She was aware of her monozygotic twins now formally disproves any profound heterochromia, which had been wholly genetic aetiology for FHU. The twins in present since birth. On examination she had case 1 shared all 25 bands seen with DNA on September 29, 2021 by guest. Protected copyright. clear evidence of right-sided heterochromic fingerprinting. The chance of dizygotic twins uveitis, with widespread stellate keratic precipi- sharing one band is about 0.6,8 and the chance of tates and typical iris atrophy with hypochromia. sharing all 25 is (0.6)25 or 3 x 10-6. Thus they are There was incipient band keratopathy. The monozygotic, and they are certainly discordant affected iris was blue, the unaffected one being for FHU. Probably the twins in case 2 were also light brown. The lens was clear but there was monozygotic, since the heterochromia in one of cellular activity in the anterior vitreous. them was reportedly the only distinguishing The diagnosis of FHU was made. The patient feature in childhood. had no family history of heterochromia and was one of twins. The maternal pregnancy and delivery had been uneventful. The twin had EVIDENCE FOR FAMILIAL TRANSMISSION unfortunately died recently at the age of 72, and Some authors90 have described FHU as a domi- a planned ocular examination and DNA analysis nant condition with low penetrance, but the had not been possible. Anecdotally the surviving reported series show that in the vast majority of twin was convinced both of their monozygosity instances it is not familial. In the literature to and their discordance for heterochromia. The date approximately 1800 cases of FHU have been heterochromia had apparently been the only reported.'1-16 Familial cases have been published distinguishing feature in childhood. in a few instances, but it should be noted that selective reporting of familial transmission3-5 may overestimate the possibility of heritability. Discussion The reports of familial transmission include: The issue ofa possible genetic basis for FHU has two sisters2; a mother and daughter3; an uncle been raised on several occasions in the past. and nephew4; two sisters5; and five further Evidence for this might be sought from twin families.'3 '7 In 1956 Makley7 reported the studies, from evidence that FHU tends to be coexistence of FHU in a pair of twins, who were 24 4Jones, Read

judged to be monozygotic on the basis of blood in association with the Waardenburg syndrome grouping and hand-print comparison. Loewen- and it appears unlikely that the two conditions Br J Ophthalmol: first published as 10.1136/bjo.76.1.22 on 1 January 1992. Downloaded from feld and Thompson" 12 have critically reviewed are related. the earlier reports above257 and many other reported familial cases; only those cited above seem likely to be genuine. The proportion of Conclusions familial cases is certainly <1-0% and does not It is clear that FHU and its antecedent hetero- provide adequate evidence of direct heritability chromia do not show regular Mendelian inherit- ofFHU. ance. Genetic predisposition does not play a large part in the overall risk ofFHU. The very low rate offamilial concurrence, and the lack oftemporal RELATIONSHIP TO GENETICALLY DETERMINED relationship between the onset of heterochromia CONDITIONS and of the FHU in those with congenital hetero- There is a possibility that both sector hyperpig- chromia, suggest that at least two rare events are mentation ofthe iris, and heterochromia without required, one (which may be intrauterine) to inflammation ('simple' heterochromia) may be cause the heterochromia and a second event to transmitted as a genetic trait.'8"9 Could such a trigger the progression to FHU. mechanism be of relevance to FHU? Patients with FHU can have either congenital or acquired 1 Fuchs E. Ueber Komplicationen der Heterochromie. heterochromia.616 If the FHU itself were con- ZAugenheilkd 1906; 15: 191-212. genital in those with congenital heterochromia, 2 Kranz HW. Beobachtungen und Bemerkungen zum Heterochromie-problem. Graefes Arch Ophthalmol 1926; then such patients would present earlier than 117: 554-74. those with acquired heterochromia. This, how- 3 Becker J. Heterochromieglaukom bei Mutter und Tochter. KlinMonatsblAugenheilkd 1927; 78: 707. ever, is not the case.'6 In this series of 103 4 Streiff EB. Sur l'heredite de 1'hetetochromie. Arch Klaus patients the age at diagnosis of FHU in those Stiftung Vererb-Forsch 1947; 22: 256-60. 5 De Rosa C. Su due casi familiari di ciclite etrocromica di Fuchs with congenital heterochromia is, paradoxically, complicata da glaucoma. Arch Ottalmol 1959; 63: 437-9. actually later than that for those with acquired 6 Franceschetti A. Heterochromic cyclitis (Fuchs' syndrome). AmJ Ophthalmol 1955; 39: 50-8. heterochromia (mean 41-4 years and 33-7 years, 7 Makley TA. Heterochromic cyclitis in identical twins. Am J respectively). Thus patients with congenital Ophthalmol 1956; 41: 768-72. 8 Jeffreys AJ, Wilson V, Thein SL. Individual-specific finger- heterochromia must have a latent period without prints of human DNA. Nature 1985; 316: 76-9. inflammation before FHU develops. At this 9 Bistis J. La paralysie du sympathique dans l'etiologie de l'hetrochromie. Arch Ophtalmol (Paris) 1912; 32: 578. time, therefore, they have 'simple' hetero- 10 Francois J. Fuchs' heterochromia. Ann Ocultist (Paris) 1954; chromia. It should be considered a possibility 187:255. 11 Loewenfeld IE, Thompson S. Fuchs's heterochromic cyclitis. that simple heterochromia is transmitted as a A critical review ofthe literature I. Clinical characteristics of genetic trait, and that FHU arises as a complica- the syndrome. Sunv Ophthalmol 1973; 17: 394-457. 12 Loewenfeld IE, Thompson S. Fuchs's heterochromic cyclitis. tion in some (probably most) ofthese. A critical review of the literature II. Etiology and mecha- Heterochromia can occur as a dominant condi- nisms. Surv Ophthalmol 1973; 18: 2-61.

13 Liesegang TJ. Clinical features and prognosis in Fuchs's http://bjo.bmj.com/ tion, either as part of the Waardenburg syn- uveitis syndrome. Arch Ophthalmol 1982; 100: 1622-6. drome or, more questionably, in isolation.'9 In 14 Jain IS, Gupta A, Gangwar DN, Dhir SP. Fuchs' heterochromic cyclitis: Some observations on clinical picture and the Waardenburg syndrome the underlying on cataract surgery. Ann Ophthalmol 1983; 15: 640-2. cause lies in the neural crest.20 In our series there 15 Tabbtttt BR, Tessler HH, Williams D. Fuchs' heterochromic iridocyclitis in blacks. Arch Ophthalmol 1988; 106: 1688-90. was anecdotal evidence of heterochromia in six 16 Jones NP. Fuchs' heterochromic uveitis: A reappraisal of the out of 601 first degree relatives. In the two clinical spectrum. Eye 1991; accepted for publication. relatives we were able to examine there was 17 Saari M, Vuorre I, Tiilikainen A, Algvere P. Genetic back- ground of Fuchs' heterochromic cyclitis. Can J Ophthalmol unilateral sector hyperpigmentation. The 1978; 13:240-6. on September 29, 2021 by guest. Protected copyright. 18 Waardenburg PJ, Franceschetti A, Klein D. Genetics and heterochromia seen in Waardenburg syndrome ophthalmology. Oxford: Blackwell, 1961. is also often unilateral and segmental (Newton V, 19 McKusick VA. Mendelian inheritance in man. 9th ed. Entry 14250: Heterochromia iridis. Baltimore: Johns Hopkins personal communication). However the under- University Press, 1990. lying pathology must be quite different because 20 Foy C, Newton VE, Wellesley D, Harris R, Read AP. Localisation of the gene for Waardenburg syndrome type I FHU is not a complication of Waardenburg to 2q37 and possible homology to the Splotch mouse. Amj syndrome.'2 True FHU has not been described Hum Genet 1990; 46: 1017-23.