C h Genet 1998: 54: 315-320 Printed in Irehnd. All rights resewed

Copyright 0 Munksgaard 1998 CLINICAL GENETICS

ISSN l3N9-9163

Short Report

Autosomal recessive familial exudative vitreoretinopathy: evidence for he tero eeneitv

de Crecchio G, Simonelli F, Nunziata G, Mazzeo S, Greco GM, Ri- naldi E, Ventruto V, Ciccodicola A, Miano MG, Testa F, Curci A, D'Urso M, Rinaldi MM, Cavaliere ML, Castelluccio P. Autosomal recessive familial exudative vitreoretinopathy: evidence for genetic het- erogeneity. Clin Genet 1998: 54: 315-320. 0 Munksgaard, 1998

Two unrelated families with familial exudative vitreoretinopathy (FEVR) show apparent autosomal recessive inheritance rather than the previously reported autosomal dominant or X-linked recessive mode of inheritance. Compared with the other modes of inheritance, the inher- ited clinical features here include earlier onset (at birth) and a more severe progressive course.

genetic

Giuseppe de Crecchioa, Francesca Simonelli', Giuseppe Nunziataa, Salvatore Mazzeo', Giovanni Maria Grecoa, Ernest0 Rinaldia, Valerio Ventrutob, Alfredo Ciccodicolab, Maria Giuseppina Mianob, Francesco Testab, Anna Curcib, Michele D'Ursob, Maria Michela Rinaldi", Maria Luigia Cavaliere" and Pia Castelluccio' a Eye Clinic, University of Naples,

International Institute of Genetics and Biophysics, CNR, and Smno di Genetica Media, Ospedale 'A. Cardarelli', Naples, Italy

Key words: autosomal recessve inheritance - exudative vitreoretinopathy - retinal detachment - retinal vessals

Corresponding author: Professor Valerio Ventruto, International Institute of Genetics and Biophysics, CNR, Via Marconi, 10- 801 25 Naples, Italy. Tel.: + 39 81 579783515797840; fax: + 39 81 5607593

Received 1 November 1997. revised and accepted for publication 3 April 1998

Introduction

Familial exudative vitreoretinopathy (FEVR) is an uncommon and heterogeneous group of bilateral congenital eye diseases characterized by severely decreased visual acuity, exudative tractional de- tachment of the retina, and the abnormal invasion of blood vessels into the vitreous cavity. These features and hereditary patterns permit it to be discriminated from several other eye diseases, in- cluding persistent hyperplastic primary vitreous disease, Wagner disease (hyaloretinopathy), Eales disease, Norrie disease, Coats disease, incontinen- tia pigmenti, retinoschisis, prematurity (retrolental

fibroplasia), and effects of oxygen administration at birth.

Investigations to date have shown that the dis- ease, like retinitis pigmentosa (I), is genetically heterogeneous. The first cases were described in 1969 (2) and were associated with autosomal dom- inant inheritance (3-5). The gene for that form has been localized by linkage analysis between INT2 and DllS35 markers at llq13-q23 (6, 7). Re- cently a series of cases with an X-linked recessive inheritance were reported and confirmed (8- 10); those cases prove to result from mutations in the same gene in which other mutations cause Norrie disease (1 1).

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Here we report the occurrence of FEVR with a third pattern of inheritance. Autosomal recessive transmission was observed in two unrelated families, consistent with other instances recently reported by Shastry and Trese (21).

Case reports Family pedigree 1

The only two female siblings (Fig. la), born from healthy parents, are affected by a severe congenital form of FEVR. Born at term, after unremarkable pregnancies and deliveries without exposure to oxygen, their birthweight was in the normal range. Maternal and paternal grandparents were natives of a village of less than lo00 inhabitants, but none of their many relatives was affected. Patient 111, 1: ‘Ablatio falciformis congenita’ was diagnosed in both eyes of this female patient at age 5 . At successive times, she underwent photocoagu- lation, peripheral cryopexy, and later vitrectomy by silicone. In 1982, visual acuity was 20/400 in OD with absence of light perception in 0s . Recent examination (at age 29) showed the following data:

OD: Anterior segment: local opacity of the pos- terior lens capsule at the site of attachment of a vitreous strand. Gonioscopy: open angle with some synechiae. Intraocular pression: 16 mmHg. Fundus examination: dragged disc, retinal vessels stretched in temporal direction; preretinal fibrosis at the posterior pole along the vascular arcades and in the temporal quadrants. White gliotic vitreal mass attached to the posterior lens capsule in the infe- rior temporal quadrant. The temporal periphery shows nonconfluent areas of evolved chorioretini- t is and effects of laser photocoagulation, including some gross pigment deposits and some scattered retinal exudate (Fig. 2). 0s: Anterior segment: complicated cataract with

pupillary irregularity, posterior synechiae and rubeosis iridis. Extensive area of preretinal fibrosis and exudative mass. No light perception. Patient 111, 2: ‘Ablatio falciformis congenita’ was diagnosed in both eyes of this female patient at age 7. At age 15, visual acuity was 20/200 in OD and 20/400 in 0s. Cryopexy and vitrectomy were done in 1984; preretinal haemorrhage occurred in 1990. Recent examination (at age 31) showed the follow- ing data:

OD: Anterior segment: local opacity of the pos- tenor lens capsule. Fundus examination: dragged disc; vascular network distorted and stretched in temporal direction, with vertical course of the arte- rial and venous branches in the superior sectors. A falciform fold extends from the disc through the

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inferior temporal quadrant. Stretching into the vit- reous mainly in the peripheral arefi, where it termi- nates in whitish mass of glial tissue attached to the posterior capsule of the lens. 0s: Anterior segment: local opacity of the poste-

rior lens capsule. Fundus examination: dragged disc; retinal vessels are stretched horizontally- in a temporal direction. From the disc a falciform fold extends towards the superior temporal quadrant (Fig. 3). Abrupt termination of retinal vessels and initial stage neovascularization in the inferior tem- poral sector. Ectopia of the macula, likely situated 1/2 DD from the disc in the superior sectors. Large areas of subretinal and intraretinal exudate in the inferior and nasal sectors. Horizontal pendular nystagmus.

Family pedigree 2

A male and a female (Fig. lb), born from healthy parents, both show severe FEVR. Both were born with normal weights at term by eutocic delivery without exposure to oxygen. Psychomotor devel- opment was normal, and neither has had traumas, infections, or systemic disease. Parents were first degree cousins with no history of ocular or sys- temic diseases. Patient IV, 1: Now age 12, this patient was diag- nosed with bilateral retinal detachment at 6 months and has undergone no surgical interven- tion. Current data:

OD: Visual acuity: no light perception. Anterior segment: paracentral corneal leukoma at 10- 1 1 h; irregular pupilla, shifted upward and to the nasal side; anterior chamber with irregular depth and some iridocorneal peripheral adherences; nascent opacity, mainly under the posterior capsule of the lens. Fundus examination: total retinal detachment (occurring some time ago), reaching the lens. A falciform fold extends from the disc to the periph- eral upper temporal sector. 0s: Visual acuity: 20/400. Anterior segment:

posterior subcapsular opacities of the lens. Fundus examination: retina on the plane. A falciform fold extends from the disk to the peripheral upper tem- poral sector, reaching the posterior end of the lens. Along the fold some spots of hypertrophy of the retinal pigmented epithelium. Retinal exudation in the lower sectors. Horizontal pendular nystagmus. Patient IV, 2: Now age 10, the patient underwent surgery for retinal detachment in the right eye at age 8. Current data:

OD: Visual acuity: 20/400. Anterior segment: posterior subcapsular opacities of the lens. Fundus examination: dragged disc; the disc is turned to-

I

I l l

I V

Autosomal recessive familial exudative vitreoretinopathy

Family 1

1

I A 2 4

Mmily 2

Ill Q affected a examined unaffected

/ deceased

(b)

affected

@ examined unaffected

/ deceased

Fig. 1. a) Pedigree of family 1. b) Pedigree of family 2.

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Fig. 2. Dragged disc of OD in patient 111, 1 (family 1). Retinal vessels are stretched in temporal direction and retinal exudate is scattered in temporal periphery.

ward the temporal side and the upper temporal arcade is stretched and horizontally oriented. In the macular region, atrophy of the pigmented ep- ithelium and some subretinal pigmented stripes are observed. In the nasal sector, some spots of hyper- trophy of the pigmented epithelium. 0s: Visual acuity: no light perception. Anterior

segment: posterior subcapsular opacities of the lens. Fundus examination: total retinal detachment (occurring much earlier). A falciform fold extends from the disc to the peripheral upper temporal sector. Retinal exudation in the temporal sector. Horizontal pendular nystagmus.

Results and discussion

Since the first description of FEVR more than 25 years ago (2), the best characterized mode of inher- itance of FEVR was autosomal dominant with complete penetrance (about 100Y0) but variable expressivity (12). Only one family with autosomal recessive pattern of inheritance has been recently reported by Shastry and Trese (21).

Autosomal recessive vitreoretinal degeneration has been described by Cook and Knobloch (13), but in that syndrome a congenital encephalocele was also present in all affected individuals.

Among other cases of FEVR, four reported by Miyakubo et al. (17) and five among the 101 families reported by Van Nouhuys (3, 4, 14) were sporadic. In the former, all cases occurred in males, raising the possibility of X-linkage. In the latter, where the sex of five individual cases was not specified, close relatives had no perceptible anomalies, and several possible origins of disease have been hypothesized, including a new mutation or non-penetrance of a lesion in the gene giving rise to the autosomal dominant form (14).

The two unrelated families reported here, like one in Shastry and Trese (21), strongly suggest autosomal recessive inheritance. X-linked recessive transmission is ruled out because there are female- affected members. Excluding autosomal dominant transmission is more difficult because many pa- tients have very mild clinical expression of FEVR. However, careful examination of the unaffected parents, including fluorescein angiography, has shown no indication of any abnormalities, nor has any vascular tortuosity been observed. It is worth- while noting that the association in the same farn- ily of FEVR and retinal vascular tortuosity has

Fig. 3. Dragged disc of 0s in patient 111, 2 (family 1). Falciform fold is extended towards the superior temporal quadrant where some exudate are scattered. The macula. presumably, is in the superior sector.

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Autosomal recessive familial exudative vitreoretinopathy

Table 1. Ocular involvement in affected members of two families with autosomal recessive vitreoretinopathy

Family Age Sex Visual acuity Nystagmus Cataract Retinal de- Falciform Macular Peripheral Vascular tachment retinal fold heterotopia avascular abnormalities

areas

Pedigree 1 Case 1 31 F OD 20/400 No Yes No Yes Yes Yes Yes (Ill, 1) 0s NLP Case2 29 F OD 20/200 Yes Yes No Yes Yes Yes No (111, 2) 0s 20/400

Pedigree 2 Case 3 12 M OD NLP Yes Yes Yes Yes No Yes No (N, 1) 0s 20/400 Case4 10 F OD 20/400 Yes Yes Yes Yes No Yes No (No 2) OS NLP

Table 2. Spectrum of the main clinical features in familial exudative vitreoretinopathy ~~~ ~~

No. Retinal Nystagmus Macular Falciform Cataract Peripheral Vascular cases detachment heterotopia retinal fold avascular areas abnormalities

AD 112 24 1 53 8 19 80 83 XL 21 8 7 1 12 3 6 4 AR 4' 4 ? ? 4 ? 4 ?

4 4 3 1 3 4 2 2

AD: Feldman et al. (5), Khairallah et al. (15). Miyakubo et al. (171, Nicholson (18). Ober et al. (IZ), Saraux (19). Van Nouhuys (3, 4, 14) XL: Clement et al. (10). Fullwood et al. (9), Godel (20). Plager et al. (a), Shastry et al. (1, l l ) , Shastry and Trese (21). AR: de Crecchio G (present study), Shastry et al. (1, 11). Shastry and Trese (21y.

suggested some etiological connection of the two autosomal dominant disorders (1 5) . Consistent with the possibility of autosomal recessive inheri- tance, in our first family, the parents and the grandparents were natives of a very small village and in the second family, the parents are consanguineous.

The wide variability in severity and in progres- sion observed even in the same family (1 6) makes it difficult to make a prognostic evaluation in FEVR. Nevertheless, a comparison of autosomal domi- nan't and X-linked inherited cases has been re- ported (1 0), where the prognosis seems worse in the X-linked form. In our cases, visual acuity is less than 20/60 in all patients observed, nystagmus is present in three patients and retinal detachment in both patients of one family (Table 1). Similar to the X-linked form, the patients are seriously visu- ally impaired, with signs of the disease at birth. It is likely that the autosomal recessive FEVR form is the most severe in terms of onset and progression (Table 2).

Acknowledgements The authors would like to thank both families for their contributions to these studies. This work was supported by research grants awarded from the CNR and Telethon-Italy, grant no. E546 to AC; M G M is a Telethon-Italy fellow.

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