The clinical progression of disease can vary greatly even within a family with some patients rapidly progressing to total exudative retinal detachment at a young age. Continued progression of the disease past the pediatric age group is uncommon, and stability of the vascularproliferationandexudationischaracteristic.Treatment for the exudative phase of the disease with laser or cryotherapy can be considered. Rhegmatogenous retinal detachment is a possible complication in the second and third decade of life.

laser should be considered. Cryotherapy, which is useful in the presence of more severe exudation, has been shown to cause regression of the peripheral fibrovascular mass in a patient with FEVR [56]. Surgical treatment is warranted in patients with retinal detachment and can be considered for patients with macular folds. The goal of surgical treatment is release of the vitreous traction by either scleral buckling and/or vitrectomy. Studies have shown that for selected cases of FEVR, surgical intervention can be beneficial [51, 57].

Diagnosis of FEVR is made by clinical examination and may necessitate examination under anesthesia in a child. Extensive exudative retinal detachment may warrant intraoperative ultrasound to rule out retinoblastoma or other intraocular tumor. Intraoperative fluorescein angiography may be helpful in identifying avascular peripheral retina and retinal vascular leakage (Fig. 13.10). Examination of asymptomatic family members may be very helpful in confirming the diagnosis for a suspected case.

The differential diagnosis of FEVR includes ROP, retinoblastoma,toxocariasis,Goldmann-FavreDisease, and X-linked juvenile retinoschisis.

13.4.10 Treatment

The goal of treatment of patients with FEVR is prevention of retinal detachment and macular exudates. Treatment of the exudative phase of the disorder with

Patients with FEVR may have decreased visual acuity due to macular exudates or macular dragging and retinal detachment. Complications such as vitreous hemorrhage and exudative retinal detachments can limit visual outcomes. Treatment of the exudative phase of the disorder may alleviate the macular exudates. FEVR is not associated with any systemic associations.

13.4.12 Social and Family Impact

FEVR has an impact on the family given its autosomal dominant mode of inheritance. However, the variable expressivity can lead to uncertainty for visual prognosis and outcome. Early detection in children of families with known history of FEVR may identify early peripheral vascular proliferation more amendable to treatment with laser or cryotherapy [51].

13.5 Goldmann-Favre Syndrome

13.5.1 Introduction

Goldmann-Favre syndrome (GFS) is a rare, bilateral, progressive vitreotapetoretinal degeneration that can affect the choroid, retina, vitreous, and lens.

13.5.2 Historical Context

Fig. 13.10 Fluorescein angiography of the peripheral retina in a child with FEVR showing truncated vessels and leakage

GFS was first described in 1957 [27, 58, 59] by both Goldmann and Favre. More recent studies have

suggested that GFS may be a spectrum of disease that includes enhanced S cone syndrome (ESCS) [60, 61].

13.5.3  Overview with Clinical Significance

Patients with GFS have a classic presentation of early night blindness associated with bilateral pigmentary changes in the retina, degenerative changes in the vitreous cavity, and peripheral or foveal schisis. The vitreous has been described as optically empty, similar to that found in WGN. The peripheral retinal pigmentary changes are similar to retinitis pigmentosa but without bone spicules and with perivascular pigmentation of a nummular variety. Visual prognosis can vary and can be poor due to the extent of macular findings [62].

13.5.4  Classification

No classification system exists for GFS.

13.5.5  Genetics

GFS has an autosomal recessive inheritance pattern that affects both sexes equally. In several families with classic GFS, a mutation in the NR2E3 gene has been demonstrated (Chavala et al. 2005; Haider et al. 2000; Sharon et al. 2003; Wright et al. 2004; Pachydaki et al. 2009). NR2E3 encodes a ligand-dependent orphan transcription factor that is exclusively expressed in the nuclei of rod photoreceptors. Causally associated mutations in NR2E3 have been identified not only in patients with GFS, but also in patients with recessive ESCS and clumped pigment retinal dystrophy (CPRD) (Sharon et al. 2003; Audo et al. 2008). Mutations in NR2E3 have also been identified in autosomal dominant retinitis pigmentosa (Coppieters et al. 2007).

13.5.6  Pathophysiology

The NR2E3 gene encodes a transcription factor that is involved in the specification and maintenance of rod photoreceptor fate (Haider et al. 2000, 2001; Milam

et al. 2002; Chen et al. 2005; Peng et al. 2005; Cheng et al. 2004, 2006). NR2E3 is expressed in primordial retinal cells that are destined for rod photoreceptor fate. It interacts with other transcription factors including the cone rod homeobox protein (CRX) and the neural retinal leucine zipper protein (NRL) to achieve two outcomes: (1) the activation of rod-specific photoreceptor genes such as rhodopsin and (2) the suppression of cone photoreceptor-specific genes. Cones precede rod development and differentiation during human and mammalian ocular development. In failures of rod differentiation, it appears that alternative cone differentiation or degeneration is the default pathway. In the human retina, the lack of the NR2E3 transcription factor in the recessive or null state leads to a complete lack of rod photoreceptors, with coincident nyctalopia and absent scotopic light responses, and an overabundance of short wave sensitive (SWS) or blue cones. The ERG response to scotopic or photopic flashes is very similar due to the lack of functional rods and the overabundance of blue cones. The number of middle and long wave sensitive green and red cones, respectively, is also suppressed in the human retina. The normal human retina has about 120 million rods and about six million cones (~5%) where there are approximately equal numbers of middle wave sensitive (green) and long wave sensitive (red) cones and a smaller fraction (~0.5%) of SWS cones. In early GFS or ESCS, a substantial fraction of the excess blue cones forms whorls and rosettes that can be observed as whitish dots in the outer retina at the RPE level. The distribution of these lesions at least initially follows the perivascular distribution but may also be found in the macula and peripheral retina. Whorls and rosettes appear to represent excess photoreceptors that are unable to integrate into an emerging retinal network. These patterns of excess blue cones appear to underlie the nummular retinal pigmented dystrophy that may appear, commonly following the vasculature to create a dense ring of nummular pigmentary retinal degeneration that surrounds the macula. The white dots in ESCS and the perivascular pattern of pigmented retinal dystrophy seen in GFS and CPRD suggest an underlying pathophysiological relationship between these diseases, which are linked by mutations in a common gene, NR2E3. The relationship of foveal retinoschisis and the optically empty vitreous in GFS to the underlying mutations in NR2E3 remains unclear, but it is tempting to speculate that this also results from a developmental problem. GFS, ESCS, and CPRD resulting from autosomal recessive

NR2E3 mutations appear to represent a unique form of retinal degeneration, which, at least initially, represents a gain of function appreciated by excess SWS blue cone numbers and excess associated blue cone function at the expense of both rod and green/red cone numbers and functions. In most retinal degenerations, a fully mature retinal phenotype emerges and is stabilized prior to the later onset of degeneration, which is due to apoptotic loss of selective cell types in which the mutant gene(s) are expressed.

CRX is an essential transcriptional factor that specifies photoreceptor fate. In primordial photoreceptors, the expression of NRL through a CRX-responsive promoter leads to specification of the rod-differentiated state. NR2E3 is an NRL-responsive gene. Of related interest, ESCS is also a syndrome that can appear in the NRL null state. Under wild type conditions, NR2E3 interacts with CRX, which interacts independently with NRL, in order to promote marked upregulated expression of rod-specific genes. NR2E3 also interacts with CRX to promote suppression of cone-specific genes. Under conditions of recessive null mutations or mutations in the DNA-binding domain (C-terminal) or ligand-binding domain (N-terminal) of NR2E3, the default conditions of cone specification in rod photoreceptors emerge (e.g., ESCS), or a lack of full rod specification results with poor expression of rod-specific genes in rod photoreceptors, with the result of incipient photoreceptor and outer retinal degeneration. Given that CRX, NRL, and NR2E3 are expressed in mature photoreceptors in adult life suggests that the maintenance of the specific photoreceptor differentiation state requires continued modulation by such transcription factors. This is very interesting in that these intrinsic modulatory processes could be the focus of therapeutic endeavors in certain retinal degenerative disease states.

the first decade of life. Peripheral atypical pigmentation as well as peripheral and macular schisis can occur and is usually bilateral and symmetric. Secondary cataracts, usually posterior subcapsular cataracts, can lead to visual loss necessitating surgery [63]. The disorder is progressive, and macular changes as well as peripheral pigmentary changes lead to poor visual prognosis.

13.5.9  Diagnosis and Diagnostic Aids

Diagnosis of GFS is generally based on clinical exam. It clinically can resemble retinitis pigmentosa given the peripheral atypical pigmentation. Fluorescein angiography can be helpful with the macular schisis resembling cystoid macular edema, but no leakage of fluorescein is noted.

ERG findings are dependent on the age of the patient. Both a- and b-wave involvement is usually evident with rod function affected prior to cone function and with progressive worsening of the ERG. Late in the disease, the ERG may be nonrecordable [62]. Recent Optical Coherence Tomography findings showed confluent macular cystoid changes with inner retinal layer loss consistent with a macular hole in one eye and splitting of the neurosensory retina in the macula of the other eye [64].

13.5.10  Treatment

No treatment for GFS is available. Patients are prone to retinal detachments given the peripheral schisis, and these may necessitate scleral buckling and advanced vitreoretinal techniques depending on the presence of vitreoretinal traction.

13.5.7  Incidence

GFS is a rare inherited vitreoretinal dystrophy.

13.5.8  Natural History and Prognosis

(Signs, Symptoms, Timing, etc.)

The presenting symptom of patients with GFS is frequently­ night blindness, which may occur as early as

13.5.11  Complications and Associations

Rhegmatogenous retinal detachments are common arising from the areas of peripheral schisis. These detachments may require advanced vitreoretinal techniques with silicone oil tamponade similar to patients with JXRS. Associated posterior subcapsular cataracts that are contributing to decreased vision should warrant surgical intervention.