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Sorsby fundus dystrophy (SFD) is a dominantly inherited macular dystrophy in which bilateral central visual loss occurs in the fifth decade of life.1 Duke-Elder and Perkins described it as pseudo-inflammatory macular dystrophy.2 It is now known to be caused by mutations in exon 5 of the gene for TIMP3,3 tissue inhibitor of metalloproteinases-3. The disorder has variable expressivity and signs vary depending on age at review, but common fundus characteristics include diffuse fine yellow-white deposits, macular choroidal neovascularistion (CNV), and delayed choroidal filling and retinal pigment epithelial (RPE) mottling on fluorescein angiography (FFA). Later stages include atrophy of the macula and periphery.1,2
Punctate inner choroidopathy (PIC) is characterised by multiple yellow opacities at the level of the inner choroid of the posterior pole and mid periphery without other evidence of inflammation. CNV is a frequent complication which responds to steroid treatment.4
We describe a patient who presented with clinical signs consistent with PIC complicated by bilateral CNV. The CNV was treated over a period of six years using either oral or subTenon steroids with improvement in vision. She was subsequently found to have SFD.
A 36 year old woman presented with a two month history of difficulty reading with the left eye. Past ocular and medical history were unremarkable except for mild myopia (−2.00 dioptres).
On examination, visual acuities (VAs) were 6/5 in the right and 6/18 in the left eye with contact lenses. Fundoscopy revealed a retinal haemorrhage encroaching on the centre of the left fovea and a small chorioretinal scar temporal to the right fovea, which did not appear treatable on fluorescein angiography (FFA). Four months later, she became symptomatic in the right eye with distortion and blurring of vision (fig 1). The RVA was 6/24 and the LVA had stabilised at 6/12 with an old chorioretinal scar in the inferotemporal macula and a small white lesion superior to the fovea. There were several mid-peripheral chorio-retinal scars in both eyes (fig 2). Repeat FFA demonstrated right subfoveal CNV that was not amenable to laser treatment.
Investigations including full blood count, erythrocyte sedimentation rate, electrolytes, renal function, glucose, and chest x ray were all normal. Toxoplasma serology was negative. Serum angiotensin converting enzyme was mildly elevated at 65 U/l (20–54 U/l).
A diagnosis of punctate inner choroidopathy was made based on the clinical signs and the patient was started on 60 mg of daily oral prednisolone, reducing to 5 mg daily by six weeks. This was increased to 30 mg after her RVA deteriorated to 6/60. She remained on a low dose for another three months, by which time her vision returned to a RVA of 6/9 and LVA of 6/6 with glasses.
Three weeks later, she reported a large central scotoma affecting the right eye. RVA was 6/12 and LVA was 6/6. Fundoscopy revealed a small right foveal haemorrhage associated with subretinal oedema. Following a subTenon injection of 20 mg depomedrone, the RVA improved with a subjective reduction in the size of the central scotoma. For the next two years, her vision remained stable.
Four years after initial presentation, her left vision deteriorated again. Fundoscopy revealed areas of CNV superior and adjacent to the old scar in the left eye and FFA confirmed active CNV. She was started on a reducing course of 30 mg oral steroids daily. However, three more episodes of recurrent CNV occurred during oral steroid dose reduction, and were treated by a transient increase in oral steroid dose followed by two subTenon injections of 40 mg triamcinolone. Her LVA improved to 6/9 and remained at 6/12 in the right with resolution of the oedema and scarring. She eventually stopped her steroids for 18 months.
Five years after presentation, a paternal cousin was diagnosed with SFD. Although her family history at presentation was unremarkable, subsequent enquiries revealed that her paternal aunt had been diagnosed with age related macular degeneration (AMD) in her forties. Her father died at the age of 39. She was consequently screened for mutations in the TIMP3 gene which confirmed that she had the same Ser181Cys mutation as her cousin.
Currently, her RVA is 6/12 and her LVA is 6/9 after a recent recurrence was treated with subTenon triamcinolone injection. Six years following presentation, she has developed the characteristic yellow-white deposits originally described by Sorsby in both eyes.
This case highlights two main points. Firstly, the fundus features at presentation mimicked those of PIC, and the characteristic yellow-white deposits of SFD were not obvious until six years later. Although it is possible that this patient may have had a combination of PIC and SFD, she may just illustrate the phenotypic variability of SFD.
Secondly, a clear objective improvement in vision was demonstrated after systemic and peri-ocular steroid treatment. There is now experimental and clinical evidence for using steroids in the treatment of choroidal neovascularisation and thus potentially for SFD. Angiostatic steroids inhibit experimental neovascularisation of the choroid5 and have been used successfully in patients with CNV secondary to ocular histoplasmosis6 and AMD.7
In SFD, mutations in the TIMP3 gene result in the characteristic accumulation of extracellular deposits in Bruch’s membrane which are rich in TIMP-3 protein.8 The TIMP family of proteins regulate extracellular matrix (ECM) degradation by matrix metalloproteinases (MMPs) and therefore play a key role in a range of physiological processes that include angiogenesis. In the homozygous Timp3-null mouse, absent TIMP-3 inhibitory activity leads to the unscheduled activation of MMPs.9 The resultant breakdown of the ECM would allow endothelial cells to initiate the process of sprouting or release sequestered angiogenic factors such as vascular endothelial growth factor and/or basic fibroblast growth factor, which promote endothelial cell proliferation and migration. A third possibility is the exposure of an angiogenic cryptic site upon proteolytic cleavage of ECM molecules such as collagen type IV10 This may account for the reported inhibitory effect of TIMP-3 on angiogenesis11 although mutant TIMP-3 may not have this property.
Interestingly, MMP expression is significantly attenuated by high concentrations of corticosteroids in the eye12 which have also been shown to stimulate TIMP-3 expression.13 Both actions would have the predicted effect of reducing ECM breakdown and inhibiting angiogenesis. It is therefore not unexpected that steroid treatment in our patient had the effect of improving or stabilising vision with suppression of growth of CNV.
It has been noted that laser treatment in SFD is generally unhelpful,14 although the role of photodynamic therapy has yet to be fully evaluated. Therefore, early intervention with steroids, whether orally, peri-ocularly, or even by intravitreal injection, may be a useful treatment in this condition with a notoriously poor natural history.