Achondroplasia is the most common form of human dwarfism, caused by a mutation in the FGFR3 gene. This mutation may be inherited in an autosomal dominant fashion, though 80% of individuals acquire the mutation de novo.1 Several characteristic ophthalmic features are found in achondroplasia, including telecanthus, strabismus, and anterior chamber anomalies.2 Less frequently, case reports have described macular coloboma,3 bilateral keratoconus,4 and cone-rod retinal dystrophy.5 Herein, we present clinical and angiographic findings in a 12-year-old girl with achondroplasia who presented with bilateral retinal peripheral nonperfusion and unilateral rhegmatogenous retinal detachment (RD), which has not been previously described in achondroplasia.
A 12-year-old girl with achondroplasia presented with 5 days of progressive vision loss in the left eye. She was born at full term and was otherwise healthy, though her family noted one mechanical fall with head trauma 2 years prior. She had no personal nor family history of ophthalmic disorders. On examination, she displayed achondroplastic features, including short stature, short limbs, macrocephaly, frontal bossing, telecanthus, and a depressed nasal bridge. On ophthalmic examination, with most recent cycloplegic refraction of −6.25 + 2.00 × 180 and −3.50 + 0.50 × 180, her best-corrected visual acuity (BCVA) was 20/25 and 20/100 in the right and left eyes, respectively. Anterior segment examination was normal. Fundus examination demonstrated lattice degeneration in both eyes, and a macula-involving RD from 1 o'clock to 6 o'clock with a single temporal retinal break in the left eye. The decision was made for exam under anesthesia, intraoperative fluorescein angiography (FA), and a primary scleral buckle under the operating microscope. FA demonstrated early vascular truncation with peripheral nonperfusion in both eyes (Figure 1). After conjunctival peritomy and isolation of the rectus muscles, a chandelier was placed through a 25-gauge trocar through the pars plana 3.75 mm posterior to the limbus, 180° away from the retinal break. The break was directly visualized and marked using the Resight wide-field viewing system (Zeiss, Oberkochen, Germany), O'Connor scleral depressor (Storz Ophthalmics/Bausch + Lomb, Rochester, NY), and a sterile surgical marker. An encircling silicone band and 106 meridional implant was placed to support the break. A 30-gauge needle was inserted under the buckle to drain the subretinal fluid under direct visualization, and laser photocoagulation was placed 360°. A 30-gauge needle was then used to inject 0.35 mL of 100% SF6 gas intravitreally. At postoperative month 3, BCVA was 20/20 and 20/60 in the right and left eyes, respectively, with fully attached retina posterior to the buckle.
(A, B) Right eye: Fundus photograph demonstrating an unremarkable retina, and fluorescein angiography (FA) at 1 minute 45 seconds demonstrating early vascular truncation with peripheral nonperfusion. No leakage was observed in late phases. (C–E) Left eye: Fundus photograph demonstrating a macula involving temporal retinal detachment. The detachment extends posteriorly to an area of chorioretinal scaring suggestive of a demarcation line (white arrow). FA at three minutes shows early vascular truncation, peripheral nonperfusion, and small vessel leakage.
We report the case of bilateral retinal peripheral nonperfusion and unilateral macula-involving RD in an achondroplastic patient to add incremental knowledge regarding aberrant retinal vascular phenomena observed in pediatric disease states. Prior data support a degree of peripheral nonperfusion as ubiquitous and nonpathologic.6 Blair et al. quantified this range of normal peripheral nonperfusion in pediatric patients aged 2 months to 13 years and proposed a threshold of avascular retina extending less than 2.0 disc diameters from the ora serrata as normal.7 In light of these prior data, we infer the peripheral avascularity observed in this patient was abnormal and may be linked to her history of achondroplasia, as she did not have other etiologic comorbidities. Specifically, she was born at full-term, and outside of her achondroplasia, she was otherwise healthy with no other systemic disease. She had moderate myopia in both eyes, but otherwise did not have personal or family history of ophthalmic disease. The small vessel leakage noted in the left eye can be attributed to the RD; however, RD would not explain the parallel peripheral vascular nonperfusion observed in both eyes.
Pathologic peripheral nonperfusion is well-described in several pediatric ophthalmic disorders, including retinopathy of prematurity (ROP),8 familial exudative vitreoretinopathy (FEVR),8 incontinentia pigmenti (IP),8 Coat's disease,9 Norrie disease,10 Eales disease,11 and pathologic myopia.12 Although in many of these conditions, prompt treatment of retinal ischemia is needed to prevent devastating proliferative retinopathy, at this time, the clinical importance of peripheral nonperfusion in achondroplasia is not entirely clear. The authors queried whether chronic peripheral retinal ischemia may have predisposed this patient to degeneration of the peripheral retina and to retinal breaks. In the case of ROP,13 FEVR,13,14 and Norrie disease,14 abnormalities in the Wnt-signaling pathway have been implicated as a molecular mechanism of disease. Similarly, we propose a molecular mechanism for the aberrant retinal angiogenesis observed in achondroplasia.
More than 99% of achondroplasia cases stem from two mutations in the fibroblast growth factor receptor 3 (FGFR3) gene.2 During embryonic development, fibroblast growth factors (FGFs) are important regulators of mesenchymal and neuroectodermal cells, and play a key role retinal development and survival.15 In a murine model, Cinaroglu et al. reported FGFR9 and its preferred receptors FGFR2IIIc and FGFR3IIIc expressed in vivo in whole rat retina.16 In vitro, cultured Muller glia exposed to exogenous FGF9 exhibited a dose-dependent increase in Muller glial proliferation.16 These data suggest a role for FGF in retinal differentiation and maturation, and it is possible that anomalies in the FGFR3 gene responsible for the typical phenotypic systemic features associated with achondroplasia may also be implicated in the anomalous retinal vascular development observed in these patients.
Mutations in FGFR3 are also associated with a number of other developmental disorders, including camptodactyly, Crouzon syndrome, hypochondroplasia, Muenke syndrome, and thanatophoric dysplasia.17 Thus, given the implicated role of FGFR3 mutations in aberrant retinal development in achondroplasia, one may consider FA screening in patients with these related developmental disorders, most notably if they present with ophthalmic symptoms and abnormalities.
- Vajo Z, Francomano CA, Wilkin DJ. The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: The achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr Rev. 2000;21(1):23–39.
- Rosenthal AR, Ryan SJ Jr, Horowitz P. Ocular manifestations of dwarfism. Trans Am Acad Ophthalmol Otolaryngol. 1972;76(6):1500–1518.
- Ahoor MH, Amizadeh Y, Sorkhabi R. Achondroplasia and macular coloboma. Middle East Afr J Ophthalmol. 2015;22(4):522–524. doi:10.4103/0974-9233.167819 [CrossRef]
- Al Mahmood AM, Al Katan HM, Al Bin Ali GY, Al-Swailem SA. Achondroplasia associated with bilateral keratoconus. Case Rep Ophthalmol Med. 2012;2012:573045.
- Guirgis MF, Thornton SS, Tychsen L, Lueder GT. Cone-rod retinal dystrophy and Duane retraction syndrome in a patient with achondroplasia. J AAPOS. 2002;6(6):400–401. doi:10.1067/mpa.2002.129561 [CrossRef]
- Asdourian GK, Goldberg MF. The angiographic pattern of the peripheral retinal vasculature. Arch Ophthalmol. 1979;97(12):2316–2318. doi:10.1001/archopht.1979.01020020532003 [CrossRef]
- Blair MP, Shapiro MJ, Hartnett ME. Fluorescein angiography to estimate normal peripheral retinal nonperfusion in children. J AAPOS. 2012;16(3):234–237. doi:10.1016/j.jaapos.2011.12.157 [CrossRef]
- Fung TH, Yusuf IH, Smith LM, Brett J, Weston L, Patel CK. Outpatient ultra wide-field intravenous fundus fluorescein angiography in infants using the Optos P200MA scanning laser ophthalmoscope. Br J Ophthalmol. 2014;98(3):302–304. doi:10.1136/bjophthalmol-2013-304450 [CrossRef]
- Tsui I, Franco-Cardenas V, Hubschman JP, Schwartz SD. Pediatric retinal conditions imaged by ultra wide field fluorescein angiography. Ophthalmic Surg Lasers Imaging Retina. 2013;44(1):59–67. doi:10.3928/23258160-20121221-14 [CrossRef]
- Drenser KA, Fecko A, Dailey W, Trese MT. A characteristic phenotypic retinal appearance in Norrie disease. Retina. 2007;27(2):243–246. doi:10.1097/01.iae.0000231380.29644.c3 [CrossRef]
- Kumar V, Chandra P, Kumar A. Ultra-wide field angiography in the management of Eales disease. Indian J Ophthalmol. 2016;64(7):504–507. doi:10.4103/0301-4738.190138 [CrossRef]
- Kaneko Y, Moriyama M, Hirahara S, Ogura Y, Ohno-Matsui K. Areas of nonperfusion in peripheral retina of eyes with pathologic myopia detected by ultra-widefield fluorescein angiography. Invest Ophthalmol Vis Sci. 2014;55(3):1432–1439. doi:10.1167/iovs.13-13706 [CrossRef]
- Dailey WA, Gryc W, Garg PG, Drenser KA. Frizzled-4 variations associated with retinopathy and intrauterine growth retardation: A potential marker for prematurity and retinopathy. Ophthalmology. 2015;122(9):1917–1923. doi:10.1016/j.ophtha.2015.05.036 [CrossRef]
- Warden SM, Andreoli CM, Mukai S. The Wnt signaling pathway in familial exudative vitreoretinopathy and Norrie disease. Semin Ophthalmol. 2007;22(4):211–217. doi:10.1080/08820530701745124 [CrossRef]
- Wilkin DJ, Szabo JK, Cameron R, et al. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet. 1998;63(3):711–716. doi:10.1086/302000 [CrossRef]
- Cinaroglu A, Ozmen Y, Ozdemir A, et al. Expression and possible function of fibroblast growth factor 9 (FGF9) and its cognate receptors FGFR2 and FGFR3 in postnatal and adult retina. J Neurosci Res. 2005;79(3):329–339. doi:10.1002/jnr.20363 [CrossRef]
- FGFR3 fibroblast growth factor receptor 3 [Homo sapiens (human)]Hugo Gene Nomenclature Committee 2016. www.ncbi.nlm.nih.gov/gene/2261. Accessed March 8, 2016.