Nanophthalmos

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Nanophthalmos

Nanophthalmos is a rare genetic disease, included in the spectrum of developmental eye disorders, characterized by a small eye secondary to compromised growth1. Nanophthalmos is derived from the Greek word nano, meaning dwarf, and nanophthalmic eyes typically present very high to extreme axial hyperopia without other obvious structural defects2,3.

Classification

Warburg (1981, 1993) defined nanophthalmos or pure microphthalmos as a developmental arrest of ocular growth not associated with other ocular malformations. Later, it was underscored that nanophthalmos was a form of total microphthalmos, where both anterior and posterior segments are shortened4,5.

Syndromic VS Non-syndromic nanophthalmos

Nanophthalmos may present as an isolated disorder, or be part of a syndrome, such as the “nanophthalmos, retinitis pigmentosa, foveoschisis and optic drusen syndrome”6,7, the “oculo-dento-digital syndrome (ODD syndrome)”8, “autosomal dominant vitreoretinochoroidopathy with nanophthalmos (ADVIRC)”9 and the “Kenny-Caffey syndrome”10.

Genetics

Most cases of nanophthalmos are sporadic5, but autosomal dominant and recessive modes of inheritance have been described3,11,12.
Two loci for autosomal dominant non-syndromic nanophthalmos (NNO1 and NNO3) have been identified11,13. The NNO1 (OMIM #600165) locus maps to chromosome 11p, while the NNO3 locus (OMIM #611897) maps to chromosome 2q11-q14. Regarding the NNO1 locus, no gene has been cloned, but an association between this locus and a more severe late-stage phenotype of angle-closure glaucoma/narrow occludable anterior-chamber angles11 has been reported. Li et al (2008) excluded the three known eye development genes that map inside NNO3 interval (Gli2, Inhibin beta B and En-1 genes). Thus, a novel gene has yet to be identified13.
Autosomal recessive non-syndromic nanophthalmos (NNO2) (OMIM #609549) is caused by mutations in the membrane-type frizzled related protein (MFRP) gene (OMIM #606227) on chromosome 11q2312, and also by mutations in the PRSS56 gene (OMIM #613858) on chromosome 2q37.114. Sundin et al (2005) performed linkage analysis using DNA samples from 16 members of an Amish-Mennonite kindred which turned out to be a branch of the family originally reported by Cross and Yoder (1976), including 5 individuals with nanophthalmos3,12. Mutations in the MFRP gene were identified as a cause of classic non-syndromic recessive nanophthalmos12.
The MFRP gene has 13 exons, which translate into a 579 amino acid protein. This resulting protein comprises three conserved domains: a transmembrane domain with homology to the frizzled family of proteins, containing two cubillin sub-units; a low density lipoprotein receptor A; and a cysteine-rich domain, that can bind to wingless type proteins (WNTs), which might be involved in eye development, mediating cell growth15.
The PRSS56 gene, first described by Gal et al (2011)16, was linked to autosomal recessive isolated posterior microphthalmos; Orr et al (2011) linked the gene to autosomal recessive isolated nanophthalmos. This gene has 13 exons and EST database analysis suggests that it is expressed in embryonic tissue, testis, brain and eye. Additionally, the GeneCards database data shows that it is expressed broadly at lower levels and slightly higher in a variety of tissues including testis, lymph node, brain, retina, and smooth muscle; possibly also in pineal gland according to BioGPS. RT-PCR of human eye showed abundant PRSS56 expression in the neural retina, cornea, sclera, and optic nerve. In the mouse eye and retina, Prss56 expression begins at embryonic day 17, increases with development, and is maintained at a high level in adulthood; moreover, high levels of expression were observed in ganglion cells. The coded protein has 603 aminoacids and is predicted to contain a serine protease enzymatic domain14,17. No genotype-phenotype correlations have been made for either gene.

Pathophysiology

The MFRP protein is selectively expressed in the retinal pigment epithelium (RPE) and the ciliary body, with low expression in the brain. MFRP concentrates towards the apical side of the RPE cells, with virtually none in Bruch’s membrane. Patients completely lacking MFRP protein have no identifiable pathology outside the eye. In the fetal eye, at 7 weeks gestation, no MFRP signal is detected in the RPE. A distinct signal is observed in the RPE at 20 weeks gestation which indicates that MFRP expression begins relatively late during eye development1.
Functionally, MFRP seems to be essential for the eye to reach its full size at birth, and also for correct emmetropization, since it is associated with regulation of ocular axial growth1. Heterozygote MFRP carriers without nanophthalmos described by Sundin et al (2005) showed no hyperopia; however, ocular features like corneal curvature and anterior chamber depth revealed semidominance as they were significantly altered when compared with the general population12. There is some controversy regarding the role of MFRP in retinal function. While Sundinet al (2008) stated that the MFRP protein is not essential for retinal function, Ayala-Ramirez et al (2006) claimed that it may be necessary for photoreceptor maintenance, considering the severe rod-cone dystrophy phenotype observed in their patients1,6. Neri et al (2012) showed progressive rod-cone degeneration as the only significant finding in a patient followed-up for 30 months18.

Histopathology

Many cases of nanophthalmos complicate with uveal effusion with or without exudative retinal detachment; the reason for such phenomena is thought to be blockage of outflow from the vortex venous system secondary to a thickened sclera. Yamani et al (1999) showed that all three scleral layers had abnormal collagen fibrils that were frayed and split; the degree of abnormality increased inwards, with less abnormal episclera and stroma, and considerable changes in lamina fusca. Ultrastructural studies also demonstrated a larger range of collagen fibril diameters with normal fibril banding periodicities. The authors suggested that the frayed fibrils contributed to scleral inelasticity which caused sequestration of extracellular fluid and consequently choroidal congestion, choroidal detachment, and/or exudative retinal detachment19.
Fukuchi (2009) showed that scleral proteoglycans were qualitatively identical in nanophthalmic and control tissues, but very different quantitatively. Nanophthalmic eyes had lower amounts of chondroitin sulfate, which could be partially responsible for fluid retention20.

Diagnosis

Nanophthalmos is usually characterized by bilateral and symmetrical small eyes, associated with: shortened axial length (20mm or less; at least two standard deviations below age-matched controls), high corneal curvature, high lens/eye volume ratio with narrow iridocorneal angle, high hyperopia (ranging from +8.00 to +25.00) and scleral thickening1. Patients with nanophthalmos usually feature a small eye, deeply-set in the orbit (enophthalmos) and covered by narrow palpebral fissures; bilateral mild ptosis may be present2,3,11.
Refractive analysis displays high to extreme hyperopia2,3. In children, both eyes usually exhibit extreme axial hyperopia but are highly functional; correction with glasses that resemble aphakic spectacles usually results in moderate to good visual acuities. Evaluation of the total axial length demonstrates reduced values as well as smaller equatorial and transverse diameters resulting in a reduced total ocular volume4,21.
Visual acuity (VA) is primarily affected by high hyperopia, present since birth, which may cause bilateral amblyopia. Secondarily, several complications (more commonly observed in adults1) can additionally worsen the patients’ vision. These include angle closure glaucoma [prominent iris convexity, due to high lens/eye volume ratio, eventually leads to peripheral anterior synechiae (PAS) and blocks the outflow of aqueous humor], retinal folds and/or exudative detachments, and cystic macular edema12. Best-corrected visual acuity (BCVA) is rarely above 20/40 at any point in nanophthalmic patients’ lives; Walsh et al (2007) reported a rudimentary foveal avascular area in 4 adult nanophthalmos patients (54 to 70 years) that could further contribute for the reduced VA22.
Slit-lamp examination discloses a transparent cornea with diameters ranging from 9 to 11.5 mm, spanning from the microcornea range to normal values. Keratometric evaluation reveals higher, regular, corneal curvatures with or without astigmatism. A shallow anterior chamber and narrow iridocorneal angle result from a normal or thicker than usual transparent lens that occupies a disproportionately large percentage of intraocular volume. As a consequence, the presence of a prominent iris convexity and impending angle closure with peripheral anterior synechiae (that may eventually form) may be observed beyond the fourth decade21,23.
Fundus examination may reveal a normal posterior segment. The discs may be normal or appear crowded, or display the infrequent finding of disc drusen12. A variety of macular and peripheral retinal findings have been described; these include varying degrees of macular hypoplasia, rudimentary foveal avascular zone22, foveal schisis-like changes24, foveal cysts25, macular folds, and small yellowish deposits in the mid-periphery12 similar to flecks, which can be detected as bright spots with red-free scanning imaging, or as dark spots with autofluorescence imaging, translating RPE mottling and atrophy18. Additional reported retinal manifestations include a retinitis pigmentosa-like phenotype26, choroidal effusions (spontaneous or post-surgical27,28) and nonrhegmatogenous retinal detachments26.
Structural analysis using optical coherence tomography (OCT) may reveal absence of foveal pit, diffuse macular thickening, rudimentary foveal avascular zone22, schisis of the outer retinal layers with discrete bridging elements at the fovea, or evidence of macular cysts or cystic-like changes. Jackson et al (2012) described two cases of nanophthalmos with retinal folds, where only the layers anterior to the external limiting membrane were affected; the innermost layers were normal, whereas the inner nuclear, outer plexiform, and outer nuclear layers appeared thickened. This is different from previous reports of folds where the whole neurosensory retina was affected. These two cases could simply be different, or the SD OCT used allowed a better evaluation. This finding defies the original thoughts of different embryological origin of RPE and neurosensory retina as cause for the macular folds. The authors suggest retinal vessels’ tortuosity as the potential cause for the folds, since they travel more anteriorly in the neurosensory retina29. Recently one case of retinal pigment epithelium detachment has been reported30.
Electrophysiological testing (ERG) varies from normal responses to variable degree of photopic and scotopic dysfunction12,25.
Additional clinical findings may include nystagmus and strabismus, usually non-accommodative esotropia31.

Glaucoma and nanophthalmos

Patients with nanophthalmos are prone to primary angle closure glaucoma in adulthood, result of the disproportion between the normal increase in lens volume and a smaller anterior segment32. Diagnosis and follow up are rather difficult due to a small disc, where even a small cup may be a sign of glaucoma, along with inaccurate visual field testing, because many patients have high plus lenses and reduced BCVA. In these cases SD OCT may detect subtle wedge-shaped loss of nerve fiber layer; HRT may assist in monitoring the deterioration of disc parameters; and stereo fundus photos offer reliable documentation of disc morphology33.

Management

Nanophthalmos patients pose a continuous therapeutic challenge to the ophthalmologist as early recognition and management of the diagnosis and complications are crucial to maximize visual outcome. Depending on the patient’s age, a series of problems need to be addressed in a structured manner.

In children, refractive errors must be fully corrected and complete cycloplegic retinoscopy values should be given to avoid unilateral and bilateral amblyopia. Refractive correction with spectacles should be started as early as possible. Some patients may present with incomplete accommodation; in such cases, bifocals or progressive power lenses with +3,00 adds for near vision may allow better performance for near activities. Contact lenses (soft or RGPs) represent a great alternative for the esthetically non-appealing aphakic glasses, but appropriate evaluation of the corneal curvatures and assessment of corneal diameters are essential to achieve the best possible fit. When unilateral amblyopia is identified, patching probably represents a better option to atropine penalization due to anatomical crowding of the anterior segment.
Strabismus surgery should be carried out in non-accommodative esotropia cases to allow binocular vision and prevent amblyopia.
In adults, the nanophthalmic eye poses a different set of problems such as those related with angle-closure glaucoma, cataract surgery and exudative retinal detachments. Since response to medical treatment is poor, even when started early, many surgical procedures have been tried to prevent/treat glaucoma, namely Nd YAG laser iridotomy, iridoplasty, trabeculectomy, sclerotomy and lens extraction32.
If narrow occludable anterior-chamber angles with normal intraocular pressure (IOP) values are detected iridotomy should be performed to eliminate the pupillary block component before the occurrence of PAS34. Nonetheless, its efficacy may be temporary, and the risk of PAS is still present in phakic patients. The next option is peripheral iridoplasty. In cases of high IOP levels filtration surgery should be performed, since medical treatment is unsuccessful in most cases35.
In the first report of cataract surgery in nanophthalmos, Singh et al (1982) recommended deferral due to their disastrous results36. Many breakthroughs have been made with more recent techniques of cataract extraction, such as phacoemulsification, although the appropriate choice of IOL for a small anterior segment still may lead to significant post-operative complications.
Steijns et al (2012) found cataract surgery to be relatively safe in nanophthalmic eyes. Cataract surgery was performed in 43 eyes of 32 patients (>90% with phacoemulsificaion), with no complications in 71.1% of cases and improvement of BCVA in 69.8% of cases. Complications occurred in 12 eyes; the most prevalent were uveal effusion (9.3%) and cystoid macular edema (7.0%)37.
Surgical pearls to improve cataract surgery outcome include anterior vitrectomy, medical dehydration of the vitreous and scleral lamellar resection. Wu et al (2004) performed cataract surgery in 12 eyes of eight patients. The reported cumulative complications in 4 eyes included absence of response to prednisone and subsequent phthisis, broken intraocular lens (IOL) haptic with vitreous loss, choroidal hemorrhage, glaucoma progression and severe iritis. The authors found phacoemulsification to be safe with or without scleral lamellar resection38.
Yamani et al (1999) reported the successful treatment of a choroidal detachment by full-thickness sclerectomies in all 4 quadrants, resulting in deepening of the anterior chamber, resolution of the choroidal detachment, with subsequent improvement of visual acuity19.
As consequence of small size and high levels of ocular comorbidity, nanophthalmic eyes’ surgery has less favorable results and higher complication rates when compared to the general population39. A sudden decompression of the globe following any kind of surgery, including laser iridotomy, may result in rapid progression of choroidal effusion, which may lead to secondary retinal detachment, intraocular hemorrhage and malignant glaucoma34. Despite the high rates of complications there is controversy regarding the need for prophylactic sclerostomies. Many authors consider wise to perform 2 to 4 sclerostomies before opening the eye36, especially if prior history of uveal effusion is present38.

Prognosis

Nanophthalmos has a broad clinical spectrum, determining an also broad spectrum for the patients’ quality of life. Amblyopia can be prevented or minimized if high hyperopia is detected early in life. Patients should undergo close monitoring to allow proper identification and treatment of complications.

References

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Original article contributed by: Joao Breda, MD, Eduardo J. G. Duarte Silva PhD
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