Posterior microphthalmos pigmentary retinopathy syndrome

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1 DOI /s CLINICAL CASE REPORT Posterior microphthalmos pigmentary retinopathy syndrome Niranjan Pehere Subhadra Jalali Himanshu Deshmukh Chitra Kannabiran Received: 11 September 2010 / Accepted: 3 March 2011 Ó Springer-Verlag 2011 Abstract Posterior Microphthalmos Pigmentary Retinopathy Syndrome (PMPRS). Posterior microphthalmos (PM) is a relatively infrequent type of microphthalmos where posterior segment is predominantly affected with normal anterior segment measurements. Herein, we report two siblings with posterior microphthalmos retinopathy syndrome with postulated autosomal recessive mode of inheritance. A 13-year-old child had PM and retinitis pigmentosa (RP) and his 7-year-old sister had PM, RP, and foveoschisis. The genetics of this syndrome and variable phenotype is discussed. Importance of being aware of posterior microphthalmos and its posterior segment associations is highlighted. N. Pehere S. Jalali Jasti V Ramanamma Children s Eye Care Center, LV Prasad Eye Institute, Kallam Anji Campus, Banjara Hills, Hyderabad, India S. Jalali (&) Smt Kanuri Santhamma Centre for Vitreo-Retinal Diseases, LV Prasad Eye Institute, Kallam Anji Campus, Banjara Hills, Hyderabad , India subhadra@lvpei.org H. Deshmukh Retina-Vitreous and Uvea, Drushti Foundation, Amravati, Maharashtra, India C. Kannabiran Kallam Anji Reddy Molecular Genetics Laboratory, LV Prasad Eye Institute, Kallam Anji Campus, Banjara Hills, Hyderabad, India Keywords Foveoschisis Microphthalmos Posterior microphthalmos Retinitis pigmentosa MFRP gene Introduction Microphthalmos is a condition where the axial length of eye is smaller by more than two standard deviations compared with normal for that age [1]. It is a heterogeneous group of conditions that can be classified depending on the presence of associated ocular malformations [1] or predominance of anterior or posterior segment involvement [2]. Posterior microphthalmos is a relatively infrequent type of microphthalmos where posterior segment is predominantly affected with normal anterior segment measurements [3]. A number of posterior segment pathologies have been reported in patients with posterior microphthalmos. These include an elevated papillomacular retinal fold, pigmentary retinopathy, chorioretinal folds, uveal effusion syndrome [4], and macular hole [5]. Majority of cases with posterior microphthalmos reported are sporadic. In those with familial occurrence, autosomal recessive mode of inheritance has been postulated as the commonest mode of transmission [3]. Herein, we report siblings from India with posterior microphthalmos pigmentary retinopathy syndrome (PMPRS) with postulated autosomal recessive mode of inheritance.

Case history Case 1 A 13-year-old boy presented with diminution of vision in both eyes since 10 years with predominant difficulty in night vision.

2 Case history Case 1 A 13-year-old boy presented with diminution of vision in both eyes since 10 years with predominant difficulty in night vision. The best corrected visual acuity (BCVA) in right eye was 20/200 (?7.00 DSphere) and 20/120 (?7.00 DSphere) in left eye. Anterior segment evaluation and intraocular pressure were normal. Vitreous showed pigmented cells in both eyes. Fundus revealed optic disc pallor with gliosis, midperipheral retinal pigment epithelium mottling changes, and punctate white foveal deposits (Fig. 1a, b). The patient s ocular biometry readings are as shown in Table 1. The axial length was mm in the right eye and mm in the left eye. OCT revealed reduced foveal thickness of 104l in OD and 87l in OS as compared with mean normal of 194 microns (Fig. 1c, d). The ERG showed extinguished wave characteristics (Fig. 1e). ERG was performed in all cases as per International Society for Electrophysiology of Vision standard, 2008, using the Metrovision Monitor (France) [6]. There was no clinically evident optic nerve head drusen in either eye. The patient was the offspring of a consanguineous marriage as depicted in Fig. 2. As seen in the pedigree chart, there is a tendency for consanguineous marriages in the family. Proband s sister, father, paternal aunt, and 2 other family members in father s generation also had a history of night blindness. Case 2 This 7-year-old elder sister of the proband had similar symptoms. Her BCVA was 20/160 with?8dsphere in both eyes. Fundus evaluation showed gliosis nasal Fig. 1 Clinical features of Proband: a Fundus picture of right eye; b Fundus picture of left eye. Both pictures show disc pallor, gliosis nasal to disc, midperipheral pigment mottling, and punctuate lesions at macula. c OCT line scan of right eye and d of left eye showing thinning of fovea. e Flash ERG showing extinguished wave characteristics

3 Table 1 Details of biometry readings of three siblings. Biometry measurements of affected and unaffected siblings Patient Eye Keratometry Horizontal corneal diameter (mm) Axial length (mm) Anterior chamber depth (mm) Lens thickness (mm) Case 1 (13 years) OD at 90, at OS at 90, at Case 2 (7 years) OD 43.0 at 90, 42.0 at OS 43.0 at 90, 42.0 at Case 3 (9 years) OD 44.5 at 90, 43.5 at OS 44.0 at 90, 43.5 at Fig. 2 Pedigree chart of the family (* indicates subjects examined) to disc, arteriolar attenuation, and midperipheral pigmentary mottling in both eyes (Fig. 3a, b). Axial length was mm in OD and mm in OS with biometry readings as mentioned in Table 1. The OCT showed foveoschisis in both eyes (Fig. 3c, d). Her ERG showed extinguished wave characteristics (Fig. 3e). Low vision services were organized for both affected siblings. Their 9-year-old brother was asymptomatic. His unaided VA was 20/20 in both eyes. On clinical examination, both eyes were normal with normal ERG and OCT. The biometry readings are as shown in Table 1. Normal ERG from our laboratory is depicted in Fig. 4. The father of these children (age 36 years) had only perception of light in both eyes. He had a history of night blindness since childhood with complete rapid loss of vision since 2 years. Clinical examination revealed complicated cataract with advanced angle closure glaucoma with IOP of 46 mmhg in OD and 54 mmhg in OS. B-scan in right eye showed retinal detachment with optic nerve head cupping in both eyes. His ocular dimensions were normal. He did not agree to undergo ERG due to logistics of travel and stay. The patient s mother was normal on detailed examination. The genetic analysis done by complete sequencing of all exons of the MFRP gene in the proband did not reveal any pathogenic changes. Sequence alterations found were two known SNPs. Discussion Posterior microphthalmos is diagnosed, as in our two cases (Table 1), in eyes with normal horizontal corneal diameter (11.00 mm or more) and normal anterior chamber depth but with axial length of less than 20.5 mm. This differentiates it from nanophthalmos where corneal diameter is small and anterior chamber is shallow. Various posterior segment manifestations of PM have been reported. These include an elevated papillomacular retinal fold, pigmentary retinopathy, chorioretinal folds, foveoschisis, and optic nerve head drusen. Recently, there have been two reports describing a new syndrome called

4 Fig. 3 Clinical manifestations of case 2. a Fundus picture of right eye and b left eye. Both pictures show disc pallor, gliosis nasal to disc, midperipheral pigment mottling, and punctuate lesions at macula. c OCT line scan of right eye and d of left eye. Both pictures show schisis cavities in neurosensory retina at fovea. e Flash ERG showing extinguished waveforms posterior microphthalmos pigmentary retinopathy syndrome (PMPRS) comprising of posterior microphthalmos, retinitis pigmentosa, optic nerve (ON) drusen, and foveoschisis [7, 8]. In our two cases, PM was associated with a typical RP like pigmentary retinopathy in both siblings associated with extinguished ERG and symptoms of night blindness. However, we did not find any clinical or autofluorescence evidence of ON drusen. Foveoschisis was present in one affected. It seems that the syndrome may have some constant features and some variable features: constant features might include PM and retinitis pigmentosa (RP) while ON drusen and foveoschisis may be the variable features. Phenotypic variability has been reported in a study of 4 families with posterior microphthalmos retinopathy syndrome arising due to MFRP gene mutations [9]. The authors noted a variable presence of optic nerve head drusen, serous retinal detachments, and foveal cysts. In both previous reports of PMPRS, mutations in membrane type frizzled-related protein (MFRP) gene (located at 11q23) was demonstrated to be present [7 9]. The role of MFRP as a gene controlling both axial length and retinal development is not understood although it is implicated in the Frizzled/Wnt signaling pathway. However, the genetic analysis of MFRP in our cases did not show any mutation. This may suggest role of other genes for this phenotype. The other possible genes involved in microphthalmos like orthodenticle homeobox 2 [OTX2], retina and anterior neural fold homeobox [RAX], SRY-box 2 [SOX2], CEH10 homeodomain-containing homolog [CHX10], and growth differentiation factor 6 [GDF6] may be involved [10]. It may be possible that any gene responsible for retinitis pigmentosa could also be involved. A comprehensive screening would be required to find the gene mutation.

Fig. 4 Figure showing a normal ERG tracing from our laboratory Zenteno JC & et al 1 have described compound heterozygosity for MFRP mutations as the source of this disease and suggested that some

5 Fig. 4 Figure showing a normal ERG tracing from our laboratory Zenteno JC & et al 1 have described compound heterozygosity for MFRP mutations as the source of this disease and suggested that some aspects of the phenotype are probably age-dependent like glaucoma. The father in this study (age 36 years) had advanced angle closure glaucoma in both eyes and children did not. While not observed in young patients, (as reported by Ayala-Ramirez et al. [7] and Zenteno et al. [11]) glaucoma was noted in older participants in the research performed by Crespi et al. [8]. It is interesting to note in the current family reported, the father does not have microphthalmos and due to no view of the retina, we could not ascertain definitely whether he had retinitis pigmentosa, though he had history of night blindness since childhood. Patient did not agree for ERG testing. A robust ERG in the left eye of the father may have helped to rule out RP. However, if the left eye had showed no responses, it would be difficult to rule in RP as there could be confounders behind the total cataract such as spontaneously attached retina or vascular occlusions making ERG interpretation difficult. Due to the presence of retinal detachment in the right eye, ERG would not help. Transmission of the disease in this family could be by AR mode (whether or not the father was affected with RP) because the wife was a close relative. Analysis of a larger series of cases at the clinical and genetic levels would certainly help us to understand phenotype of this syndrome better. Acknowledgments We are grateful to Hyderabad Eye Research Foundation for funding this work. References 1. Elder MJ (1994) Aetiology of severe visual impairment and blindness in microphthalmos. Br J Ophthalmol 78:

6 2. Auffarth GU, Blum M, Faller Ute Tetz MR, Völcker HE (2000) Relative anterior microphthalmos. Ophthalmology 107: Spitznas M, Gerke E, Bateman VB (1983) Hereditary posterior microphthalmos with papillomacular fold and high hyperopia. Arch Ophthalmol 101: Khairallah M, Messaoud R, Zaouali S, Ben Yahia S, Ladjimi A, Jenzri S (2002) Posterior segment changes associated with posterior microphthalmos. Ophthalmology 109: Lee S, Ai E, Lowe M, Wang T (1990) Bilateral macular holes in sporadic microphthalmos. Retina 10: Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M (2009) Standard for clinical electroretinography (2008 update). 118: Ayala-Ramirez R, Graue-Wiechers F, Robredo V (2006) A new autosomal recessive syndrome consisting of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disc drusen is caused by a MFRP gene mutation. Mol Vis 12: Crespí J, Buil JA (2008) A novel mutation confirms MFRP as the gene causing the syndrome of nanophthalmos-retinitis pigmentosa-foveoschisis-optic disk drusen. Am J Ophthalmol 146: Mukhopadhyay R, Sergouniotis PI, Mackay DS, Day AC, Wright G, Devery S, Leroy BP, Robson AG, Holder GE, Li Z, Webster AR (2010) A detailed phenotypic assessment of individuals affected by MFRP-related oculopathy. Mol Vis 26: Desmaison A, Vigouroux A, Rieubland C, Peres C, Calvas P, Chassaing N (2010) Mutations in the LHX2 gene are not a frequent cause of micro/anophthalmia. Mol Vis 16: Zenteno JC, Buentello-Volante B, Quiroz-González MA, Quiroz-Reyes MA (2009) Compound heterozygosity for a novel and a recurrent MFRP gene mutation in a family with the nanophthalmos-retinitis pigmentosa complex. Mol Vis 15:

Bilateral Microphthalmos Associated with Papillomacular Fold, Severe Hyperopia and Steep Cornea

Bilateral Microphthalmos Associated with Papillomacular Fold, Severe Hyperopia and Steep Cornea Mojtaba Abrishami, MD 1 Alireza Maleki, MD 2 Ali Hamidian-Shoormasti, MD 3 Mostafa Abrishami, MD 4 Abstract