Long-term myofibroblast persistence in the capsular bag contributes to the late spontaneous in-the-bag intraocular lens dislocation.

Late spontaneous in-the-bag intraocular lens (IOL) dislocation is a complication presenting 6 months or later after cataract surgery. We aimed to characterize the cells in the lens capsules (LCs) of 18 patients with spontaneous late in-the-bag IOL dislocation. Patients' average age was 82.6 ± 1.5 years (range 72-98), and most of them had pseudoexfoliation syndrome (PEX). Cells from the LCs were positive for myofibroblast (αSMA), proliferation (Ki-67, PCNA), early lens development/lens progenitor (SOX2, PAX6), chemokine receptor (CXCR4), and transmembrane (N-cadherin) markers, while negative for epithelial (E-cadherin) marker. Moreover, the cells produced abundant fibronectin, type I and type V collagen in the nearby extracellular matrix (ECM). During ex vivo cultivation of dislocated IOL-LCs in toto, the cells proliferated and likely migrated onto the IOL's anterior side. EdU proliferation assay confirmed the proliferation potential of the myofibroblasts (MFBs) in dislocated IOL-LCs. Primary cultured lens epithelial cells/MFBs isolated from the LC of dislocated IOLs could induce collagen matrix contraction and continuously proliferated, migrated, and induced ECM remodeling. Taken together, this indicates that long-lived MFBs of dislocated IOLs might contribute to the pathogenic mechanisms in late in-the-bag IOL dislocation.

WAGRO syndrome: a rare genetic condition associated with aniridia and additional ophthalmologic abnormalities / Síndrome WAGRO: uma condição genética rara associada à aniridia e a anormalidades oftalmológicas adicionais

ABSTRACT Aniridia is a congenital eye disorder with a variable degree of hypoplasia or absence of iris tissue. It is caused by loss of function of the PAX6 gene and may be an isolated ocular abnormality or part of a syndrome. WAGRO refers to a rare genetic condition leading to Wilms tumor, aniridia, genitourinary anomalies, mental retardation, and obesity and is caused by a deletion of the short arm of chromosome 11 (11p), where the PAX6 gene is located. Here, we report on an 8-year-old boy with aniridia, polar cataract, and lens subluxation along with neuropsychomotor and speech delays. Karyotype evaluation showed an interstitial deletion including region 11p13-p14, confirming the diagnosis of WAGRO syndrome. In cases of aniridia, a diagnosis of WAGRO syndrome should be considered.

RESUMO A aniridia é uma doença ocular congênita com grau variável de hipoplasia ou ausência do tecido da íris. É causada pela perda de função do gene PAX6 e pode ser uma anormalidade ocular isolada ou parte de uma síndrome. WAGRO refere-se a uma condição genética rara que leva ao tumor de Wilms, aniridia, anomalias geniturinárias, déficit intelectual e obesidade e é causada por uma deleção do braço curto do cromossomo 11 (11p), onde o gene PAX6 está localizado. Aqui, nós relatamos um menino de 8 anos de idade com aniridia, catarata polar e subluxação do cristalino, além de retardo neuropsicomotor e de fala. A avaliação cariotípica revelou uma deleção intersticial envolvendo a região 11p13-p14, confirmando o diagnóstico da síndrome WAGRO. Em casos de aniridia, um diagnóstico de síndrome de WAGRO deve ser considerado.

WAGRO syndrome: a rare genetic condition associated with aniridia and additional ophthalmologic abnormalities.

Aniridia is a congenital eye disorder with a variable degree of hypoplasia or absence of iris tissue. It is caused by loss of function of the PAX6 gene and may be an isolated ocular abnormality or part of a syndrome. WAGRO refers to a rare genetic condition leading to Wilms tumor, aniridia, genitourinary anomalies, mental retardation, and obesity and is caused by a deletion of the short arm of chromosome 11 (11p), where the PAX6 gene is located. Here, we report on an 8-year-old boy with aniridia, polar cataract, and lens subluxation along with neuropsychomotor and speech delays. Karyotype evaluation showed an interstitial deletion including region 11p13-p14, confirming the diagnosis of WAGRO syndrome. In cases of aniridia, a diagnosis of WAGRO syndrome should be considered.

Evaluation of ADAMTS17 in Chinese Shar-Pei with primary open-angle glaucoma, primary lens luxation, or both.

OBJECTIVE To evaluate the coding regions of ADAMTS17 for potential mutations in Chinese Shar-Pei with a diagnosis of primary open-angle glaucoma (POAG), primary lens luxation (PLL), or both. ANIMALS 63 Shar-Pei and 96 dogs of other breeds. PROCEDURES ADAMTS17 exon resequencing was performed on buccal mucosal DNA from 10 Shar-Pei with a diagnosis of POAG, PLL, or both (affected dogs). A candidate causal variant sequence was identified, and additional dogs (53 Shar-Pei [11 affected and 42 unaffected] and 95 dogs of other breeds) were genotyped for the variant sequence by amplified fragment length polymorphism analysis. Total RNA was extracted from ocular tissues of 1 affected Shar-Pei and 1 ophthalmologically normal Golden Retriever; ADAMTS17 cDNA was reverse transcribed and sequenced, and ADAMTS17 expression was evaluated by quantitative reverse-transcription PCR assay. RESULTS All affected Shar-Pei were homozygous for a 6-bp deletion in exon 22 of ADAMTS17 predicted to affect the resultant protein. All unaffected Shar-Pei were heterozygous or homozygous for the wild-type allele. The variant sequence was significantly associated with affected status (diagnosis of POAG, PLL, or both). All dogs of other breeds were homozygous for the wild-type allele. The cDNA sequencing confirmed presence of the expected variant mRNA sequence in ocular tissue from the affected dog only. Gene expression analysis revealed a 4.24-fold decrease in the expression of ADAMTS17 in ocular tissue from the affected dog. CONCLUSIONS AND CLINICAL RELEVANCE Results supported that the phenotype (diagnosis of POAG, PLL, or both) is an autosomal recessive trait in Shar-Pei significantly associated with the identified mutation in ADAMTS17.

Potential Modifying Loci Associated With Primary Lens Luxation, Pedal Hyperkeratosis, and Ocular Phenotypes in Miniature Bull Terriers.

PURPOSE: Primary lens luxation (PLL) in dogs is an inherited disease in which the lens is displaced from its normal position. A truncating mutation in the ADAMTS17 orthologue on CFA03 is reported to cause PLL in several breeds, mostly terriers. However, the complex inheritance pattern of PLL in miniature bull terriers (MBTs) suggests that other loci may have a modifying effect on the ADAMTS17 mutation. This study aimed to detect such loci increasing risk of PLL in Australian MBTs. METHODS: More than 170,000 single-nucleotide polymorphisms (SNPs) across the canine genome were genotyped in 23 PLL-affected and 73 normal Australian MBTs, and association between the PLL phenotype and the genetic markers was investigated by using general mixed effects Cox model survival analysis. RESULTS: The highest association peaks, other than that associated with the ADAMTS17 mutation (P = 2.2e-05), were SNP BICF2G630420272 located at 62.2 Mb on chromosome 15 (P = 7.8e-05) and the region between 30 Mb and 32.5 Mb on chromosome 1 (P = 9.3e-05). Joint analysis showed that the PLL-associated allele of the BICF2G630420272 SNP increased risk of PLL in the presence of the ADAMTS17 mutation (P = 8.117e-04). Candidate genes in the two regions of interest included CPE on chromosome 15 and CTGF on chromosome 1. The ADAMTS17 mutation was also associated with abnormal foot and nail shapes, pedal hyperkeratosis, and persistent pupillary membranes. CONCLUSIONS: Two loci with potentially enhancing effects on the ADAMTS17 mutation were associated with PLL in Australian MBTs. Association of the ADAMTS17 mutation with possible pedal skeletal abnormalities in MBTs supports PLL in this breed and Weill-Marchesani syndrome-like disease in humans as being homologous diseases.

Lens subluxation and retinal dysfunction in a girl with homozygous VSX2 mutation.

OBJECTIVE: To describe a unique lens subluxation phenotype in a child from a consanguineous family and to determine its genetic basis. METHODS: Ophthalmologic examination (including ocular biometry and electroretinography [ERG] for the proband) and autozygosity-analysis-guided exome sequencing for the family; confirmatory candidate gene sequencing in the family and ethnically matched controls. RESULTS: An otherwise healthy 3-year-old Saudi Arabian girl with poor vision since birth had smooth irides, lens subluxation, cone-rod dysfunction, and high myopia - features resembling Knobloch syndrome but differing in regard to direction of lens subluxation (superior rather than temporal) and the pattern of chorioretinal atrophy (without vitreous condensations or distinct macular atrophy). Autozygome-guided exome sequencing revealed the girl to harbor a homozygous exon 5 mutation in the ocular transcription factor gene visual homeobox 2 (VSX2) [c.773delA; p.Lys258SerfsX44] that was heterozygous in the unaffected brother and parents and absent in 100 healthy ethnically matched controls and on-line databases. Previously reported VSX2 mutations have affected the DNA-binding domains and only been associated with microphthalmia. Unlike previously reported mutations, the current VSX2 mutation is downstream to the protein's DNA binding domains. CONCLUSIONS: The phenotype of this girl is unique and suggests a normal regulatory role for VSX2 in iris, zonule, and cone-rod development. For a consanguineous family with suspected recessive ocular disease but without a clear candidate gene, autozygome-guided exome analysis is a powerful technique, even when only a single patient is affected.

Recessive mutations in LEPREL1 underlie a recognizable lens subluxation phenotype.

PURPOSE: To uncover the homozygous recessive gene mutation underlying familial lens subluxation and/or juvenile lens opacities in four sisters from a consanguineous family. METHODS: Prospective family study (clinical phenotyping; homozygosity-analysis-guided candidate gene testing). RESULTS: The proband was a 14-year-old girl with long-standing poor vision, bilateral temporal lens subluxation, lens opacities, and axial high myopia. There were no syndromic findings, and fibrillin-1 sequencing was normal. Three sisters, also non-syndromic, had undergone bilateral juvenile lens surgery (two for juvenile cataract, 1 for lens subluxation) within the first two decades of life. Both sisters who had cataract surgery developed bilateral post-operative retinal detachments and one had documented lens instability during cataract surgery. Genetic analysis revealed the phenotype to segregate with a novel homozygous recessive mutation in LEPREL1 (c.292delC; p.Gly100Alafs*104). Recessive mutations in this gene were recently highlighted as a cause for axial myopia and early-onset cataract in two families for whom some affected members also had ectopia lentis and/or post-operative retinal detachments. CONCLUSIONS: Recessive LEPREL1 mutations should be recognized as part of the differential diagnosis of lens subluxation. The associated phenotype is non-syndromic and distinguishable from other causes of ectopia lentis in the context of its additional features: juvenile lens opacities, axial myopia, and a predisposition to retinal tears/detachment following intraocular surgery.

Spontaneous dislocation of a crystalline lens to the anterior chamber with pupillary block glaucoma in Noonan Syndrome: a case report.

We report a 13-year-old child with Noonan Syndrome who developed spontaneous dislocation of the crystalline lens in anterior chamber leading to pupillary block glaucoma in the left eye and subluxation of lens in right eye. Intracapsular extraction of the dislocated lens was done in the left eye. Prompt diagnosis and management is needed in such cases to avoid glaucoma and corneal endothelial cell damage. We could not find any such case after thorough Medline search.

Results of fibrillin-1 gene analysis in children from inbred families with lens subluxation.

BACKGROUND: Autosomal dominant mutation of the FBN1 gene (fibrillin-1) results in a spectrum of disease (type 1 fibrillopathies) ranging from Marfan syndrome with lens subluxation and cardiovascular complications to milder connective tissues phenotypes. The likelihood of FBN1 mutation in children referred to ophthalmologists because of lens subluxation is unclear. We report the results of routine FBN1 sequencing for children from inbred families referred with nontraumatic lens subluxation without cataract or vitreoretinal degeneration. METHODS: Medical records of such patients from 2009 to 2012 were retrospectively reviewed. RESULTS: Eight identified probands (3-11 years old; 4 boys) from consanguineous and/or endogamous Saudi Arabian families all harbored FBN1 mutation--7 autosomal dominant and 1 autosomal recessive (homozygous). Four mutations were novel. One child had a family history for lens subluxation. Seven had facial and/or skeletal features suggestive of type 1 fibrillinopathy. The parents of the autosomal recessive case were confirmed to be heterozygous carriers without lens subluxation or other clinical signs of type 1 fibrillinopathy. CONCLUSIONS: Autosomal dominant type 1 fibrillinopathy was the major cause for lens subluxation in this cohort despite the fact that families were inbred and thus at higher risk for recessive disease. This highlights the frequency of new mutations in the gene and has important implications for genetic counseling and systemic assessment. The autosomal recessive case represents the fourth such case reported to date. Her heterozygous parents were unaffected carriers, suggesting that some FBN1 mutations can act as hypomorphic alleles rather than exhibiting the dominant negative effect typically attributed to FBN1 mutations.

Surgical management of lens subluxation in Marfan syndrome.

PURPOSE: To review the literature on the surgical management, describe a simplified surgical technique, and to report the postoperative clinical course of ectopia lentis removal in patients with Marfan syndrome. METHODS: The medical records of patients with a clinical diagnosis of Marfan syndrome and clinically significant lens subluxation were retrospectively reviewed. Patients underwent lens extraction by a single surgeon via a simplified anterior segment approach. The pre- and postoperative best-corrected visual acuity, biometric measurements, intraocular pressure, and incidence of surgery-related complications were reviewed. RESULTS: A total of 42 eyes of 22 patients were included. Mean postoperative follow-up was 4.9 ± 2.9 years (range, 1-10 years). Average age at surgery was 10.2 ± 9.2 years (range, 2-37 years), with 18 patients (36 eyes) ≤ 18 years of age. The average preoperative best-corrected visual acuity was 20/80, and the average postoperative best-corrected visual acuity at last follow-up was 20/25, with an average improvement of 6 lines on the Snellen chart. All eyes had a best-corrected visual acuity > 20/30 at last follow-up with aphakic correction. One eye of 1 patient developed a retinal detachment following blunt trauma. No other intra- or postoperative complications were reported. CONCLUSIONS: Anterior lensectomy and limited vitrectomy with aphakic correction is safe and provides a consistent visual outcome in patients with lens subluxation secondary to Marfan syndrome. This is especially important in pediatric patients, in whom long-term follow-up for iris- and scleral-fixated intraocular lenses is limited.

ADAMTS17 mutation associated with primary lens luxation is widespread among breeds.

Primary lens luxation (PLL) is a well-recognized, painful and potentially blinding inherited ocular condition in dogs. We screened PLL-affected dogs of 30 different breeds, to identify those which carried a previously described c.1473+1 G>A mutation in ADAMTS17 that is associated with PLL in Miniature Bull terriers, Lancashire Heelers, and Jack Russell terriers. This ADAMTS17 mutation was identified in PLL-affected dogs from 14 additional breeds. PLL-affected dogs from some breeds (most notably the Shar pei and the Brittany spaniel) did not carry the G1473+1A ADAMTS17 mutation, indicating they must suffer from a genetically distinct form of the condition. We also estimated the frequency of this ADAMTS17 mutation in some of the breeds. Our findings indicate the mutation segregates in a large number of different breeds of dog, many of which are terriers or breeds with terrier co-ancestry, but some of which have more diverse origins. Our results also indicate that the mutation is present at high frequency within most of the breeds in which it segregates. In the miniature bull terrier breed estimates of mutation frequency ranged from 0.27 to 0.39, corresponding to 7.3-15.2% PLL-affected dogs in this breed. We also identified an increased risk of PLL associated with heterozygosity at ADAMTS17, suggesting that carriers carry a low risk of developing PLL.

Primary lens instability in ten related cats: clinical and genetic considerations.

OBJECTIVES: To describe bilateral lens instability in 10 related domestic shorthair cats over three generations. METHODS: Complete ophthalmic examinations were performed. Lentectomies were carried out. Sections of affected lenses focused on the equatorial area were examined by transmission electron microscopy. The potential involvement of several candidate genes (ADAMTS17, ADAMTSL4, ADAMTS10 and FBN1) known to be associated with lens luxation in other species was investigated. RESULTS: The group of animals included 10 related cats, nine of them being affected by lens instability over three generations. Transmission electron microscopy showed the presence of zonular material at the lens equator. Signs of lens instability were not associated with other ocular disease. Analysis of the pedigree suggests a dominantly inherited condition. A mutation in ADAMTS17 was excluded, but a possible association between the condition and a microsatellite flanking FBN1 indicates this gene should be considered a strong candidate responsible for primary lens luxation in this pedigree. CLINICAL SIGNIFICANCE: These observations suggest an inherent zonular defect unrelated to extraneous factors. The family relationship is compatible with a possible genetic basis, and the pedigree suggests that the condition could be dominant. Data also suggest the mutation in the FBN1 gene could be responsible for primary lens luxation in this pedigree of cats.

Congenital ocular malformations (lens subluxation, pupillary displacement, cataract, myopia) and classic galactosaemia associated with Q188R and /or G1391A mutations.

PURPOSE: Observations of multiple ocular malformations together with heterozygosity for galactosaemia in siblings and homozygosity in one child are highly unusual. In these case histories, a series of investigations in one family are reported. METHODS: Members of a family of two brothers and one sister and their children were pre- and post-surgically examined over several years. Blood examination was carried out in a laboratory specializing in investigation into genetic diseases (Dr Podskarbi, Munich). RESULTS: Two brothers and one sister suffered from cataract-induced visual deterioration at 38, 34 and 35 years of age, respectively. All three siblings reported having had bilateral poor vision since early childhood. The three siblings' parents had no congenital ocular malformations, nor was there any parental consanguinity. One child, the 10-year-old son of the 35-year-old sister, exhibited classic galactosaemia and normal ocular findings. This sister's other child was healthy. All three siblings presented congenital lens luxation, axial myopia, cataract and iridodonesis. In addition, the 34-year-old brother showed unilateral right corectopia and left coloboma adjacent to the optic disc. The 38-year-old brother revealed myopic fundus changes, but no coloboma. The three siblings experienced a distinct increase in visual acuity after cataract surgery. Both eyes of the patients were partially or distinctly amblyopic, respectively. We assume an autosomal-recessive transmission. Molecular genetic examination of the 10-year-old child with classic galactosaemia showed homozygosity for the mutation Q188R with a complete galactose-1-phosphate-uridyltransferase (GALT) deficiency. Because of his galactose-free diet, the child showed normal values for galactose-1-phosphate. The 35-year-old mother showed compound heterozygosity for Q188R and G1391A (D2/G). The 10-year-old boy's father also revealed heterozygosity for galactosaemia caused by GALT deficiency. The two children of the 38-year-old brother were heterozygous for G1391A. They did not show any clinical abnormality. None of the family members had clinical signs of Marfan's syndrome or homocysteinuria. The three siblings' parents were not consanguineous. CONCLUSIONS: Patients with worsening cataracts occurring at a pre-senile age should be examined for galactosaemia. We describe for the first time the molecular genetic findings in congenital ectopia lentis et pupillae. Early treatment in conjunction with a galactose-free diet is mandatory in patients with galactosaemia. Members of a family with heterozygosity for galactosaemia should be advised to attend a human genetic consultation.

An ADAMTS17 splice donor site mutation in dogs with primary lens luxation.

PURPOSE: To identify the genetic cause of isolated canine ectopia lentis, a well-characterized veterinary disease commonly referred to as primary lens luxation (PLL) and to compare the canine disease with a newly described human Weill-Marchesani syndrome (WMS)-like disease of similar genetic etiology. METHODS: Genomewide association analysis and fine mapping by homozygosity were used to identify the chromosomal segment harboring the PLL locus. The resequencing of a regional candidate gene was used to discover a mutation in a splice donor site predicted to cause exon skipping. Exon skipping was confirmed by reverse transcription-polymerase chain reaction amplification of RNA isolated from PLL-affected eyes and from skin fibroblast cultures from PLL-affected dogs. An allelic discrimination assay was used to genotype individual dogs at the splice donor site mutation. RESULTS: The PLL locus was mapped to a 664-kb region of canine chromosome 3 containing regional candidate gene ADAMTS17. Resequencing ADAMTS17 revealed a GT-->AT splice-donor-site mutation at the 5' end of intron 10. The predicted exon 10 skipping and resultant frame shift were confirmed with RNA derived from PLL-affected dogs. The ADAMTS17 mutation was significantly associated with clinical PLL in three different dog breeds. CONCLUSIONS: A truncating mutation in canine ADAMTS17 causes PLL, a well-characterized veterinary disease, which can now be compared to a recently described rare WMS-like disease caused by truncating mutations of the human ADAMTS17 ortholog.

Late-onset bilateral lens dislocation and glaucoma associated with a novel mutation in FBN1.

PURPOSE: To describe the clinical and genetic findings in one Chinese family with late-onset bilateral lens dislocation and secondary glaucoma. METHODS: One family including three affected members and 16 unaffected family members was examined clinically. After informed consent was obtained, genomic DNA was extracted from venous blood of all participants. Linkage analysis was performed with two microsatellite markers around the fibrillin-1 (FBN1) gene (D15S992 and D15S126). Mutation screening was performed using direct DNA sequence analysis and single strand conformation polymorphism (SSCP). RESULTS: Clinical examination and pedigree analysis revealed that four members in three generations were affected by late-onset lens dislocation and secondary glaucoma but had no signs of cardiovascular abnormality or abnormal skeletal features. By genotyping, the family showed the linkage to FBN1 on 15q21.1. After mutation screening analysis on 65 exons of FBN1, a novel heterozygous missense mutation, c.2860C>T (R954C), was detected. This mutation cosegregated with the disease phenotype in the family and was not found in 100 normal controls. CONCLUSIONS: Late-onset isolated ectopia lentis with secondary glaucoma is consistent with a novel mutation in FBN1. Our finding expands the spectrum of FBN1 mutations and is useful for further genetic consultation and genetic diagnosis.

A case of Weill-Marchesani syndrome with inversion of chromosome 15.

PURPOSE: To present a case of Weill-Marchesani syndrome with corneal endothelial dysfunction due to anterior dislocation of a spherophakic lens and corneolenticular contact. METHODS: A 17-year-old woman presented with high myopia and progressive visual disturbance. She was of short stature and had brachydactyly. Her initial Snellen best corrected visual acuity (BCVA) was 20/50 (-sph 20.50 -cyl 3.00 Ax 180) in her right eye and 20/40 (-sph 16.00 -cyl 6.00 Ax 30) in her left eye. Slit lamp examination revealed a dislocated spherophakic lens touching corenal endothelium. A microspherophakic lens, hypoplastic ciliary body, and elongated zonules were confirmed on rotating Scheimpflug camera (Pentacam) and on ultrasound biomicroscopy. Specular microscopy showed corneal endothealial dysfunction. Systemic evaluation was performed, and chromosomal study showed 46, XX, inv (15) (q13qter). The patient was diagnosed with Weill-Marchesani syndrome. RESULTS: Due to impending corneal decompensation, phacoemulsification and suture fixation of the intraocular lens were performed. The operation and postoperative course were uneventful. Three months postoperatively, the visual acuity was 20/30 (OD) and 20/40 (OS) without correction, and BCVA was 20/20 (+sph 0.50 -cyl 2.00 Ax 160 : OD) and 20/25 (+sph 1.50 -cyl 3.00 Ax 30 : OS). During the follow-up period, increased corneal endothelial counts, hexagonality, and decreased corneal thickness were achieved. CONCLUSIONS: In Weill-Marchesani syndrome with a chromosomal anomaly, a dislocated spherophakic lens may cause severe corneal endothelial dysfunction due to corneolenticular contact, and prompt lensectomy is important to prevent such complications.

Mapping the mutation causing lens luxation in several terrier breeds.

Primary lens luxation (PLL), a painful and blinding inherited condition, is common in several breeds of terrier. Here we have examined the Veterinary Medical Database of patient encounters and Canine Eye Registration Foundation (CERF) cases records for the last 10 years and found the diagnosis recorded in 85 breeds. We have performed association analysis using a genome-wide microsatellite screen to map mutations underlying the condition in miniature bull terriers and Lancashire heelers. These studies show microsatellite alleles in disequilibrium with disease status with highest support in a 6.3-Mbp region in the central part of chromosome 3 (-log P(max) = 6.4). The same region also shows an association to the disease in Tibetan terriers. Tight junction protein-1 (TJP1) is a positional candidate to contain the PLL mutation. All recognized exons and splice junctions of TJP1 have been sequenced from affected, obligate carrier and control Lancashire heeler dogs. Several polymorphisms have been found, but these are not likely to cause the disease.

Weill-Marchesani syndrome associated with retinitis pigmentosa.

Retinitis pigmentosa (RP) is associated with a wide variety of ocular and systemic disorders. The Weill-Marchesani syndrome is a multi-system disorder with microspherophakia as one of the common manifestations. A 14-year-old girl presented with short stature, short and stubby fingers, hypodontia and low-set ears. Slit-lamp examination revealed microspherophakia, with shallow anterior chambers with irido and phacodonesis. Ultrasonographic biomicroscopy confirmed the clinical findings and revealed hypoplastic ciliary body. Electroretinogram confirmed the diagnosis of RP. Though RP has been associated with ectopia lentis in earlier reports, this is, to the best of our knowledge, the first case report describing the association of RP and Weill-Marchesani syndrome.

Juvenile bilateral lens dislocation and glaucoma associated with a novel mutation in the fibrillin 1 gene.

PURPOSE: To describe the clinical, ocular, and genetic findings in multiple members of a family with early-onset and bilateral lens dislocation, clinical corneal guttae, and glaucoma. METHODS: All family members underwent complete physical and ophthalmic examinations. After informed consent was given, DNA was obtained from eleven family members, eight of whom were affected. Three polymorphic markers near the fibrillin 1 (FBN1) locus were genotyped and the results analyzed using the VITESSE program. Amplification of the 65 exons and flanking intronic sequences of FBN1 was performed using polymerase chain reaction (PCR), followed by conformation sensitive gel electrophoresis (CSGE). Then, all fragments with mobility variations were sequenced. RESULTS: Pedigree analysis revealed a three generation family with eight of eleven individuals affected by early onset lens dislocation, high myopia, typical facies, frontal bossing, flexion contractures, proximal interphalangeal (PIP) joint thickening, clinical corneal guttae, and glaucoma. Genetic linkage analysis using polymorphic markers near FBN1 demonstrated an LOD score of 1.78 (maximum possible LOD score 1.78). Conformation sequence gel electrophoresis analysis suggested a sequence variation in exon 3. Sequencing revealed a C965G substitution, resulting in an S322C coding change. This sequence variant segregated with affection status and was not identified in 154 control chromosomes. CONCLUSIONS: This syndrome is consistent with a novel mutation in the FBN1 gene. FBN1 mutations have been previously described as causative for Marfan syndrome. The early-onset of complete lens dislocation, progressive corneal guttae, and glaucoma is unusual for Marfan syndrome. This study expands the Marfan phenotype and demonstrates a possible link between guttae, glaucoma, and fibrillin 1 disorders.