Search

OBJECTIVES: This is a report of the audiological and vestibular characteristics of a Dutch DFNA9 family with a novel mutation, I109T, in the LCCL domain of COCH. METHODS: From the family with the novel I109T COCH mutation, audiometric data were collected and analyzed longitudinally. Results were compared to those obtained in previously identified P51 S, G88E, and G87W COCH mutation carriers. Special attention was also given to a comparison of age-related features such as progressive hearing loss and vestibular impairment. RESULTS: A novel mutation (I109T) in COCH segregates with hearing impairment and vestibular dysfunction in the present family. Pure tone thresholds, phoneme recognition scores, and vestibular responses of the I109T mutation carriers were essentially similar to those previously established in P51S, G87W, and G88E mutation carriers. Deterioration of hearing in the I109T mutation carriers started at 43 years of age, and vestibular function deteriorated at least 7 years later. CONCLUSIONS: The phenotype associated with the novel COCH (I109T) mutation is largely similar to that associated with P51S and G88E mutation carriers. However, subtle differences in terms of onset age and rate of progression seem to exist. [ABSTRACT FROM AUTHOR]

Purpose: To determine the full spectrum of ocular manifestations in patients with Noonan syndrome (NS)., Design: Prospective cross-sectional clinical and genetic study in a tertiary referral center., Participants: Twenty-five patients with NS (mean age, 14 years; range, 8 months-25 years) clinically diagnosed by validated criteria., Methods: All patients were examined by the same team following a detailed study protocol. Genetic analyses were performed in 23 patients., Main Outcome Measures: Ocular abnormalities of vision and refraction, external ocular features, ocular position and motility, anterior segment, posterior segment, and intraocular pressure., Results: Ocular features of vision and refraction were amblyopia (32%), myopia (40%), and astigmatism (52%). External ocular features were epicanthic folds (84%), hypertelorism (68%), ptosis (56%), high upper eyelid crease (64%), lower eyelid retraction (60%), abnormal upward slanting palpebral fissures (36%), downward slanting palpebral fissures (32%), and lagophthalmos (28%). Orthoptic abnormalities included strabismus (40%), abnormal stereopsis (44%), and limited ocular motility (40%). Anterior segment abnormalities included prominent corneal nerves (72%) and posterior embryotoxon (32%). Additional ocular features were found, including nonglaucomatous optic disc excavation (20%), relatively low (<10 mmHg) intraocular pressure (22%), and optic nerve hypoplasia (4%). Mutations were established in 22 patients: 19 PTPN11 mutations (76%), 1 SOS1 mutation, 1 BRAF mutation, and 1 KRAS mutation. The patient with the highest number of prominent corneal nerves had an SOS1 mutation. The patient with the lowest visual acuity, associated with bilateral optic nerve hypoplasia, had a BRAF mutation. Patients with severe ptosis and nearly total absence of levator muscle function had PTPN11 mutations. All patients showed at least 3 ocular features (range, 3-13; mean, 7), including at least 1 external ocular feature in more than 95% of the patients., Conclusions: Noonan syndrome is a clinical diagnosis with multiple genetic bases associated with an extensive variety of congenital ocular abnormalities. Ocular features of NS are characterized by 1 or more developmental anomalies of the eyelids (involving the position, opening, and closure) associated with various other ocular abnormalities in childhood, including amblyopia, myopia, astigmatism, strabismus, limited ocular motility, prominent corneal nerves, and posterior embryotoxon., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

In the nineteen-nineties, there was much hype in the European media about presumed laser pointer maculopathy. However, the recent introduction of more powerful and therefore more dangerous laser pointers and their easy availability on the internet necessitates vigilance on the issue. This is an urgent matter, as here we report three cases of proven maculopathy due to an unsafe laser pointer. Three boys aged 13, 9 and 12 years used an unsafe laser pointer as a toy and looked repeatedly into the pointer, resulting in a permanent reduction in visual acuity due to macular damage. Laser pointers are not designed to be children's toys or instruments to annoy people in a crowd. Health authorities and the ophthalmic community should be aware of the potential danger of improper use of high-output laser pointers and warn the general public before the widespread availability of unsafe laser pointers and consequently laser pointer-induced macular damage becomes a true social problem.

Objectives: To identify the phenotype, genetic defect and inheritance pattern of ectopia lentis et pupillae (ELP) in a large Dutch family, previously diagnosed as presumed autosomal dominant ELP because of the occurrence of ELP in three generations., Design: A clinical and genetic study of children and adults., Participants: Eight patients of the ELP family, including five new patients from the youngest generation., Methods: Standard ophthalmological examinations were performed. For molecular genetic analysis, the coding region of ADAMTSL4 was sequenced. Main outcome measures were the ocular phenotype of the new ELP patients, the inheritance pattern and the identification of mutations in the ADAMTSL4 gene in the family., Results: Of the eight patients with ectopia lentis, seven fulfilled the clinical diagnostic criteria of ELP. Molecular genetic analysis of these seven patients disclosed two novel mutations in the ADAMTSL4 gene: homozygous (p.Q752X/p.Q752X) in six patients and compound heterozygous (p.Q752X/p.Q758fs) in one patient. Heterozygosity in phenotypically normal parents proved autosomal recessive (AR) inheritance. The pseudodominant inheritance pattern can be explained by high carrier frequency in this small community and/or consanguinity., Conclusions: Patients from a family with ELP in four generations have AR ELP caused by novel mutations in ADAMTSL4. The clinical presentation of ELP can be variable, but all patients of our study with homozygous p.Q752X mutation have ectopia lentis and pupillary dysfunction in common.

The Nathalie syndrome (OMIM 255990) comprises a combination of features that do not resemble any other known syndrome and is as such an independent, rare entity. It is characterized by sensorineural hearing impairment, juvenile cataract, spinal muscular atrophy, skeletal abnormalities, retardation of growth, underdeveloped secondary gender characteristics and cardiomyopathy. Worldwide, only one family with this syndrome is known. An update of the clinical follow-up in this family and the results of autopsy are given. Audiometry showed a downsloping configuration that corresponded to the findings at histopathological examination of the cochlea: a diffuse atrophy of the organ of Corti, severe and diffuse atrophy of the stria vascularis and moderate loss of cochlear neurons in all turns. Another new striking feature is that individuals with the Nathalie syndrome have a shortened life expectancy with a risk of sudden death or death from heart failure resulting from (dilated) cardiomyopathy., (Copyright © 2012 S. Karger AG, Basel.)

We report on the clinical presentation of branchio-oculo-facial (BOF) syndrome in 2 patients with mutations in the TFAP2A gene (OMIM 107580). This TFAP2A gene was recently shown to be involved in the causation of BOF syndrome. An overview of the literature on BOF syndrome is given based on clinical reports written in the period during which mutation analysis was not yet available for BOF syndrome. We also give descriptions of the mutations in the TFAP2A gene in our 2 new patients with BOF syndrome. Congenital conductive hearing impairments are described, including hearing rehabilitation and the results of ear surgery.

Purpose: Sjögren-Larsson syndrome (SLS), an autosomal recessive hereditary disorder with congenital ichthyosis, spastic diplegia or tetraplegia, and mental retardation, reveals a characteristic macular dystrophy with intraretinal crystals and foveal pseudocysts. Ophthalmic symptoms in SLS are reduced visual acuity and photophobia. This article reports the deficiency of macular pigment as a novel finding in this peculiar, congenital maculopathy., Design: Cross-sectional, observational case study., Participants: Patients with clinically and genetically proven SLS., Methods: Besides general ophthalmologic examination, 2 different methods were used, fundus autofluorescence (FAF) and fundus reflectometry with the macular pigment reflectometer (MPR), for measuring macular pigment (MP)., Main Outcome Measures: Distribution profiles and quantity of MP in eyes of SLS patients., Results: Twenty-eight eyes of 14 patients were included. The technique to measure MP depended on the ability of the mentally handicapped patients to cooperate. Fundus autofluorescence images providing qualitative estimates were obtained from 9 eyes of 5 patients, and MPR measures providing quantitative estimates were obtained from 19 eyes of 10 patients. Fundus autofluorescence images of SLS patients lacked the typical attenuation of macular FAF signal expected in normal eyes. Mean foveal MP levels measured by MPR showed significantly lower values in SLS patients (0.10+/-0.07) than in healthy individuals (0.69+/-0.17; P<0.001, Student t test)., Conclusions: The group of SLS patients studied here had significantly reduced levels of foveal MP. The crystalline macular dystrophy in SLS seems to be the first known disease with a genetically caused deficiency of MP., (Copyright 2010. Published by Elsevier Inc.)

Purpose: To describe the phenotype of a novel Wolframin (WFS1) mutation in a family with autosomal dominant optic neuropathy and deafness. The study is designed as a retrospective observational case series., Methods: Seven members of a Dutch family underwent ophthalmological, otological, and genetical examinations in one institution. Fasting serum glucose was assessed in the affected family members., Results: All affected individuals showed loss of neuroretinal rim of the optic nerve at fundoscopy with enlarged blind spots at perimetry. They showed a red-green color vision defect at color vision tests and deviations at visually evoked response tests. The audiograms of the affected individuals showed hearing loss and were relatively flat. The unaffected individuals showed no visual deviations or hearing impairment. The affected family members had no glucose intolerance. Leber hereditary optic neuropathy (LHON) mitochondrial mutations and mutations in the Optic atrophy-1 gene (OPA1) were excluded. In the affected individuals, a novel missense mutation c.2508G>C (p.Lys836Asn) in exon 8 of WFS1 was identified., Conclusions: This study describes the phenotype of a family with autosomal dominant optic neuropathy and hearing impairment associated with a novel missense mutation in WFS1.

Objective: Infantile esotropia, a common form of strabismus, is treated either by bilateral recession (BR) or by unilateral recession-resection (RR). Differences in degree of alignment achieved by these two procedures have not previously been examined in a randomised controlled trial., Design: Controlled, randomised multicentre trial., Setting: 12 university clinics., Participants and Intervention: 124 patients were randomly assigned to either BR or RR. Standardised protocol prescribed that the total relocation of the muscles, in millimetres, was calculated by dividing the preoperative latent angle of strabismus at distance, in degrees, by 1.6., Main Outcome Measure: Alignment assessed as the variation of the postoperative angle of strabismus during alternating cover., Results: The mean preoperative latent angle of strabismus at distance fixation was +17.2 degrees (SD 4.4) for BR and +17.5 degrees (4.0) for RR. The mean postoperative angle of strabismus at distance was +2.3 degrees (5.1) for BR and +2.9 degrees (3.5) for RR (p = 0.46 for reduction in the angle and p = 0.22 for the within-group variation). The mean reduction in the angle of strabismus was 1.41 degrees (0.45) per millimetre of muscle relocation for RR and 1.47 (0.50) for BR (p = 0.50 for reduction in the angle). Alignment was associated with postoperative binocular vision (p = 0.001) in both groups., Conclusions: No statistically significant difference was found between BR and RR as surgery for infantile esotropia.

Background: Children with congenital disorders of glycosylation (CDG) type Ia frequently present with ocular involvement and visual loss. Little is known, however, about the occurrence of ophthalmological abnormalities in other subtypes of CDG syndrome., Methods: We evaluated 45 children sequentially diagnosed with CDG type I for the presence of ocular abnormalities at the time of the diagnosis and during follow-up. We compared the various ophthalmic findings in the different CDG subgroups., Results: Of the 45 patients, 22 had CDG type Ia, nine had CDG type Ic and 14 had a so-far undiagnosed biochemical background (CDG type Ix). We found ocular anomalies in 28 of the 45 children. Three had unique findings, including congenital cataract, retinal coloboma and glaucoma. A few CDG type Ia patients showed a sequential occurrence of symptoms, including retinitis pigmentosa or cataract., Conclusions: Ophthalmic findings are frequent in CDG syndrome involving both the anterior and posterior segment of the eye. The disorder might lead to abnormal development of the lens or the retina, cause diminished vision, alter ocular motility and intraocular pressure. We suggest routine screening and follow-up for ophthalmological anomalies in all children diagnosed with CDG syndrome to provide early treatment and adequate counselling.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS: MIM 270550) is a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. This disorder, considered to be rare, was first described in the late seventies among French Canadians in the isolated Charlevoix-Saguenay region of Quebec. Nowadays, it is known that the disorder is not only limited to this region but occurs worldwide. Our objective was to identify cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) in Dutch patients with recessive early-onset cerebellar ataxia by sequencing the complete SACS gene. In a Dutch cohort of 43 index patients with ataxia onset before age 25, we identified 16 index patients (total 23 patients) with mutations in the SACS gene. Nine of them had homozygous mutations, and seven of them had compound heterozygous mutations. Retrospectively, the phenotype of patients carrying mutations was remarkably uniform: cerebellar ataxia with onset before age 13 years, lower limb spasticity and sensorimotor axonal neuropathy, and cerebellar (vermis) atrophy on magnetic resonance imaging, consistent with the core ARSACS phenotype previously described. The high rate of mutations (37%) identified in this cohort of Dutch patients suggests that ARSACS is substantially more frequent than previously estimated. We predict that the availability of SACS mutation analysis as well as an increasing awareness of the characteristic ARSACS phenotype will lead to the diagnosis of many additional patients, possibly even at a younger age.

Purpose: To study morphologic changes in the macula by optical coherence tomography (OCT) in patients with a crystalline macular dystrophy due to the autosomal recessive neurocutaneous Sjögren-Larsson syndrome (SLS)., Design: Retrospective observational case series., Participants: Twenty-seven eyes of 14 patients, mean age 14.6 (range, 3-24) years, with biochemically and genetically proven SLS underwent clinical and OCT investigation between September 2004 and September 2006., Methods: All patients underwent full ophthalmologic examination including slit-lamp biomicroscopy and binocular ophthalmoscopy. Optical coherence tomography of all eyes was performed using the macular thickness map protocol of Stratus OCT., Main Outcome Measures: Macular morphology in clinical examination and OCT., Results: Beside clinically visible perimacular crystalline deposits in all eyes of all study participants, macular morphology and reflectivity were significantly changed on OCT compared with healthy eyes. We found focal hyperreflectivities in all study eyes within the perifoveal ganglion cell layer and the inner plexiform layer, corresponding to the clinical localization of retinal crystals. More interestingly, a cystoid foveal degeneration on OCT was present in the majority of patients with SLS (18/27 eyes, or 67% of all eyes studied), varying from multiple microcystoid spaces to cystoid foveal atrophy. In general, patients who were severely affected on OCT showed intense changes on previously performed cerebral magnetic resonance spectroscopy., Conclusions: Patients with SLS show a childhood-onset crystalline macular dystrophy with cystoid foveal atrophy on OCT in most cases. The intraretinal deposition of lipid metabolites may lead to Müller cell degeneration with subsequent formation of cystoid spaces or atrophic changes within the fovea. Because this macular dystrophy is present in all examined patients with SLS, familiarity with this maculopathy seems important for the diagnosis of this rare systemic disease.

Two female neonates were diagnosed post partum with bilateral aniridia. The first patient had the familial form, caused by a point mutation in the paired box 6 (PAX6) gene. The second patient had a sporadic aniridia caused by a de novo microdeletion involving both the PAX6 gene as well as the Wilms tumour suppressor-I (WT1) gene. This made screening for the presence of a Wilms tumour necessary. The second patient died several months after birth, due to respiratory insufficiency. Aniridia is a rare developmental disorder of the eye, with absence of most of the iris tissue, caused by an abnormality in the PAX6 gene on chromosome 11p13. Familial aniridia is usually due to a point mutation of the PAX6 gene, which causes solely ocular abnormalities. Sporadic aniridia is caused by a de novo deletion or microdeletion of chromosome 11p13, which affects not only the PAX6 gene but also the adjacent WT1 gene. In these patients, the Wilms tumour, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome can be present, and screening for a Wilms tumour is indicated. Unless previous investigation of a family member has demonstrated the WT1 gene to be normal, chromosome studies should always be performed in patients with aniridia.

A 44-year-old man with a facial skin wound after working with a motor lawn mower had an orbital and ocular penetration by a 2.4 cm metal wire, with endophthalmitis caused by a Klebsiella ozaenae.

Purpose: Investigation of a possible association between vertical corneal striae and mutations in the COCH gene, observed in four DFNA9 families with autosomal dominant hearing loss and vestibular dysfunction., Design: Prospective case series., Methods: Ophthalmologic examinations with photography of the cornea after instillation of fluorescein were performed in 98 family members with 61 mutation carriers of four DFNA9 families at the Radboud University Nijmegen Medical Centre. Families 1 and 2 harbor the Pro51Ser mutation, and families 3 and 4 harbor the Gly88Glu and the Gly87Trp mutation, respectively. Statistical analysis was performed to find an association between the vertical corneal striae and the COCH mutation for each family and to test whether the four families were different in this respect., Results: The vertical corneal striae were exclusively visible after instillation of fluorescein. They caused minor problems, as dry eye symptoms, and were not present in the general Dutch ophthalmologic population. The striae were present from an age of 47 years in 32 individuals, of whom 27 individuals had a COCH mutation. Statistical analysis on the striae and the COCH mutations showed a significant association in families 1, 2, and 3 (P = .0006), but not in family 4 (P = .63)., Conclusions: Data analysis demonstrated a significant association between vertical corneal striae and the Pro51Ser and Gly88Glu mutations in the COCH gene in DFNA9 families 1, 2, and 3 with cochleovestibular dysfunction. Our findings suggest that the vertical corneal striae and cochleovestibular dysfunction may be caused by the same COCH mutations.

We report a patient with Leber hereditary optic neuropathy (G11778A mtDNA) and a severe demyelinating neuropathy, for which no other cause except his mitochondrial disorder could be found. The involvement of the peripheral nervous system of patients with LHON, in particular with a 11778 mtDNA, is discussed.

Objectives: To report hearing impairment and vestibular and ocular features in a Dutch DFNA11 family and to compare these results to reported data on three other DFNA11 families., Study Design: Family study., Methods: Regression analysis was performed in relation to age to outline the development of hearing thresholds and speech recognition scores. Vestibular and ocular functions were examined., Results: First symptoms of hearing impairment started between the ages of 4 and 43 years. Most of the audiograms were symmetric and flat or downsloping. The annual threshold deterioration increased from 0.2 to 2.6 dB per year at 0.25 to 8 kHz in the longitudinal analyses and in the cross-sectional analysis from 0.3 to 0.9 dB per year. The speech recognition score was quite good, deteriorating by 0.9% per year from a 90% score at the age of 36 years onward. Remarkably, extensive ocular examination including corrected visual acuity and refraction measurements, slit-lamp examination, ophthalmoscopy, Goldmann perimetry, electroretinography and electro-oculography revealed signs of subclinical retinal dysfunction. None of the patients showed the classic triad of retinitis pigmentosa. Pure-tone thresholds, phoneme recognition scores, and vestibular responses of the mutation carriers were fairly similar to previously described DFNA11 families., Conclusion: Even though the diverse mutations are located in different regions of the myosin VIIa gene, the cochleovestibular phenotype is fairly similar in all DFNA11 families. Surprisingly, only in this family was subclinical retinal dysfunction detected.

Purpose: To test the efficiency of a microarray chip as a diagnostic tool in a cohort of northwestern European patients with Leber congenital amaurosis (LCA) and to perform a genotype-phenotype analysis in patients in whom pathologic mutations were identified., Methods: DNAs from 58 patients with LCA were analyzed using a microarray chip containing previously identified disease-associated sequence variants in six LCA genes. Mutations identified by chip analysis were confirmed by sequence analysis. On identification of one mutation, all protein coding exons of the relevant genes were sequenced. In addition, sequence analysis of the RDH12 gene was performed in 22 patients. Patients with mutations were phenotyped., Results: Pathogenic mutations were identified in 19 of the 58 patients with LCA (32.8%). Four novel sequence variants were identified. Mutations were most frequently found in CRB1 (15.5%), followed by GUCY2D (10.3%). The p.R768W mutation was found in 8 of 10 GUCY2D alleles, suggesting that it is a founder mutation in the northwest of Europe. In early childhood, patients with AIPL1 or GUCY2D mutations show normal fundi. Those with AIPL1-associated LCA progress to an RP-like fundus before the age of 8, whereas patients with GUCY2D-associated LCA still have relatively normal fundi in their mid-20s. Patients with CRB1 mutations present with distinct fundus abnormalities at birth and consistently show characteristics of RP12. Pathogenic GUCY2D mutations result in the most severe form of LCA., Conclusions: Microarray-based mutation detection allowed the identification of 32% of LCA sequence variants and represents an efficient first-pass screening tool. Mutations in CRB1, and to a lesser extent, in GUCY2D, underlie most LCA cases in this cohort. The present study establishes a genotype-phenotype correlation for AIPL1, CRB1, and GUCY2D.

Background: Ptosis and dysphagia are important features in oculopharyngeal muscular dystrophy (OPMD)., Objective: Retroflexion of the head is a well known compensatory mechanism for ptosis, but generally retroflexion has a negative effect on swallowing. We hypothesised that severity of ptosis is related to degree of retroflexion and that this compensation is responsible for deteriorating dysphagia., Methods: Nine OPMD patients were examined in the conditions "head position adapted to ptosis" and "head position slightly flexed". Ptosis was quantified by photogrammetry and retroflexion of the head by digital photographs. The severity of dysphagia was measured using visual analogue scales (VAS) and by calculating swallowing volumes and oropharyngeal swallow efficiency (OPSE) based on videofluoroscopy., Results: Statistical analyses show a significant relationship between ptosis and degree of retroflexion. The degree of retroflexion of the head correlated significantly with VAS scores and with the maximum swallowing volume. The slightly flexed head position significantly improved VAS scores as well as swallowing volumes and OPSE., Conclusion: In OPMD patients, ptosis significantly correlates with retroflexion of the head, which has a negative effect on swallowing. Subjective and objective reduction of swallowing problems was found when patients were instructed to eat and drink with a slightly flexed head position.

Purpose: Several types of inborn errors of the O-glycan biosynthesis are known, leading to clinically very distinct phenotypes. Children with O-mannosyl glycan biosynthesis defects commonly present as a severe form of congenital muscular dystrophy with decreased alpha-dystroglycan staining, congenital eye anomalies, and brain migration defects. Alpha-dystroglycan is an O-mannosylated glycoprotein with additional mucin type O-glycans., Methods: Based on overlapping clinical features with O-mannosyl glycan defects, especially with muscle-eye-brain disease, the authors performed a muscle biopsy in a child with severe congenital hypotonia, high myopia, partial pachygyria, mental retardation, cutis laxa, and an inborn error affecting the biosynthesis of both mucin type O-glycans and N-linked glycans., Results: The histology showed no signs of muscle dystrophy, but a mild myopathy with slight increase in the muscle fiber diameter variability and type I fiber predominance. No significant decrease in the alpha-dystroglycan staining was detected; therefore, in spite of the phenotypic similarities the authors could not confirm the role of abnormal dystroglycan in the etiology of the muscle weakness and the developmental anomalies., Conclusions: High myopia, muscle weakness, and cortical neuronal migration abnormalities are common in disorders of O-mannosylation and also observed in the authors' patient. However, compared to the severe generalized defect observed in mannosyl glycan defects, in this child the cerebral white matter and cerebellum were spared, and no muscle dystrophy could be confirmed. This is the first description of high myopia in cutis laxa syndrome in combination with congenital disorders of glycosylation.

Congenital cataracts facial dysmorphism neuropathy syndrome is a recently delineated autosomal recessive condition exclusively found in the Gypsy population. Congenital cataracts facial dysmorphism neuropathy syndrome is caused by a homozygous mutation in the CTDP1 gene, leading to disruption of the ribonucleic acid transcription machinery. This report presents a young Gypsy female affected by this rare disorder. Electromyography and sural nerve histology were in accordance with a hypomyelinating neuropathy. After clinical recognition of congenital cataracts facial dysmorphism neuropathy syndrome some years ago, we recently demonstrated the presence of the homozygous IVS6+389C-->T mutation in the CTDP1 gene in this family.

Nail-patella syndrome (NPS) is characterized by developmental defects of dorsal limb structures, nephropathy, and glaucoma and is caused by heterozygous mutations in the LIM homeodomain transcription factor LMX1B. In order to identify possible genotype-phenotype correlations, we performed LMX1B mutation analysis and comprehensive investigations of limb, renal, ocular, and audiological characteristics in 106 subjects from 32 NPS families. Remarkable phenotypic variability at the individual, intrafamilial, and interfamilial level was observed for different NPS manifestations. Quantitative urinanalysis revealed proteinuria in 21.3% of individuals. Microalbuminuria was detected in 21.7% of subjects without overt proteinuria. Interestingly, nephropathy appeared significantly more frequent in females. A significant association was established between the presence of clinically relevant renal involvement in an NPS patient and a positive family history of nephropathy. We identified normal-tension glaucoma (NTG) and sensorineural hearing impairment as new symptoms associated with NPS. Sequencing of LMX1B revealed 18 different mutations, including six novel variants, in 28 families. Individuals with an LMX1B mutation located in the homeodomain showed significantly more frequent and higher values of proteinuria compared to subjects carrying mutations in the LIM domains. No clear genotype-phenotype association was apparent for extrarenal manifestations. This is the first study indicating that family history of nephropathy and mutation location might be important in precipitating individual risks for developing NPS renal disease. We suggest that the NPS phenotype is broader than previously described and that NTG and hearing impairment are part of NPS. Further studies on modifier factors are needed to understand the mechanisms underlying phenotypic heterogeneity.

Previous studies have shown an increased risk of retinal vein occlusion (RVO) in patients with hypertension, hypercholesterolemia and diabetes mellitus. Literature on the association between thrombophilic factors and RVO consists of small studies and case reports. The objective was to determine the relationship between thrombophilic risk factors and RVO. Thrombophilic risk factors analyzed were hyperhomocysteinemia, MTHFR gene mutation, factor V Leiden mutation, protein C and S deficiency, antithrombin deficiency, prothrombin gene mutation, anticardiolipin antibodies and lupus anticoagulant. For all currently known thrombophilic risk factors odds ratios for RVO were calculated as estimates of relative risk. The odds ratios were 8.9 (95% CI 5.7 - 13.7) for hyperhomocysteinemia, 3.9 (95% CI 2.3 - 6.7) for anticardiolipin antibodies, 1.2 (95% CI 0.9 - 1.6) for MTHFR, 1.5 (95% CI 1.0 - 2.2) for factor V Leiden mutation and 1.6 (95% CI 0.8 - 3.2) for prothrombin gene mutation. In conclusion, regarding thrombophilic risk factors and RVO there is only evidence for an association with hyperhomocysteinemia and anticardiolipin antibodies, factors that are known as risk factors for venous thrombosis as well as for arterial vascular disease. The minor effect of factor V Leiden mutation and the protrombin gene mutation (risk factors for venous thrombosis only) suggests that atherosclerosis might be an important factor in the development of CRVO.

A case of a patient with a zygoma fracture in combination with a carotid-cavernous sinus fistula--an arterio-venous fistula between the internal carotid artery and the cavernous sinus--is presented. The most frequent cause is trauma, but the carotid-cavernous sinus fistula itself may have been the cause of trauma. The patient showed complete loss of ocular motility and total monocular blindness. Treatment of the fistula with endoarterial coil embolization was followed by improvement of vision and ocular motility, until finally complete recovery of ocular functions, which is exceptional. In this case, careful analysis of the MRA's showed that the CCSF most likely developed in the posttraumatic phase.

Objective: To describe clinical and radiologic features, results of ear surgery, and genetic analysis in three families with Teunissen-Cremers syndrome., Design: Case series., Setting: Tertiary referral center., Background: The NOG gene encodes the protein noggin, which has antagonist action in osteogenesis. Malformation of bones and joints may result from defects in noggin. Teunissen-Cremers syndrome is caused by mutations in the NOG gene. Two mutations in this gene were reported previously. The proximal symphalangism-hearing impairment syndrome, also caused by mutations in the NOG gene, is characterized by proximal symphalangism, conductive hearing loss, and occasionally synostoses., Methods: We examined nine affected members of three Dutch families. Reconstructive middle ear surgery was performed in five patients (nine ears), and we sequenced the NOG gene in these families., Results: Affected members had conductive hearing impairment, hyperopia, and broad thumbs and first toes with brachytelephalangia. Surgery manifested stapes ankylosis with additional incudal fixation frequently in the fossa incudis. Air-bone gaps decreased to less than 10 dB in six ears. Genetic analysis revealed three new mutations in the NOG gene., Conclusion: The Teunissen-Cremers syndrome is an entity in its clinical presentation, distinct from other syndromes with proximal symphalangism and hearing impairment. So far, in five families with Teunissen-Cremers syndrome, four truncating mutations and one amino acid substitution were found in the NOG gene. The majority of other mutations found in this gene are missense mutations, which might result in some residual protein activity. Reconstructive middle ear surgery is an option for treatment.

Objective: To report a successful stapedectomy for stapedial fixation in a patient with Stickler syndrome type I (COL2A1)., Setting: University Hospital Department for Otology, Pathology, Ophthalmology and Clinical Genetics., Study Design: A clinical and genetic evaluation of a mother and daughter focusing mainly on the otological, ophthalmological, histological and genetical aspects., Intervention: A stapedectomy was performed successfully., Results: Hearing impairment improved after stapedectomy. Postoperatively a shift in high-frequency threshold wa seen related to the stapedectomy. A new mutation in COL2A1 gene was dectected., Conclusion: Stapedial fixation can be the cause of hearing impairment in Stickler syndrome type I (COL2A1). The hearing impairment can be improved by stapes surgery.

Purpose: To report the occurrence of recurrent multiple giant chalazia in the hyperimmunoglobulin E syndrome (hyper-IgE syndrome or Job syndrome)., Methods: Two patients with hyperimmunoglobulinemia E (>500 IU/ml) had ophthalmologic examination and surgical treatment for chalazia of the eyelids., Results: The hyper-IgE syndrome is a rare immunodeficiency and multisystem disorder characterized by recurrent skin and pulmonary abscesses, connective tissue abnormalities, and elevated levels of serum IgE. In two patients with the hyper-IgE syndrome, multiple giant chalazia were seen in upper and lower eyelids. Despite surgical incision new giant chalazia arose., Conclusions: Recurrent multiple giant chalazia may occur as an ophthalmic feature of the hyper-IgE syndrome. (Eur J Ophthalmol 2004; 14: 258-60).

Purpose: To report a case of bacterial endophthalmitis after otitis media in a healthy adult., Design: Interventional case report., Methods: A healthy 49-year-old Caucasian woman developed acute otitis media of the right ear. Three weeks after the first onset there was a recurrence of the otitis media, with perforation of the tympanic membrane. Two days after this, the woman presented at our clinic with endophthalmitis of the right eye., Results: A culture of vitreous material grew Streptococcus pyogenes (Streptococcus Lancefield group A). The same strain was found in a smear from the perforated ear. Despite aggressive treatment, the affected eye had to be eviscerated., Conclusions: Otitis media can result in a bacteremia. This may, even in a healthy adult, lead to a devastating endogenous bacterial endophthalmitis.

Objective: To investigate the variable clinical picture of Möbius syndrome (MIM no. 157900) and to further understand the pathogenesis of the disorder., Methods: A standardized questionnaire was submitted to 37 Dutch patients with Möbius syndrome. All underwent standardized neurologic examination with special attention to cranial nerve functions, motor skills, and facial and limb anomalies., Results: Of 37 patients with facial paresis, 97% had bilateral and 3% had unilateral ocular abduction weakness. Further analysis showed isolated abducens nerve palsy in 9%, a conjugated horizontal gaze paresis in 48%, features of Duane retraction syndrome in 34%, and congenital fibrosis of the extraocular muscles in 9%. Other signs included lingual involvement (77%), dysfunction of palate and pharynx (56%), general motor disability (88%), poor coordination (83%), and respiratory abnormalities (19%)., Conclusion: Möbius syndrome is more than a cranial nerve or nuclear developmental disorder. It is a syndrome of rhombencephalic maldevelopment involving predominantly motor nuclei and axons, as well as traversing long tracts. The authors also noted gaze palsies, Duane retraction syndrome, feeding and respiratory problems, and poor motor development, suggesting a regional developmental disorder.

Purpose: To describe the occurrence of atypical, bilateral detachment of the macular neuroepithelium and Klinefelter syndrome in a young patient., Methods: Case report., Results: A 20-year-old male of Chinese origin with karyotype 47,XXY presented with bilateral central neurosensory retinal detachment. There was spontaneous improvement., Conclusions: An atypical form of detachment of the macular neuroepithelium was seen in a young patient with Klinefelter syndrome. The pathophysiological mechanism is not clear. The possibility of a hormonal imbalance is discussed. A differential diagnostic consideration is central serous chorioretinopathy and a mild form of Vogt-Koyanagi-Harada syndrome. This case is of interest because of the rarity of association between Klinefelter syndrome and chorioretinal abnormalities.

Every year, 3000 women in the Netherlands are treated with in-vitro fertilisation (IVF), and results from studies suggest that the offspring of these women do not have a heightened risk of cancer. Between November, 2000, and February, 2002, we diagnosed retinoblastoma in five patients born after IVF. To calculate the relative risk of the disease, we assumed that the proportion of children conceived by IVF in the Netherlands is between 1.0 and 1.5%, and that the five patients who we diagnosed with the disease represent all new cases in the Netherlands during that period. Relative risks for retinoblastoma were significantly raised (7.2 [95% CI 2.4-17.0], and 4.9 [1.6-11.3], for 1% and 1.5% rates, respectively). This possible association of an increased risk of retinoblastoma in a population-based study needs to be established.

A 10-year-old girl showed ectropion uveae of the iris of her right eye. Ocular examination established severe unilateral juvenile glaucoma: iridotrabecular dysgenesis.