Nonsyndromic bilateral and unilateral optic nerve aplasia: first familial occurrence and potential implication of CYP26A1 and CYP26C1 genes

Purpose: Optic nerve aplasia (ONA, OMIM 165550) is a very rare unilateral or bilateral condition that leads to blindness in the affected eye, and is usually associated with other ocular abnormalities. Although bilateral ONA often occurs in association with severe congenital anomalies of the brain, nonsyndromic sporadic forms with bilateral ONA have been described. So far, no autosomal-dominant nonsyndromic ONA has been reported. The genetic basis of this condition remains largely unknown, as no developmental genes other than paired box gene 6 (PAX6) are known to be implicated in sporadic bilateral ONA. Methods: The individuals reported underwent extensive ophthalmological, endocrinological, and neurologic evaluation, including neuroimaging of the visual pathways. In addition genomewide copy number screening was performed. Results: Here we report an autosomal-dominant form of nonsyndromic ONA in a Belgian pedigree, with unilateral microphthalmia and ONA in the second generation (II:1), and bilateral ONA in two sibs of the third generation (III: 1; III: 2). No PAX6 mutation was found. Genome wide copy number screening revealed a microdeletion of maximal 363 kb of chromosome 10q23.33q23.33 in all affected individuals (II: 1, III: 1; III: 2) and in unaffected I: 1, containing three genes: exocyst complex component 6 (EXOC6), cytochrome p450, subfamily XXVIA, polypeptide 1 (CYP26A1), and cytochrome p450, subfamily XXVIC, polypeptide 1 (CYP26C1). The latter two encode retinoic acid-degrading enzymes. Conclusions: This is the first study reporting an autosomal-dominant form of nonsyndromic ONA. The diagnostic value of neuroimaging in uncovering ONA in microphthalmic patients is demonstrated. Although involvement of other genetic factors cannot be ruled out, our study might point to a role of CYP26A1 and CYP26C1 in the pathogenesis of nonsyndromic ONA

Nonsyndromic bilateral and unilateral optic nerve aplasia: first familial occurrence and potential implication of CYP26A1 and CYP26C1 genes

Purpose: Optic nerve aplasia (ONA, OMIM 165550) is a very rare unilateral or bilateral condition that leads to blindness in the affected eye, and is usually associated with other ocular abnormalities. Although bilateral ONA often occurs in association with severe congenital anomalies of the brain, nonsyndromic sporadic forms with bilateral ONA have been described. So far, no autosomal-dominant nonsyndromic ONA has been reported. The genetic basis of this condition remains largely unknown, as no developmental genes other than paired box gene 6 (PAX6) are known to be implicated in sporadic bilateral ONA. Methods: The individuals reported underwent extensive ophthalmological, endocrinological, and neurologic evaluation, including neuroimaging of the visual pathways. In addition genomewide copy number screening was performed. Results: Here we report an autosomal-dominant form of nonsyndromic ONA in a Belgian pedigree, with unilateral microphthalmia and ONA in the second generation (II:1), and bilateral ONA in two sibs of the third generation (III:1; III: 2). No PAX6 mutation was found. Genome wide copy number screening revealed a microdeletion of maximal 363 kb of chromosome 10q23.33q23.33 in all affected individuals (II:1, III:1; III:2) and in unaffected I:1, containing three genes: exocyst complex component 6 (EXOC6), cytochrome p450, subfamily XXVIA, polypeptide 1 (CYP26A1), and cytochrome p450, subfamily XXVIC, polypeptide 1 (CYP26C1). The latter two encode retinoic acid-degrading enzymes. Conclusions: This is the first study reporting an autosomal-dominant form of nonsyndromic ONA. The diagnostic value of neuroimaging in uncovering ONA in microphthalmic patients is demonstrated. Although involvement of other genetic factors cannot be ruled out, our study might point to a role of CYP26A1 and CYP26C1 in the pathogenesis of nonsyndromic ONA. © 2011 Molecular Vision.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma

The latent TGFβ-binding proteins (LTBPs) and fibrillins are a superfamily of large, multidomain proteins with structural and TGFβ-signalling roles in the extracellular matrix. Their importance is underscored by fibrillin-1 mutations responsible for Marfan syndrome, but their respective roles are still incompletely understood. We report here on two families where children from healthy, consanguineous parents, presented with megalocornea and impaired vision associated with small, round, dislocated lenses (microspherophakia and ectopia lentis) and myopia, as well as a high-arched palate, and, in older children, tall stature with an abnormally large arm span over body height ratio, that is, associated features of Marfan syndrome. Glaucoma was not present at birth, but was diagnosed in older children. Whole genome homozygosity mapping followed by candidate gene analysis identified homozygous truncating mutations of LTBP2 gene in patients from both families. Fibroblast mRNA analysis was consistent with nonsense-mediated mRNA decay, with no evidence of mutated exon skipping. We conclude that biallelic null LTBP2 mutations cause the ocular phenotype in both families and could lead to Marfan-like features in older children. We suggest that intraocular pressures should be followed-up in young children with an ocular phenotype consisting of megalocornea, spherophakia and/or lens dislocation, and recommend LTBP2 gene analysis in these patients

Rétine et epithélium pigmentaire--le desferal.

Deferoxamine mesylate (Desferal) is a chelating agent used in hemosiderosis and aluminium overload consecutive to renal dialysis. This drug is the most efficacious for treating iron overload but is associated with ocular toxicity: dose and duration related symptomatic optic neuropathy on the one hand, reversible if treatment stopped, and acute retinal involvement followed by irreversible paucisymptomatic pigmentary changes on the other hand. Toxic risk factors are intravenous mode of administration, high doses, small iron or aluminium overload, diabetes and young age. Hence, dosis should be adapted to the amount of overload and ophthalmological follow-up should be instaured. Indeed, if treatment is stopped at the beginning of the toxic effect, ocular involvement is reversible. The baseline ophthalmological examination should include visual acuity measurement, color vision, visual fields, slit lamp and fundus. In case of risk factors, electrophysiology and fluoangiography should be added.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Corneal opacities in the Hallermann-Streiff syndrome

We present six patients with typical Hallermann-Streiff syndrome. All have microphthalmia and were operated for congenital cataract. Three of the patients developed a severe glaucoma and one patient presented repeated uveal effusions. Five of our patients have the same pattern of corneal stromal opacities. The opacities are ill defined and bilateral; the stroma between the opacities is clear. The opacities are observed in two children around the age of 5. Follow up of 10 years did not reveal a manifest increase of the lesions. The authors believe that corneal stromal opacities are a feature of the Hallermann-Streiff syndrome and they would urge ophthalmologists to look for this

Orbital myositis in a child with linear scleroderma en coup de sabre

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Exome Sequencing in a Swiss Childhood Glaucoma Cohort Reveals CYP1B1 and FOXC1 Variants as Most Frequent Causes

Purpose The aim of this study was to investigate the molecular basis of childhood glaucoma in Switzerland to recommend future targeted genetic analysis in the Swiss population. Methods Whole-exome sequencing and copy number variation (CNV) analysis was performed in a Swiss cohort of 18 patients from 14 unrelated families. Identified variants were validated by Sanger sequencing and multiplex ligation-dependent probe amplification. Breakpoints of structural variants were determined by a microarray. A minigene assay was conducted for functional analysis of a splice site variant. Results A diagnosis of primary congenital glaucoma was made in 14 patients, of which six (43%) harbored pathogenic variants in CYP1B1, one (7%) a frameshift variant in FOXC1, and seven (50%) remained without a genetic diagnosis. Three patients were diagnosed with glaucoma associated with nonacquired ocular anomalies, of which two patients with mild ocular features of Axenfeld-Rieger syndrome harbored a FOXC1 duplication plus an additional FOXC1 missense variant, and one patient with a Barkan membrane remained without genetic diagnosis. A diagnosis of juvenile open-angle glaucoma was made in one patient, and genetic analysis revealed a FOXC1 duplication. Conclusions Sequencing of CYP1B1 and FOXC1, as well as analysis of CNVs in FOXC1, should be performed before extended gene panel sequencing. Translational Relevance The identification of the molecular cause of childhood glaucoma is a prerequisite for genetic counseling and personalized care for patients and families

Congenital fixed dilated pupils due to ACTA2-multisystemic smooth muscle dysfunction syndrome

Congenital fixed dilated pupils (congenital mydriasis) is characterized by hypoplasia or aplasia of the iris muscles, with absence of iris between the collarette and pupillary border, creating a scalloped pupillary margin. This condition has been reported in a multisystemic smooth muscle cell dysfunction syndrome, combined with congenital patent ductus arteriosus, cerebrovascular disease (Moya-moya-like), coronary artery disease, thoracic aorta aneurysm, and dysfunction of smooth muscle cells in organs throughout the body. All affected individuals carry a p.R179H heterozygous mutation in the ACTA2 gene. We add to the ophthalmologic involvement with 3 more patients. Congenital fixed dilated pupils is a rare condition and should alert ophthalmologists to the possibility of the coexistence of systemic life-threatening disorders. 2014 by North American Neuro-Ophthalmology Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Expanding the spectrum of FOXC1 and PITX2 mutations and copy number changes in patients with anterior segment malformations

PURPOSE. Anterior segment dysgenesis (ASD) comprises a heterogeneous group of developmental abnormalities that affect several structures of the anterior segment of the eye. The main purpose of this study was to assess the proportion of FOXC1 and PITX2 mutations and copy number changes in 80 probands with ASD. METHODS. The patients were examined for FOXC1 and PITX2 copy number changes and mutations using MLPA (multiplex ligation-dependent probe amplification) and direct sequencing. Subsequently, the identified copy number changes were fine-mapped using high-resolution microarrays. In the remaining mutation-negative patients, sequencing of the FOXC1 and- PITX2 3″untranslated regions (UTRs) and three other candidate genes (P32, PDP2, and FOXC2) was performed. RESULTS. Thirteen FOXC1 and eight PITX2 mutations were identified, accounting for 26% (21/80) of the cases. In addition, six FOXC1 and five PITX2 deletions were found, explaining 14% (11/80) of the cases. The smallest FOXC1 and PITX2deletions were 5.4 and 1.6 kb in size, respectively. Six patients carrying FOXC1 deletions presented with variable extraocular phenotypic features such as hearing defects (in 4/6) and mental retardation (in 2/6). No further genetic defects were found in the remaining mutation-negative patients. CONCLUSIONS. FOXC1 and PITX2 genetic defects explain 40% of our large ASD cohort. The current spectrum of intragenic FOXC1 and PITX2 mutations was extended considerably, the identified copy number changes were fine mapped, the smallest FOXC1 and PITX2 deletions reported so far were identified, and the need for dedicated copy number screening of the FOXC1 and PITX2 genomic landscape was emphasized. This study is unique in that sequence and copy number changes were screened simultaneously in both genes