A novel syndrome of congenital lid and punctal anomalies,corneal and chorioretinal dystrophy

A 28-year old woman had an ocular syndrome consisting of congenital lid and punctal anomalies, and corneal and chorioretinal dystrophy without facial dysmorphism. These combined malformations of the ocular adnexae and both anterior and posterior ocular segments have not been previously described and appear to represent a novel syndrome. Direct sequencing of PAX6 and the DNA-binding domain of FOXC1 failed to detect a mutation.     

A novel syndrome of congenital lid and punctal anomalies,corneal and chorioretinal dystrophy

A 28-year old woman had an ocular syndrome consisting of congenital lid and punctal anomalies, and corneal and chorioretinal dystrophy without facial dysmorphism.These combined malformations of the ocular adnexae and both anterior and posterior ocular segments have not been previously described and appear to represent a novel syndrome. Direct sequencing of PAX6 and the DNA-binding domain of FOXC1 failed to detect a mutation.     

Bilateral macular detachment caused by bilateral optic nerve malformation in a papillorenal syndrome due to a new PAX2 mutation

PURPOSE: Papillorenal syndrome is an autosomal dominant entity due to PAX2 gene mutation, involving optic nerve and renal malformations. METHODS: The authors report a 19-year-old man with bilateral macular detachment associated with optic nerve pit in one eye and morning glory syndrome in the other eye. The patient underwent three-port pars plana vitrectomy, endolaser photocoagulation, and C3F8 gas tamponade in his best eye. A medical history of vesicoureteric reflux and kidney hypoplasia led to genetic analysis. RESULTS: Molecular genetic PAX2 analysis revealed a novel nondescribed mutation in exon 3. One year postoperatively, ophthalmologic outcomes were satisfactory with complete flattening of the retina and improvement of the best-corrected visual acuity to 11/10. CONCLUSIONS: PAX2 is involved in the optic vesicles, genital tracts, kidney, and central nervous system embryogenic development. The association of optic nerve and renal malformations should lead to the suspicion of papillorenal syndrome with PAX2 mutation.     

Variable phenotype related to a novel PAX 6 mutation (IVS4+5G>C) in a family presenting congenital nystagmus and foveal hypoplasia

PURPOSE: Several ocular defects have been identified as a consequence of the PAX6 gene mutations. With regard to the implication of this gene in unusual phenotypes, we report a family presenting with congenital nystagmus, foveal hypoplasia, and iris hypoplasia or atypical coloboma. DESIGN: Observational case report. METHODS: The entire transcribed region of the PAX6 gene was submitted to mutation search at the DNA and mRNA levels in five affected members of a French family in test with 82 normal subjects. RESULTS: A novel heterozygous PAX6 gene splice mutation (IVS4 + 5G>C) was identified. The mutation is located in IVS4 within the consensus donor splice site. A mutant mRNA lacking exon 4 as the sole defect was evidenced. The resultant protein was predicted to contain a cryptic ATG initiation codon in exon 3 and a slightly altered paired-domain in an open reading frame extended by 13 amino acids. CONCLUSIONS: The association of anterior segment anomalies and foveal hypoplasia with one of the slightest alterations of the PAX6 protein described to date confirms the association of variant phenotypes with hypomorphic alleles. Mutation screening of the PAX6 gene could be useful in elucidating the origin of complex ocular malformations.     

Clinical and molecular aspects of congenital aniridia – A review of current concepts

Congenital aniridia is a pan ocular disorder characterized by partial or total loss of iris tissue as the defining feature. Classic aniridia, however, has a spectrum of ocular findings, including foveal hypoplasia, optic nerve hypoplasia, nystagmus, late-onset cataract, glaucoma, and keratopathy. The latter three are reasons for further visual compromise in such patients. This entity is often due to mutations in the PAX6 (Paired box protein Pax-6) gene. Recently, aniridia-like phenotypes have been reported due to non-PAX6 mutations as in PITX2, FOXC1, FOXD3, TRIM44, and CYP1B1 as well wherein there is an overlap of aniridia, such as iris defects with congenital glaucoma or anterior segment dysgenesis. In this review, we describe the various clinical features of classic aniridia, the comorbidities and their management, the mutation spectrum of the genes involved, genotype-phenotype correlation of PAX6 and non-PAX6 mutations, and the genetic testing plan. The various systemic associations and their implications in screening and genetic testing have been discussed. Finally, the future course of aniridia treatment in the form of drugs (such as ataluren) and targeted gene therapy has been discussed.     

Renal coloboma syndrome

OBJECTIVE: To characterize the ocular features of renal coloboma syndrome. DESIGN: Prospective, observational case series. PARTICIPANTS: Twelve patients referred by the pediatric nephrology clinic and the ophthalmic records of five additional patients. METHODS: For each patient, age at the time of examination, gender, renal function, and presence of a mutation in the PAX2 gene were noted. All patients underwent measurement of visual acuity and anterior and posterior segment examination with fundus photography. Goldmann visual fields were tested in four cases. MAIN OUTCOME MEASURES: Visual acuity, optic disc abnormalities, and mutation in the PAX2 gene. RESULTS: Mean age was 21.5 years. Renal failure was mild in 6 patients and severe in 11 patients. A mutation in the PAX2 gene was identified in nine patients, without correlation to the ocular phenotype. Ocular features could be divided into five groups: optic disc dysplasia limited to an unusual pattern of retinal vessels without functional consequence; optic disc pit with normal visual acuity and blind spot enlargement; large optic disc coloboma; large coloboma of the optic disc and adjacent retina; morning glory anomaly (these last three conditions were accompanied by poor visual acuity). Fundus abnormalities were symmetrical in most cases and unrelated to renal status. CONCLUSIONS: Ophthalmic and renal characteristics of the renal coloboma syndrome are highly variable. The need for dialysis or renal transplantation can occur early in life or several years later. A wide range of ocular abnormalities located in the posterior segment can be observed. Mild optic disc dysplasia or pit have no functional consequence and can be underdiagnosed. More severe colobomas or related abnormalities, such as morning glory anomaly, often lead to poor visual acuity. Molecular biology allows detection of the mutations in the PAX2 gene, but can be negative in approximately 50% of cases. The observation of an optic disc coloboma or related abnormality stimulates the ophthalmologist to propose simple nephrologic investigations to check for renal hypoplasia, a potentially life-threatening disease. Conversely, renal hypoplasia stimulates the nephrologist to ask for a fundus examination to confirm the diagnosis and check for complications such as retinal detachment.     

Optic nerve dysplasia and renal insufficiency in a family with a novel PAX2 mutation,Arg115X: further ophthalmologic delineation of the renal-coloboma syndrome

Renal-coloboma syndrome, an autosomal dominant disorder associated with mutations in PAX2 , is characterized by colobomatous eye defects, renal hypoplasia, vesicoureteral reflux, high-frequency hearing loss, and rarely central nervous system abnormalities. We identified a three-generation family with optic nerve colobomatous dysplasia and renal disease. We report the identification of a novel mutation in PAX2 in this family with renal-coloboma syndrome, Arg115X. We also report on the ocular and extraocular manifestations of PAX2 mutations for all cases of renal-coloboma syndrome reported to date.     

Optic nerve dysplasia and renal insufficiency in a family with a novel PAX2 mutation, Arg115X: further ophthalmologic delineation of the renal-coloboma syndrome

Renal-coloboma syndrome, an autosomal dominant disorder associated with mutations in PAX2, is characterized by colobomatous eye defects, renal hypoplasia, vesicoureteral reflux, high-frequency hearing loss, and rarely central nervous system abnormalities. We identified a three-generation family with optic nerve colobomatous dysplasia and renal disease. We report the identification of a novel mutation in PAX2 in this family with renal-coloboma syndrome, Arg115X. We also report on the ocular and extraocular manifestations of PAX2 mutations for all cases of renal-coloboma syndrome reported to date.     

三个先天性无虹膜症家系中PAX6基因的突变分析

背景 人类配对盒基因(PAX6)编码一个转录调节子,对眼和大脑形态的形成起关键作用.PAX6突变可导致许多先天性眼部发育异常,如先天性无虹膜症,通常为常染色体显性遗传方式. 目的 对三个先天性无虹膜症家系成员进行PAX6基因分析,探索这些家系发病的遗传基础. 方法 收集三个先天性无虹膜症家系的5例患病者和正常成员13名的外周血标本提取DNA,根据PAX6基因的序列设计4～ 13外显子序列,通过聚合酶链反应(PCR)扩增引物并测序,将目标序列与已发表的PAX6基因序列进行对比分析.结果 三个家系中共有5例患病者,在家系A中2例患者发现一个杂合突变(c.718 C＞T),导致第240位氨基酸由精氨酸突变为终止密码子(p.A rg240X),而其他正常表型者未发现此突变.家系B中的患病者和正常成员均未检测到PAX6基因的突变.家系C中1例患病者发现c.331 delG(p.Val111SerfsX13)的缺失突变,此单个碱基的缺失造成了移码突变,使PAX6蛋白羧基端的299个氨基酸缺失,而此家系的其他正常表型成员未发现此突变. 结论 家系A和家系C先天性无虹膜症的致病与PAX6基因的突变有关.     

Three New PAX2 Gene Mutations in Patients with Papillorenal Syndrome

Papillorenal syndrome (PAPRS; Mendelian Inheritance in Man [MIM] 120330) is an autosomal dominant disease characterised by the presence of congenital renal and optic nerve abnormalities associated with mutations of the PAX2 gene. In this article, the authors present four patients with PAPRS who are carriers of three new PAX2 mutations, as well as another patient with a possible non-pathogenic variant of the PAX2 gene. All patients were given a full neurophthalmological examination, and all patients underwent a genetic test for PAX2. Patients 1 and 2 presented with the classic signs of PAPRS: renal disease associated with a congenitally abnormal optic disc, whereas patients 3 and 4 only presented with a congenital optic nerve abnormality and no renal involvement. In patients 1 and 2, the optic nerves were affected by the presence of a central excavation within the optic disc, absence of the central retinal artery, as well as multiple cilioretinal arteries radiating from the periphery of the optic disc. Bilateral optic nerve pits were seen in patient 3, and lastly, in patient 4 there was the presence of superficial gliotic tissue on the left optic disc. All patients presented with a missense mutation in the PAX2 gene, where in patient 4 possibly being only a non-pathogenic variant of the gene. In conclusion, the authors present two patients with classic clinical signs of PAPRS, having two new PAX2 mutations, which until now have not been described in the current literature; another patient with a new PAX2 mutation showing only ocular manifestations of the disease, and lastly, a patient who is a carrier of a variant of the PAX2 gene has a congenitally abnormal optic disc, which is probably not related to PAPRS.     

Continuous expression of the homeobox gene Pax6 in the ageing human retina

PURPOSE: In the past few years, the essential role of the homeobox gene Pax6 for eye development has been demonstrated unambiguously in a variety of species including humans. In humans, Pax6 mutations lead to a variety of ocular malformations of the anterior and posterior segment. However, little is known about PAX6 expression in the adult human retina. We have therefore investigated PAX6 levels and localization in the human retina at various ages. METHODS: Adult human eyes of various ages (17-79 years) were obtained from the Zurich Eye Bank. PAX6 expression levels and patterns were analysed by Western blot analysis of total retinal protein and by immunohistochemistry on paraffin sections, respectively. RESULTS: PAX6 expression in the retina was detected up to 79 years of donor age and was predominantly localized to the ganglion cell layer and the inner part of the inner nuclear layer. CONCLUSIONS: PAX6 remains distinctly expressed throughout the lifespan of the human retina suggesting a role for PAX6 in the retina after completion of eye morphogenesis.     

Two novel mutations of the PAX6 gene causing different phenotype in a cohort of Chinese patients

Purpose

Aniridia (AN) is a rare congenital panocular disorder caused by the mutations of the paired box homeotic gene 6(PAX6) gene. The PAX6gene is also involved in other anterior segment malformations including Peters anomaly. We studied the PAX6gene mutations in a cohort of affected individuals with different clinical phenotype including AN, coloboma of iris and choroid, or anterior segment malformations.

Patients and methods

Six unrelated families and 10 sporadic patients were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Mutation screening of all exons of the PAX6gene was performed by direct sequencing of PCR-amplified DNA fragments. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect large deletions.

Results

By clinical examination, the patients and the pedigrees were divided into the following three groups: AN, coloboma of iris and choroids, and the anterior segment malformations including peters anomaly. Sequencing of the PAX6gene, three intragenic mutations including a novel heterozygous splicing-site mutations c.357-3C>G (p.Ser119fsX) were identified in the patients of the AN group. A novel missense mutation c.643T>C (p.S216P) was detected in the anterior segment malformation group. The mutation p.S216P located in the homeodomain region of the PAX6 caused the phenotype of Peters anomaly in family A6 with different expressing. Through MLPA analysis, a large deletion including the whole PAX6gene and DKFZ p686k1684gene was detected in one sporadic patient from the AN group. Neither intragenic mutation nor large deletion was identified in the group with coloboma of iris and choroid.

Conclusion

Our findings further confirmed that different kind of mutations might cause different ocular phenotype, and clearly clinical phenotype classification might increase the mutation detection rate of the PAX6gene.     

Renal-coloboma syndrome: report of a novel PAX2 gene mutation

PURPOSE: To report a novel sporadic PAX2 gene mutation in a child with atypical bilateral optic nerve coloboma and congenital renal hypoplasia.DESIGN: Observational case report and experimental study.METHODS: Mutational analysis of the PAX2 gene in a family.RESULTS: A 9-year-old patient with a history of renal transplantation for congenital renal hypoplasia was found to have bilateral optic nerve coloboma during ophthalmic examination for cytomegalovirus retinitis. A previously unreported mutation in exon 2, delT 602 leading to a prematurely truncated protein was identified in the child but in neither of her parents, demonstrating a de novo mutation or germline mosaicism.CONCLUSIONS: The causal relationship between PAX2 gene mutations and renal-coloboma syndrome is further supported by this novel mutation. Awareness of the systemic associations with optic nerve abnormalities and the ocular findings in syndromic renal diseases will facilitate the management of these highly variable disorders.     

Frequent coexistence of ocular malformations in externally malformed human fetuses.

60 undamaged human fetuses with some types of external malformations were taken from the human embryo and fetus collection at the Department of Anatomy, Kyoto University. They were examined macroscopically and stereo-microscopically for ocular and other external and internal malformations. 18 cases, that is 30% of the group, showed ocular malformations of the following type: approximated eyes (2 cases), approximated eyes + microcornea (1), microphthalmia (8), microcornea (3), corneal opacity (1), transparent sclera (2), antimongoloid obliquity of the palpebral fissure (1). In addition, asymmetric insertion site of the recti muscle(s) which can be regarded as a minor deviation, was found in 10 cases (16.7%). Other types of malformations were found simultaneously in a variety of organ systems and regions. No particular maternal factors were suggested to be related to such coexisting ocular malformations.     

Ocular manifestations in Proteus syndrome

CASE REPORT: Congenital disfiguring malformations are rare and usually have a multifactorial aetiology. Here we report on the ocular manifestations seen in a patient with Proteus syndrome. The retina showed retinal dysgenesia, retinal pigmentary abnormalities and optic nerve hypoplasia. Other abnormalities included strabismus and high myopia. DISCUSSION: Proteus syndrome is a complex hamartomatous disorder defined by local overgrowth, subcutaneous tumours and various bone, cutaneous and/or vascular anomalies. The incidence of ocular malformations in Proteus syndrome is unknown, however a meticulous cranio-facial examination and a systematic study of the eye is required to improve the medical care of these patients.     

Oculocerebrocutaneous syndrome: a case report

There are many congenital ocular malformations associated with systemic findings. In cases such as oculocerebrocutaneous syndrome, the severity of systemic findings makes diagnosis particularly important. This case report presents a case of this uncommon syndrome and demonstrates the common findings.     

Renal-coloboma syndrome: report of a novel PAX2 gene mutation.

PURPOSE: To report a novel sporadic PAX2 gene mutation in a child with atypical bilateral optic nerve coloboma and congenital renal hypoplasia. DESIGN: Observational case report and experimental study. METHODS: Mutational analysis of the PAX2 gene in a family. RESULTS: A 9-year-old patient with a history of renal transplantation for congenital renal hypoplasia was found to have bilateral optic nerve coloboma during ophthalmic examination for cytomegalovirus retinitis. A previously unreported mutation in exon 2, delT 602 leading to a prematurely truncated protein was identified in the child but in neither of her parents, demonstrating a de novo mutation or germline mosaicism. CONCLUSIONS: The causal relationship between PAX2 gene mutations and renal-coloboma syndrome is further supported by this novel mutation. Awareness of the systemic associations with optic nerve abnormalities and the ocular findings in syndromic renal diseases will facilitate the management of these highly variable disorders.     

LEOPARD-Syndrom mit Iris-Netzhaut-Aderhaut-Kolobom Diskordanter Befund bei monozygoten Zwillingen (MIM # 151 100)

Introduction. The LEOPARD syndrome is an autosomal dominant inherited disease with severe lentiginosis associated with various abnormalities such as electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of the genitalia, retardation of growth and deafness. Ocular manifestations such as coloboma of the iris, the retina and the choroid have not been reported so far. Patients. We report the cases of two 10-year-old identical twins and their mother, showing typical manifestations consistent with the LEOPARD syndrome. Additionally, colobomas of the iris, the retina and the choroid were detected. Results. In addition to the findings typical for the LEOPARD syndrome, we observed unusual ocular abnormalities in all three patients. It represents a discordant phenotype in monozygotic twins. Conclusion. LEOPARD syndrome is a disease with multiple alterations and abnormalities. Although ocular malformations seem to be rare, an ophthalmological examination is recommended in order to initiate early visual rehabilitation.     

Mosaic cat eye syndrome in a child with unilateral iris coloboma

ABSTRACT

Background

Cat eye syndrome (CES) is a rare chromosomal disorder with a known incidence of 1 per 50,000–150,000 live newborns. The classic triad of iris coloboma, anorectal malformations, and auricular abnormalities is present in 40% of patients. In addition, other ocular malformations and systemic defects can be present. The aim of this report is to present a patient with unilateral iris coloboma related to a mosaicism of cat eye syndrome.