Congenital Microcoria: Clinical Features and Molecular Genetics.

Iris integrity is required to regulate both the amount of light reaching the retina and intraocular pressure (IOP), with elevated IOP being a major risk factor for glaucoma. Congenital microcoria (MCOR) is an extremely rare, autosomal dominant disease affecting iris development and hindering both of these functions. It is characterized by absent or underdeveloped dilator muscle fibers and immaturity of the iridocorneal angle-where the aqueous humor is drained-which play a central role in IOP regulation. The dilator muscle anomaly is manifested in pinhole pupils (<2 mm) and thin transilluminable irises, causing both hemeralopia and photoaversion. Axial myopia and juvenile open-angle glaucoma are very frequent (80% and 30% of all cases, respectively). It has been suggested that the immaturity of the chamber angle contributes to glaucoma, and myopia has been ascribed to photoaversion and elevated IOP. Though possible, these mechanisms are insufficient. The disease has been tied to chromosome 13q32.1 structural variations. In addition to compromising iris development, modification of the 13q32.1 architecture could alter signaling pathways for axial ocular length and IOP regulation. Here, we summarize the clinical, histological, and molecular features of this disease, and we discuss the possible etiology of associated anomalies.

Microcoria due to first duplication of 13q32.1 including the GPR180 gene and maternal mosaicism.

Congenital microcoria (MCOR) is an eye anomaly characterized by a pupil with diameter below 2 mm, and is caused by underdevelopment or absence of the dilator muscle of the pupil. Two types have been described: a recessive, syndromic (Pierson syndrome OMIM 609049) and a dominant, isolated form (MCOR syndrome OMIM 156600). Fares-Taie and colleagues described inherited microdeletions in chromosome band 13q32.1 segregating with dominant microcoria in several families. The GPR180 gene is located within the smallest commonly deleted region and encodes a G protein-coupled receptor involved in smooth muscle cells growth. We here describe a patient with isolated, non-syndromic MCOR. The patient presented with a blue iris and small pupils, non-reactive to cycloplegic agents. Her mother had a milder ocular phenotype, namely a blue iris with hypoplastic crypts and mild myopia. We present a detailed clinical examination and follow up. DNA from the index patient was analyzed for the presence of chromosomal imbalances using molecular karyotyping. The genetic test revealed a small duplication of chromosome band 13q32.1. The duplication affected a 289 kb region, encompassing 11 genes including GPR180. Interestingly, the patient displays only MCOR in contrast to patients with the reciprocal deletion who present with MCOR and iridocorneal angle dysgenesis. This genetic anomaly was inherited from the mother who carries the duplication in mosaic form, which should be considered when offering genetic counselling. In summary, we describe the first 13q32.1 duplication encompassing GPR180 associated with MCOR.

Phacoemulsification and 1% atropine eye drops for treatment of antimetropic congenital microcoria associated with cataracts / Facoemulsificação e colírio de atropina a 1% para tratamento de microcoria congênita antimetrópica associada a catarata

ABSTRACT A rare case of bilateral congenital microcoria associated with antimetropia in a 47-year-old man is here described. The patient presented with a chief complaint of progressive vision loss in his right eye over the past five years. A slit-lamp examination and ultrasound biomicroscopy confirmed congenital microcoria and cataracts. Phacoemulsification was performed using an iris expansion device and the anterior capsule was stained using the "trypan down under" technique. Preoperative considerations, the surgical approach, and postoperative management are discussed.

RESUMO Um caso raro de microcoria congênita bilateral associada à antimetropia em um homem de 47 anos de idade é descrito aqui. O paciente queixava-se de perda visual progressiva em seu olho direito nos últimos 5 anos. Um exame com lâmpada de fenda e biomicroscopia ultrassônica confirmaram microcoria congênita e catarata. A facoemulsificação foi realizada usando dispositivo de expansão iriana, e a cápsula anterior foi corada através da técnica "trypan down under". Considerações pré-operatórias, abordagem cirúrgica e manejo pós-operatório são discutidos.

Phacoemulsification and 1% atropine eye drops for treatment of antimetropic congenital microcoria associated with cataracts.

A rare case of bilateral congenital microcoria associated with antimetropia in a 47-year-old man is here described. The patient presented with a chief complaint of progressive vision loss in his right eye over the past five years. A slit-lamp examination and ultrasound biomicroscopy confirmed congenital microcoria and cataracts. Phacoemulsification was performed using an iris expansion device and the anterior capsule was stained using the "trypan down under" technique. Preoperative considerations, the surgical approach, and postoperative management are discussed.

A novel gain-of-function mutation in ORAI1 causes late-onset tubular aggregate myopathy and congenital miosis.

We present three members of an Italian family affected by tubular aggregate myopathy (TAM) and congenital miosis harboring a novel missense mutation in ORAI1. All patients had a mild, late onset TAM revealed by asymptomatic creatine kinase (CK) elevation and congenital miosis consistent with a Stormorken-like Syndrome, in the absence of thrombocytopathy. Muscle biopsies showed classical histological findings but ultrastructural analysis revealed atypical tubular aggregates (TAs). The whole body muscle magnetic resonance imaging (MRI) showed a similar pattern of muscle involvement that correlated with clinical severity. The lower limbs were more severely affected than the scapular girdle, and thighs were more affected than legs. Molecular analysis revealed a novel c.290C>G (p.S97C) mutation in ORAI1 in all affected patients. Functional assays in both human embryonic kidney (HEK) cells and myotubes showed an increased rate of Ca2+ entry due to a constitutive activation of the CRAC channel, consistent with a 'gain-of-function' mutation. In conclusion, we describe an Italian family harboring a novel heterozygous c.290C>G (p.S97C) mutation in ORAI1 causing a mild- and late-onset TAM and congenital miosis via constitutive activation of the CRAC channel. Our findings extend the clinical and genetic spectrum of the ORAI1-related TAM.

[White pupil in an infant]. / Hvid pupil hos børn kan være tegn påalvorlig øjensygdom.

A whitish pupillary reflex (leukocoria) indicates abnormal reflection from intraocular pathology. In a child, leukocoria may be a sign of serious and even life-threatening eye disease (retinoblastoma), but the most common cause is congenital cataract. Both diagnoses require immediate referral to an ophthalmologist. Leukocoria is best detected by evaluating the reflex from the pupil with a handheld ophthalmoscope. We here present a case story of an infant with leukocoria that proved to be caused by unilateral congenital cataract.

Submicroscopic deletions at 13q32.1 cause congenital microcoria.

Congenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR.

Familial acorea, microphthalmia and cataract syndrome.

PURPOSE: To describe the clinical features of members of a family with acorea, microphthalmia and cataract syndrome. In addition, to perform linkage analysis on family members to determine possible candidate genes. METHODS: Comprehensive ophthalmic examinations were performed on five affected members of a family consisting of a paternal grandmother, father and three children. In addition, DNA was extracted from nine family members (the five affected and four normal members) and used for genome-wide single nucleotide polymorphism genotyping and linkage analysis. RESULTS: All of the affected patients had acorea or fibrous occlusion of the pupil, microphthalmia and cataracts in both eyes. They also had microcornea and iridocorneal dysgenesis. Examination of the crystalline lens was hindered by the abnormal iris surface, but cataracts were detected by ultrasound biomicroscopy. Surgical reconstruction of the pupil allowed a better view of the posterior pole of the eye, and ophthalmoscopy showed a normal retina and optic disc. No systemic abnormalities were observed. Linkage analysis did not reach significance but narrowed the location of possible candidate genes to chromosomes 1, 5, 8, 11 and 17. CONCLUSIONS: This acorea, microphthalmia and cataract syndrome has not previously been reported. Genetic analyses indicate that this syndrome is probably due to an autosomal dominant mutation.