G C A T T A C G G C A T genes Review Congenital Microcoria: Clinical Features and Molecular Genetics Clémentine Angée, Brigitte Nedelec, Elisa Erjavec, Jean-Michel Rozet and Lucas Fares Taie * Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France; [email protected] (C.A.); [email protected] (B.N.); [email protected] (E.E.); [email protected] (J.-M.R.) * Correspondence: [email protected] Abstract: 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. Keywords: congenital microcoria; congenital miosis; dilator muscle; glaucoma; myopia; chromosome Citation: Angée, C.; Nedelec, B.; 13q32.1 structural variants Erjavec, E.; Rozet, J.-M.; Fares Taie, L. Congenital Microcoria: Clinical Features and Molecular Genetics. Genes 2021, 12, 624. https://doi.org/ 1. Introduction 10.3390/genes12050624 The iris (Figures1 and2) is a flat ring-shaped ocular membrane located between the Received: 10 March 2021 cornea and the lens. Its root is attached to the corneoscleral junction on the anterior side Accepted: 19 April 2021 and the ciliary body on the posterior side, next to the lens, and its center is perforated Published: 22 April 2021 to form the pupil. The iris is composed of a stroma, bilayer epithelium, and two smooth muscles that work in opposition to adapt the pupil aperture to light intensity [1]. The Publisher’s Note: MDPI stays neutral circular sphincter muscle lies within the stroma, near the pupil margin, and can constrict with regard to jurisdictional claims in the pupil in miosis [2]. The dilator muscle extends longitudinally within the stroma, from published maps and institutional affil- the iris root to below the midpoint of the sphincter [3], and can contract to expand the iations. pupillary aperture in mydriasis [1]. The dilator muscle originates from the anterior iris epithelium, composed of a single layer of myoepithelial cells, the basal portion of which consists in elongated smooth muscle processes [4]. The ciliary body is an extension of the iris, with which it is continuous. It produces a fluid known as aqueous humor that Copyright: © 2021 by the authors. provides nourishment to eye structures. The aqueous humor flows between the iris and Licensee MDPI, Basel, Switzerland. lens, through the pupil to the anterior part of the iris, where it is drained through the This article is an open access article trabecular meshwork (TM), a sieve-like structure lying at the juncture of the corneoscleral distributed under the terms and region with the iris periphery [1]. Aqueous humor drainage is required to regulate IOP, conditions of the Creative Commons which, when elevated, is a major risk factor for optic nerve damage (glaucoma) [5,6]. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Genes 2021, 12, 624. https://doi.org/10.3390/genes12050624 https://www.mdpi.com/journal/genes Genes 2021, 12, 624 2 of 13 Genes 2021, 12, x FOR PEER REVIEW 2 of 13 Genes 2021, 12, x FOR PEER REVIEW 2 of 13 FigureFigure 1.1.Muscles Muscles of of the the iris iris and and adaptation adaptation of of pupil pupil aperture aperture to to light light intensity. intensity. The The circular circular sphincter Figure 1. Muscles of the iris and adaptation of pupil aperture to light intensity. The circular muscle,sphincter or pupillarymuscle, or constrictor, pupillary constrictor, near the pupil near margin the pupil is composed margin ofis composed smooth muscle of smooth cells, whichmuscle can cells,sphincter which muscle, can constrict or pupillary the pupil constrictor, (miosis) nearwhen the exposed pupil margin to bright is lightcomposed. It works of smooth in opposition muscle to constrict the pupil (miosis) when exposed to bright light. It works in opposition to the radial dilator thecells, radial which dilator can constrict muscle fibers,the pupil whose (miosis contraction) when exposed expands to the bright pupillary light. Itaperture works in(mydriasis opposition) in toa muscle fibers, whose contraction expands the pupillary aperture (mydriasis) in a dim environment. dimthe radial environment. dilator muscle The sphincter fibers, whose and dilator contraction muscles expands are innervat the pupillaryed by the aperture parasympathetic (mydriasis )and in a Thesympatheticdim sphincter environment. nervous and dilator The systems, sphincter muscles respectively. and are innervateddilator muscles by the are parasympathetic innervated by the and parasympathetic sympathetic nervous and systems,sympathetic respectively. nervous systems, respectively. Figure 2. Anatomy of the iris, ciliary body, and aqueous humor pathway. The iris is organized into FigurefourFigure layers 2. 2.Anatomy Anatomy (from the ofof visible thethe iris,iris, surface ciliaryciliary layer body,body, to and and the aqueous aqueousposterior humor humor region pathway. pathway. next to the The The lens): iris iris is anterioris organized organized border into into four layers (from the visible surface layer to the posterior region next to the lens): anterior border fourlayer, layers stroma, (from and the sphincter visible surfacemuscle, layer the lightly to the pigmented posterior region anterior next epithelium to the lens): layer anterior (AEL) borderand dilatorlayer, stroma, muscle, and and sphincter the heavily muscle, pigmented the lightly posterio pigmentedr epithelium anterior layer epithelium (PEL). The layer circular (AEL) sphincter and layer, stroma, and sphincter muscle, the lightly pigmented anterior epithelium layer (AEL) and dilator muscledilator muscle,lies within and the the stroma. heavily The pigmented anterior posterioiris epitheliumr epithelium is composed layer (PEL). of a single The circular layer of sphincter myoep- muscle, and the heavily pigmented posterior epithelium layer (PEL). The circular sphincter muscle ithelialmuscle cells.lies within The basal the stroma.portion Theof these anterior cells iris consists epithelium in elongated is composed smooth of musclea single processes layer of myoep- form- liesingithelial within 3 to cells.5 layers the The stroma. of basal radial The portion dilator anterior of muscle these iris epithelium cells fibers. consists The is composediris in rootelongated is ofattached a singlesmooth to layer themuscle ofciliary myoepithelial processes body and form- cells.to Thetheing basalcorneoscleral3 to 5 portionlayers of ofjunction radial these dilatorcells (iridocorneal consists muscle in angle). fibers. elongated TheNear iris smooth the root root, muscleis theattached anterior processes to theborder ciliary forming layer, body 3 stroma, to and 5 layers to ofandthe radial corneoscleral bilayer dilator epithelium muscle junction of fibers. the(iridocorneal iris The form iris rootfinger-s angle). is attachedhaped Near the processes to root, the ciliarythe and anterior become body andborder the to ciliary thelayer, corneoscleral body, stroma, the junctionanteriorand bilayer (iridocornealand epithelium posterior angle). epithelium of the Near iris form thelayers root, finger-s of thewhic anteriorhapedh are processesheavily border and layer, and lightly stroma,become pigmented, andthe bilayerciliary respectively. body, epithelium the ofTheanterior the aqueous iris and form posteriorhumor finger-shaped that epithelium provides processes layersnourishment of and whic become toh are eye heavily thestructures ciliary and body,is lightly produced the pigmented, anterior by the andciliary respectively. posterior body. epitheliumItThe flows aqueous between layers humor ofthe which thatiris and provides are lens, heavily through nourishment and lightly the pupil, to pigmented, eye and structures to the respectively. anterior is produced part The of by aqueous the the iris, ciliaryhumor where body. thatit It flows between the iris and lens, through the pupil, and to the anterior part of the iris, where it providesruns (i) across nourishment the iris and to eye anterior structures face of is the produced ciliary body, by the and ciliary out body.through It flowsthe sclera between (uveoscleral the iris pathway)runs (i) across and (ii)the throughiris and anteriorthe trabecular face of meshwork the ciliary