Grand Rounds Conference Reema Syed, MBBS University of Louisville Department of Ophthalmology and Visual Sciences March 20, 2015

Subjective CC: blurry vision right eye>left eye, for months HPI: 57 year old African American male complains of progressively decreasing distance vision for months. No pain or history of trauma

History POH: “pupil anomaly” PMH: none Meds: none Allergies: none Family Ocular Hx: none

Exam ODOS BCVA:20/3020/25 ( x90)( x90) Pupils: inferonasally displaced tear drop pupils No RAPD IOP (mmHg):55 45 EOM: Full Full orthophoric in primary gaze

Inferonasally displaced tear drop shaped pupils OU with inferior iris atrophy OD ODOS

Posterior embryotoxon in the nasal cornea OU

Anterior Segment SLE: ODOS E/L/LWNL OU Conj/scleraWhite and quiet OU CorneaWNL OU ACDeep and quiet OU LensNS 2+ CC 1+NS 1+ Gonioscopyangles open, inferior iris strands extending across angle to insert into a prominent Schwalbe line OU

Optic disc: Significant loss of neuro-retinal rim OD>OS MVP: wnl Fundus Exam

HVF 24-2 Dense inferior and early superior arcuate scotoma Full ODOS

Assessment 57 year old male with Axenfeld-Rieger syndrome and glaucoma 57 year old male with Axenfeld-Rieger syndrome and glaucoma DDx: DDx: - Iris coloboma - ICE syndrome (unilateral, corectopia, beaten bronze appearance of corneal endothelium) - Posterior polymorphous corneal dystrophy (bilateral, corectopia, posterior corneal vesicular-like lesions) Plan: Travatan and Combigan, new MRx Plan: Travatan and Combigan, new MRx

Axenfeld-Rieger Syndrome Axenfeld’s anomaly: posterior embryotoxon + abnormal iris tissue crossing the trabecular meshwork and attaching to the posterior embryotoxon Rieger’s anomaly: Axenfeld anomaly + iris changes such as hypoplastic stroma, a displaced pupil (corectopia) or extra holes in the iris (polycoria) Rieger’s Syndrome: Rieger’s anomaly + facial, dental or umbilical anomalies

Considerable overlap; the three categories represent spectrum of a single developmental disorder Considerable overlap; the three categories represent spectrum of a single developmental disorder (Axenfeld-Rieger syndrome: a theory of mechanism and distinctions from the iridocorneal endothelial syndrome. MB Shields; Trans Am Ophthalmol Soc. 1983; 81: 736–784.) For instance, iris stromal atrophy may be very subtle in some patients making it difficult to know whether the term Axenfeld's anomaly or Rieger's anomaly should be used. Some patients with ocular findings of Axenfeld’s anomaly have systemic features of Rieger’s syndrome. For instance, iris stromal atrophy may be very subtle in some patients making it difficult to know whether the term Axenfeld's anomaly or Rieger's anomaly should be used. Some patients with ocular findings of Axenfeld’s anomaly have systemic features of Rieger’s syndrome. Single diagnostic term of Axenfeld-Rieger syndrome is now used Single diagnostic term of Axenfeld-Rieger syndrome is now used

Epidemiology/Pathophysiology Seen in approximately 1/200,000 live births There is no sex predilection Defective anterior segment morphogenesis and systemic abnormalities due to defects in differentiation, migration, or arrested development of neural crest cells

Autosomal dominant but can also occur sporadically Genetically linked to loci at chromosomes 4q25 (encodes PITX2), 6p25 (FOXC1), 11 (PAX6) and 13q14 (gene unknown) Mutations in FOXC1 have been associated with ocular phenotype of Axenfeld-Rieger Syndrome without the syndromic features Genetics

Clinical features Photophobia or glare may be a symptom resulting from the pupillary and iris abnormalities Developmental abnormalities in the anterior segment: Corectopia, polycoria, ectropion uveae, posterior embryotoxon, and increased intraocular pressure The posterior embryotoxon may not be visible with the slit lamp examination and may only be visible with gonioscopy

Source: gonioscopy.org 30 year old woman with A-R syndrome, gonioscopy shows posterior embryotoxon with iris strands attached to it

Glaucoma usually develops in late childhood or adulthood in 50% of cases Developmental arrest of neural crest cells and their retention in the anterior chamber angle Incomplete development of the trabecular meshwork or Schlemm's canal

Systemically, patients may have: Craniofacial dysmorphism: hypertelorism, telecanthus, maxillary hypoplasia, broad, flat nasal bridge Dental abnormalities: microdontia, hypodontia Redundant umbilical skin, umbilical hernia In addition, patients may have hypospadias, anal stenosis, growth retardation, congenital cardiac outflow tract malformations

Purpose: To improve the understanding of Axenfeld-Rieger Malfomation (ARM) associated glaucoma in patients who have known genetic defects in FOXC1 or PITX2 Purpose: To improve the understanding of Axenfeld-Rieger Malfomation (ARM) associated glaucoma in patients who have known genetic defects in FOXC1 or PITX2 Methods: Clinical data were collected from 126 patients with diagnosed ARM, with identified mutations in FOXC1 or PITX2 genes Methods: Clinical data were collected from 126 patients with diagnosed ARM, with identified mutations in FOXC1 or PITX2 genes Results: 75% of the patients with ARM who participated in this study had glaucoma that had developed in adolescence or early adulthood. Patients with PITX2 defects developed glaucoma at an earlier age and had more severe glaucoma requiring multiple surgeries than patients with FOXC1. Glaucoma in only 18% of patients with either PITX2 or FOXC1 genetic defects responded to medical or surgical treatment (used solely or in combination) Results: 75% of the patients with ARM who participated in this study had glaucoma that had developed in adolescence or early adulthood. Patients with PITX2 defects developed glaucoma at an earlier age and had more severe glaucoma requiring multiple surgeries than patients with FOXC1. Glaucoma in only 18% of patients with either PITX2 or FOXC1 genetic defects responded to medical or surgical treatment (used solely or in combination) Conclusions: Patients with PITX2 defects have a more severe prognosis for glaucoma development. In the present study, current medical therapies do not successfully lower intraocular pressure or prevent progression of glaucoma in patients with ARM who have FOXC1 or PITX2 alterations. Conclusions: Patients with PITX2 defects have a more severe prognosis for glaucoma development. In the present study, current medical therapies do not successfully lower intraocular pressure or prevent progression of glaucoma in patients with ARM who have FOXC1 or PITX2 alterations.

References BCSC Glaucoma BCSC Glaucoma BCSC External disease and Cornea BCSC External disease and Cornea Axenfeld TH. Embryotoxon cornea posterius. Klin Monatsbl Augenheilkd. 1920;65: Rieger H. Beitrage zur Kenntnis seltener Missbildungen der Iris, II: uber Hypoplasie des Irisvorderblattes mit Verlagerung und entrundung der Pupille. Albrecht von Graefes Arch Klin Exp Ophthalmol. 1935;133: Shields MB. Axenfeld-Rieger syndrome. A theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans Am Ophthalmol Soc. 1983;81:736–84. Alward WLM: Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Ophthalmol 2000;130: Tsai JC, Grajewski AL. Cardiac valvular disease and Axenfeld-Rieger syndrome. Am J Ophthalmol Aug 15;118(2):255-6.

Thank you