Axenfeld-Rieger syndrome: more than meets the eye

Abstract

Background: Axenfeld-Rieger syndrome (ARS) is characterised by typical anterior segment anomalies, with or without systemic features. The discovery of causative genes identified ARS subtypes with distinct phenotypes, but our understanding is incomplete, complicated by the rarity of the condition.

Methods: Genetic and phenotypic characterisation of the largest reported ARS cohort through comprehensive genetic and clinical data analyses.

Results: 128 individuals with causative variants in PITX2 or FOXC1, including 81 new cases, were investigated. Ocular anomalies showed significant overlap but with broader variability and earlier onset of glaucoma for FOXC1-related ARS. Systemic anomalies were seen in all individuals with PITX2-related ARS and the majority of those with FOXC1-related ARS. PITX2-related ARS demonstrated typical umbilical anomalies and dental microdontia/hypodontia/oligodontia, along with a novel high rate of Meckel diverticulum. FOXC1-related ARS exhibited characteristic hearing loss and congenital heart defects as well as previously unrecognised phenotypes of dental enamel hypoplasia and/or crowding, a range of skeletal and joint anomalies, hypotonia/early delay and feeding disorders with structural oesophageal anomalies in some. Brain imaging revealed highly penetrant white matter hyperintensities, colpocephaly/ventriculomegaly and frequent arachnoid cysts. The expanded phenotype of FOXC1-related ARS identified here was found to fully overlap features of De Hauwere syndrome. The results were used to generate gene-specific management plans for the two types of ARS.

Conclusion: Since clinical features of ARS vary significantly based on the affected gene, it is critical that families are provided with a gene-specific diagnosis, PITX2-related ARS or FOXC1-related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy.

Keywords: congenital, hereditary, and neonatal diseases and abnormalities; eye diseases; genetics; genetics, medical.

Figure 1

Schematic of PITX2 (A) and FOXC1 (B) proteins. Positions of previously reported (thin arrows) and novel (large arrows with variant specified) variants associated with Axenfeld-Rieger syndrome and related conditions indicated: circle atop arrow indicates missense/in-frame indel variants; arrows without circles indicate truncating/splicing variants; diamond atop arrow indicates both variant types present at this position. Domains indicated with shading include homeodomain (aa 38–98) and OAR domain (aa 233–246) for PITX2 and forkhead domain (aa 77–168), nuclear localisation signal domain (aa 168–176), activation domains (aa 1–51 and 435–553) and inhibitory domain (within aa 215–365) for FOXC1.

Figure 2

Clinical images from individuals with PITX2-related ARS and FOXC1-related ARS. (A–E) Photographs from individuals with PITX2 variants. (A) Individual 7 with ARS showing posterior embryotoxon, iris hypoplasia and polycoria. (B) Individual 14 with ARS showing iris hypoplasia and posterior embryotoxon. (C) Hendee et al patient 1A showing aniridia. (D) Reis et al case 21 showing corneal opacity. (E) Dental images of individual 14 showing missing teeth and microdontia. (F–J) Photographs from individuals with FOXC1 variants. (F) Individual 42 with ARS showing corectopia, polycoria and iris hypoplasia. (G) Individual 32 showing iris hypoplasia, posterior embryotoxon and iridocorneal adhesions. (H) Individual 75 with generalised anterior segment dysgenesis, corneal opacity and glaucoma diagnosed shortly after birth. (I) Individual 47 showing absence of ASD. (J) Dental image of individual 47 showing normal size and shape but poor condition with numerous caries. ARS, Axenfeld-Rieger syndrome.

Figure 3

Images from brain MRI from Individuals with PITX2-related ARS and FOXC1-related ARS. (A) Individual 7 with PITX2 splicing variant showing a small number of punctate T2 hyperintense lesions in frontal and parietal subcortical WM. (B–D) Individual 32 with FOXC1 deletion showing numerous ill-defined T2 hyperintense lesions mainly in subcortical WM but also periventricular and deep WM (B), mild colpocephaly (C) and bilateral staphylomas with widened perivascular spaces (C, D). (E, F) Individual 33 with FOXC1 deletion showing dysgenesis of the corpus callosum and Dandy-Walker malformation. (G–I) Individual 41 with FOXC1 nonsense variant showing numerous ill-defined T2 hyperintense lesions in periventricular, deep and subcortical WM and mild colpocephaly (G), mild volume loss of the posterior corpus callosum (H) and small anterior temporal arachnoid cyst at left as well as B staphyloma (I). (J) Individual 47 with FOXC1 frameshift variant showing a small number of punctate T2 hyperintense lesions in frontal and parietal subcortical WM and enlargement of lateral ventricles. (K) Individual 54 with FOXC1 frameshift variant showing tortuosity in the right cavernous internal carotid artery. (L, M) Individual 76 with FOXC1 missense variant showing numerous ill-defined T2 hyperintense lesions in periventricular, deep and subcortical WM and mild colpocephaly (middle childhood stage, L) and very shallow anterior chambers (neonatal birth period, M). ARS, Axenfeld-Rieger syndrome; WM, white matter.

Figure 4

Comparison of features in PITX2-related ARS and FOXC1-related ARS. (A) Genotype–phenotype correlations in ARS shows a distinct pattern of features associated with PITX2 (blue) versus FOXC1 (orange). (B) Comparison of glaucoma age of onset shows significantly earlier age of onset for FOXC1. (C) Analysis of hearing loss among individuals with FOXC1-related ARS shows onset throughout the life span but significantly higher rates for those with deletions compared with intragenic and also higher rates for PTC compared with missense alleles. ARS, Axenfeld-Rieger syndrome; n.s., not significant; PTC, premature termination codon. * p <0.05; ** p<0.01; *** p<0.001