The FOXC1 gene (MIM #601090) encodes a transcription factor, FOXC1, which is characterized by a highly conserved approximately 110-amino-acid motif (69-178aa) known as the forkhead domain. The nuclear localization signals at either end of the forkhead domain support the transfer of FOXC1 to the nucleus and biding to DNA, thereby regulating the downstream target genes. FOXC1 is highly expressed in the heart, kidney and skeletal muscles, and has a role in tumor development, tissue-specific gene expression and embryogenesis. To the best of our knowledge, 85 different pathogenic variants of FOXC1 have been identified, which are related with ARS or ASD (Anterior segment dysgenesis) (Table 1, Fig. 2). Most pathogenic variants affect the amino acid within the forkhead domain, which impair the FOXC1 protein function by altering the ability of nuclear localization, transactivation activity, DNA-biding ability and protein stability [19, 20]. Pathogenic variants at the C-terminal of FOXC1 are less characterized, probably influences FOXC1 protein ubiquitination [13].
Based on genetic analyses combined with ocular and the systemic abnormalities including craniofacial dysmorphism and dental malformation, we made a diagnosis of ARS in the proband [1]. Structures of the anterior segment was affected which is characterized by pupil deformity in both eyes. Apart from pupil deformity (corectopia), patients with ARS may have various anterior segment abnormalities such as posterior embryotoxon, iris stromal hypoplasia, pseudopolycoria and angle closure [21, 22]. Among them, destruction of the chamber angle often leads to secondary glaucoma. Patients may develop glaucoma at a very young age, or they may asymptomatic for a long time from childhood to youth until high intraocular pressure occurs. It is reported that more than 50% patients with FOXC1-related ARS will develop glaucoma eventually and the median age of glaucoma diagnosis is 6 ± 13.0 years [3, 23, 24]. In this study, although the 5-year-old boy had normal intraocular pressure and there were no alterations of the optic nerve, he is still at high risk of developing glaucoma. Due to the high risk and adverse consequence, it is crucial for the patients with ARS to follow up frequently and take a comprehensive ophthalmic examination. IOP monitoring, anterior chamber angle examination and funds examination are necessary for follow-up. Automated perimetry and optic nerve head optical coherence tomography (OCT) should be further improved to evaluate visual field defect and optic nerve injury in patients who are suspected to have glaucoma. Early diagnosis and treatment are crucial to control the ocular complications of ARS and reduce the incidence of blindness caused by glaucoma. At present, surgical treatment is applied to decrease the raised IOP which correlates well with glaucoma progression and leads to satisfactory visual outcome in a long term [25].
Hearing loss is frequently characterized features in ARS patients, with sensorineural hearing loss being the most prevalent type. Structural abnormalities of the cochlea have been reported in a few individuals. Although a precise mechanism for FOXC1 in hearing or ear development is not well understood. One systematic review reported 82 FOXC1 pathogenic variants in patients with ocular disease and identified 17 variants are reported to be related with abnormal hearing [26]. Fifteen of the 17 variants found in patients reporting hearing loss either caused a frameshift or premature stop codon, leading to the loss of the forkhead domain [26]. Only one frameshift variant within the forkhead domain (p.Gln106Argfs*7) reported normal hearing [27]. There are however, many patients with FOXC1 variant involving the forkhead domain that do not report hearing problems. This observation may be due to variable expressivity of the hearing phenotype, or could implicate a second gene or other factors that impact hearing pathogenesis. Moreover, in many patients, there is no mention of the hearing phenotype, making it difficult to determine whether or not hearing tests were conducted. Although the proband in our study presented hearing loss, however, by detailed hearing evaluation, the diagnosis of conductive hearing loss induced by otitis media with effusion was reached. Hearing recovery and normal hearing was observed 3 month later, indicating that the hearing loss is reversible and might not linked to the FOXC1 variant and is coincidental.
Minor facial dysmorphism has been identified as part of the ARS spectrum since the initial reports of affected individuals, with characteristic facial features including maxillary hypoplasia with flattening of the midface, hypertelorism, a broad flat nasal root, and a thin upper lip [28]. Hypertelorism is typically a manifestation of a craniofacial deformity and not a disease in itself. It can be seen in a variety of conditions such as craniofacial clefts, craniofacial dysplasias and craniosynostosis syndromes, like Edwards Syndrome, 1q21.1 Duplication Syndrome, Basal Cell Nevus Syndrome, DiGeorge Syndrome Loeys-Dietz Syndrome, Apert Syndrome, Noonan syndrome, Neurofibromatosis, Leopard Syndrome, Crouzon Syndrome, Wolf-Hirschhorn Syndrome, Andersen–Tawil Syndrome, Waardenburg Syndrome and Cri-du-Chat Syndrome, et al [29]. Assessment of dysmorphic features, including facial dysmorphism, plays a major role in the evaluation of genetic syndromes to reach a clinical diagnosis.
In summary, the present study described the clinical and genetic characteristics of a young Chinese boy with atypical ARS caused by a novel pathogenic variant in FOXC1, c.516_518delGCG (p.Arg173del), who was successfully diagnosed by molecular genetic testing (WES). This 3-bp deletion caused one Arginine loss, in the forkhead domain, might disrupting the secondary structure of the FOXC1 protein. Generally, children with FOXC1 variants are prone to developing glaucoma and other ocular disorder, which underline the necessity of definite diagnosis by genetic methods along with subsequent early prevention of ocular defects. Regular monitoring concerning potential complications are required in ARS patients. The present results broadened the spectrum of FOXC1 variants in patients with ARS, especially within patients with atypical ARS.