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Une anomalie d'Axenfeld-Rieger familiale révélée par un glaucome congénital

The aim of this poster is to describe a familial case of Axenfeld-Rieger anomaly and responsible mutations in FOXC1 (forkhead box C1) gene that has never been described before. This case underlines the importance of systematic clinical examination of family members in case of disease of presumed genetic etiology. 

Six hours old male neonate was examined by an ophthalmologist because opacified corneas since birth. Congenital glaucoma was diagnosed and a topical as well as systemic treatment was prescribed. Trabeculotomy was carried out at nine days of age. The postoperative course of glaucoma management was satisfactory with intraocular pressure (IOP) under control after one intervention in both eyes. Genetic testing with next-generation sequencing panel with Tru-Sight One Illumina Platform was carried out to find mutations in genes that are responsible for congenital glaucoma. Two variants in FOXC1 were found that have never been described before. The first variant was a heterozygous missense mutation in the FOXC1 gene (NM_001453.2 (FOXC1): c.232A>G, p.(Lys78Glu)). This change has not previously been described as disease-related (ClinVar and HGMD databases), but has also not been reported in general population databases. The pathogenicity assessment programs (CADD, PolyPhen2, SIFT, AlignGVGD) unequivocally consider the change to be detrimental to gene function. In addition, another heterozygous change was found in the FOXC1 gene (NM_001453.2 (FOXC1): c.1001C>T, p.(Ala334Val), also never described).

Family segregation was foreseen to study the origin of the two variants in FOXC1 gene. The clinical examination of patient’s father and older brother showed milder form anterior segment dysgenesis. Because of posterior embryotoxon seen in the patient’s brother he also was tested. Genetic testing revealed the same mutation in the father and brother but not in the mother. 

The FOXC1 gene located at 6q25 encodes a protein belonging to the family of transcription factors and plays an important role in the expression of other genes. The clinical picture associated with FOXC1 gene alterations is variable and the disorder is also called the Axenfeld-Rieger spectrum. The clinical picture can be very diverse from isolated anterior segment dysgenesis to syndromic form. The most important forms in Axenfeld-Rieger spectrum are Peters anomaly, Axenfeld anomaly, Axenfeld-Rieger anomaly and Axenfeld-Rieger syndrome. The latter may be related to various organ system abnormalities (dental, facial, peritoneal, urogenital, brain, auditory and cardiovascular anomalies) (1, 2).

This case illustrates well the importance of clinical examination of the family members in a disease of presumed genetic origin. It is also important to do genetic testing to offer a proper diagnosis as well as prognosis for the patient and the family. It can also reveal need for other examinations and more systemic follow-up than for glaucoma only.

A long-term ophthalmic monitoring of the patients is indicated as there is a >50% lifetime risk of congenital glaucoma. Surveillane of hearing, dental development and growth has to be conducted. Growth retardation requires brain imaging (MRI) to screen for pituitary hypoplasia and other brain abnormalities and a consultation with a paediatric endocrinologist may be necessary. These patients should aslo be systematically examined for congenital cardiac abnormalities.