Ocular defects are important semiological clues for the internist, leading sometimes to diagnose a familial disease. Branchio-oculo-facial syndrome is a rare congenital disorder characterized by ophtalmic malformations, branchial skin defects and craniofacial anomalies. Ocular features include coloboma of choroid and/or iris, microphtalmia, cataract, ptosis and strabismus. We herein describe a new three-generation family with BOFS.
The proband (A) was the 67 years-old grandfather. He presented with a left eye coloboma and microcornea. His only 39 years-old son (B) was diagnosed as a baby with a left coloboma and microphtalmia, right pre axial polydactilia. As an adult, B had a craniopharyngioma treated with surgery and radiotherapy. The 6 years-old grand daughter (C) had a left coloboma and microphtalmia and a right kidney hydrophrosis. The sister D of the proband presented a branchial fistula and a melanoma and his son (E) had a prolactinoma. Because of this intriguing phenotype, an inherited anomaly closest to BOFS was suspected in this non consanguineous family.
In 2011, BMP4 gene study was unremarkable. In 2018 none PAX2 (coloboma-kidney sundrome) nor PAX6 gene mutation were found, among a panel of different 35 genes. Then, a panel of ocular developmental genetic anomalies was done in this family. Finally, a large MAC-ASD genetic panel found only in A, B and C patients an heterozygous frameshift variant in exon 2/7 of the TFAP2 gene: c.38-56 dup, p.(Ala20ArgfsTer149). This is a likely pathogenic variant (type IV), causing a mutation stop codon in exon 2 in transcription factor AP2-alpha gene (TFAP2A).
TFAP2A mutations have been related with BOFS, ectopic thymus and anophthalmia-microphthalmia syndrome. Reported BOFS associated malformation are diverse and heterogeneous, like in most dominant diseases.
We report a novel TFAP2A mutation in a three-generational BOFS affected family. TFAP2A is a retinoic acid response gene to direct ocular morphogenesis. It is localized on the minus strand of chromosome 6. In addition, two antisense non-coding RNA molecules have been identified. TFAP2A also regulates gene expression during embryogenesis of the eye, ear, face, body wall, limbs, kidney and neural tube in humans as well as in Tfap2 knockout mice embryos.
A, B and C presented with coloboma whereas B had also right pre axial polydactilia. We thought to also study B and D for a TFAP2A mutation, because there is a down-regulation of AP-2α in some tumors (like hepatic carcinoma), with has an impact on Wnt/β-catenin pathway (like in craniopharyngiomas), and there is abolition of TFAP2A expression in melanoma. Intriguingly, D did not have the familial TFAP2 mutation although she had a melanoma and branchial fistula. Moreover, the presence of two unrelated pituitary tumors in B and E remain unexplained. TFAP2A mosaicism could not been excluded.