Hypopituitarism in Patients with Blepharophimosis and FOXL2 Mutations

Sarah Castets (1, 2) , Florence Roucher-Boulez (1, 3) , Alexandru Saveanu (4, 5) , Delphine Mallet-Motak (1) , Olivier Chabre (6) , Patrizia Amati-Bonneau (7) , Dominique Bonneau (7) , Celine Girardin (8) , Yves Morel (1, 3) , Carine Villanueva (1) , Thierry Brue (4, 9) , Rachel Reynaud (4) , Marc Nicolino (1, 3)

1 HCL - Hospices Civils de Lyon
2 APHM - Assistance Publique - Hôpitaux de Marseille
3 UCBL - Université Claude Bernard Lyon 1
4 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
5 Laboratoire de Biochimie et de Biologie Moléculaire [Hôpital de la Conception - APHM]
6 UGA - Université Grenoble Alpes
7 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
8 HUG - Hôpitaux Universitaires de Genève
9 Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM]

Background: FOXL2 is the gene involved in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). There have been few single case reports of growth hormone deficiency (GHD) with this syndrome, and Foxl2 is known to be involved in pituitary development in mice. Our aim was to analyze the prevalence of FOXL2 gene alteration in a series of patients with congenital hypopituitarism and eyelid anomalies. Methods: FOXL2 was analyzed in 10 patients with hypopituitarism (ranging from isolated GHD to complete pituitary hormone deficiency) and eyelid anomalies (typical BPES in 4 patients and milder anomalies in 6 patients). In patients with an FOXL2 mutation, we ruled out other possible molecular explanations by analyzing a panel of 20 genes known to be associated with hypopituitarism, and a candidate gene approach was used for patients without an FOXL2mutation. Results: Three patients had an FOXL2mutation. All 3 had typical BPES. Their pituitary phenotype varied from GHD to complete pituitary hormone deficiency and their pituitary morphology ranged from normal to an interrupted pituitary stalk. No mutations were found in genes previously associated with hypopituitarism. Conclusion: Our study shows that some patients with BPES have hypopituitarism with no molecular explanation other than FOXL2 mutation. This points toward an involvement of FOXL2 in human pituitary development.

Keywords: Blepharophimosis; Hypopituitarism; Growth hormone deficiency; Ocular anomalies; FOXL2

Domains: Life Sciences [q-bio]; Human health and pathology; Life Sciences [q-bio]; Genetics; Human genetics

Sarah Castets, Florence Roucher-Boulez, Alexandru Saveanu, Delphine Mallet-Motak, Olivier Chabre, et al.. Hypopituitarism in Patients with Blepharophimosis and FOXL2 Mutations. Hormone Research in Paediatrics, 2020, 93 (1), pp.30-39. ⟨10.1159/000507249⟩. ⟨hal-03223181⟩