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      Hypopituitarism in Patients with Blepharophimosis and FOXL2 Mutations

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          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.

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          Most cited references 29

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          The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.

          In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.
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            Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse.

            During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch. Neonates exhibit abnormalities in the corpus callosum, the anterior and hippocampal commissures, and the septum pellucidum. A comparable and equally variable phenotype in humans is septo-optic dysplasia (SOD). We have cloned human HESX1 and screened for mutations in affected individuals. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain which destroyed its ability to bind target DNA. These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human.
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              Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development.

              FOXL2 mutations cause gonadal dysgenesis or premature ovarian failure (POF) in women, as well as eyelid/forehead dysmorphology in both sexes (the 'blepharophimosis-ptosis-epicanthus inversus syndrome', BPES). Here we report that mice lacking Foxl2 recapitulate relevant features of human BPES: males and females are small and show distinctive craniofacial morphology with upper eyelids absent. Furthermore, in mice as in humans, sterility is confined to females. Features of Foxl2 null animals point toward a new mechanism of POF, with all major somatic cell lineages failing to develop around growing oocytes from the time of primordial follicle formation. Foxl2 disruption thus provides a model for histogenesis and reproductive competence of the ovary.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                July 2020
                26 May 2020
                : 93
                : 1
                : 30-39
                aHospices Civils de Lyon, Hôpital Femme Mère Enfant, Service d’Endocrinologie Pédiatrique, Bron, France
                bAix-Marseille Université, AP-HM, Centre de Référence des Maladies Rares D’origine Hypophysaire HYPO, Marseille, France
                cHospices Civils de Lyon, Groupement Hospitalier Est, Laboratoire de Biochimie et Biologie Moléculaire Grand Est, UM Pathologies Endocriniennes Rénales Musculaires et Mucoviscidose, Bron, France
                dCentre de Référence du Développement Génital: du Fœtus à l’Adulte, Filière Maladies Rares Endocriniennes, Bron, France
                eUniv Lyon, Université Claude Bernard Lyon 1, Lyon, France
                fAix Marseille Université, INSERM, MMG, U 1251, Marseille, France
                gCHU de Grenoble Alpes et Université Grenoble Alpes, CS 10217 38043, Service d’Endocrinologie, Grenoble, France
                hMitoLab Team, UMR CNRS 6015 – INSERM U1083, Institut MitoVasc, Université et Hôpital d’Angers, Angers, France
                iDépartement de Biochimie et Génétique, Université et Hôpital d’Angers, Angers, France
                jHôpitaux Universitaires de Genève, Endocrinologie Pédiatrique, Genève, Switzerland
                Author notes
                *Sarah Castets, Service de Pédiatrie Multidisciplinaire, Hôpital La Timone Enfants, 264 Rue Saint Pierre, FR–13385 Marseille (France), sarah.castets@ap-hm.fr
                507249 Horm Res Paediatr 2020;93:30–39
                © 2020 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 2, Pages: 10
                Research Article


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