hrp0092rfc8.2 | Pituitary, Neuroendocrinology and Puberty Session 1 | ESPE2019

Investigation of Imprinting Alterations in MKRN3 and DLK1 in a Cohort of Girls with Central Precocious Puberty Through Specific DNA Methylation Analysis

Canton Ana , Steunou Virginie , Brito Vinicius , Laure Sobrier Marie , Montenegro Luciana , Bessa Danielle , Mendonca Berenice B , Netchine Irène , Latronico Ana Claudia

Background: Loss of imprinting has been implicated in the pathogenesis of several human diseases. Monogenic causes of central precocious puberty (CPP) were identified in families with loss-of-function mutations in two paternally expressed imprinted genes: Makorin zinc finger 3 (MKRN3) and Delta-like 1 homolog (DLK1). The role of imprinting defects in CPP has not been described so far.Objective: To inves...

hrp0086rfc14.1 | Growth : Mechanisms | ESPE2016

Important Contribution of GH, GHRHR and GHSR Mutations in Isolated Growth Hormone Deficiency with a Normal Location of the Posterior Pituitary –Functional Characterization of New Variants

Cohen Enzo , Sobrier Marie-Laure , Dastot Florence , Collot Nathalie , Rose Sophie , Soleyan Aude , Vie-Luton Marie-Pierre , Duquesnoy Philippe , Copin Bruno , Amselem Serge , Legendre Marie

Background: Although growth hormone (GH) and the GH releasing hormone receptor (GHRHR) are known as etiologic factors in non-syndromic isolated growth hormone deficiency (IGHD), very few mutations have been identified in this rare condition (accounting for only 6–12.5% and 0–6.7% of IGHD cases depending on studies). The functional consequences of the identified variants have rarely been assessed.Objective and hypotheses: To assess the contribut...

hrp0084fc11.2 | Neuroendocrinology | ESPE2015

Functional Characterisation of a POU1F1 Mutation Unexpectedly Associated with Isolated Growth Hormone Deficiency (IGHD): A Novel Aetiology of IGHD

Sobrier Marie-Laure , Tsai Yu-Cheng , Perez Christelle , Leheup Bruno , Bouceba Tahar , Duquesnoy Philippe , Sizova Daria , Liebhaber Stephen , Cooke Nancy E , Amselem Serge

Background: In humans, the GHN gene transcription is under the control of a Locus Control Region (LCR) enhancer, HSI, located 14.5 kb 5′ to the hGHN promoter. POU1F1, a pituitary-specific transcription factor, plays an essential role in the specification of the somatotroph, lactotroph and thyrotroph lineages and the activation of GHN, PRL and TSH gene transcription. All POU1F1 mutations so far reported have been linke...

hrp0086fc3.2 | Pituitary | ESPE2016

Spectrum of LHX4 Mutations in a Cohort of 510 Patients with Hypopituitarism

Cohen Enzo , Collot Nathalie , Rose Sophie , Dastot Florence , Duquesnoy Philippe , Copin Bruno , Bertrand Anne-Marie , Brioude Frederic , Hilal Latifa , Leger Juliane , Maghnie Mohamad , Oliver-Petit Isabelle , Polak Michel , Touraine Philippe , Sobrier Marie-Laure , Amselem Serge , Legendre Marie

Background: Mutations in the gene encoding LHX4, a homeodomain-containing factor with two LIM domains, are responsible for dominant hypopituitarisms with incomplete penetrance and variable expressivity. To date, only 14 unambiguous LHX4 mutations have been reported. Among those cases, 12 had an absent or ectopic posterior pituitary (EPP) and/or an abnormal sella turcica.Objective and hypotheses: To i) assess the contribution of LHX4 in combined pituitary...

hrp0089fc9.2 | Pituitary, neuroendocrinology and Puberty 1 | ESPE2018

Contribution of Functionally Assessed GHRHR Mutations to Idiopathic Isolated Growth Hormone Deficiency in a Cohort of 312 Unrelated Patients

Cohen Enzo , Belkacem Sabrina , Fedala Soumeya , Collot Nathalie , Khallouf Eliane , Dastot Florence , Polak Michel , Duquesnoy Philippe , Brioude Frederic , Rose Sophie , Viot Geraldine , Soleyan Aude , Carel Jean-Claude , Sobrier Marie-Laure , Chanson Philippe , Gatelais Frederique , Heinrichs Claudine , Kaffel Noureddine , Coutant Regis , Erdeve Şenay Savaş , Aycan Zehra , Thalassinos Caroline , Lyonnet Stanislas , Şıklar Zeynep , Berberoglu Merih , Brachet Cecile , Amselem Serge , Legendre Marie

Purpose: Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in a very large cohort of patients.Methods: All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with non-syndromic IGHD. Functional consequences of all newly identified missense variants were assessed <e...

hrp0086rfc14.2 | Growth : Mechanisms | ESPE2016

Contribution of GHR and IGFALS Mutations to Growth Hormone Resistance – Identification of New Variants and Impact on the Inheritance Pattern

Legendre Marie , Dastot Florence , Collot Nathalie , Duquesnoy Philippe , Cohen Enzo , Sobrier Marie-Laure , Adiceam Paola , Anderson Donald , Baron Sabine , Cabrol Sylvie , Callewaert Bert , Cartigny Maryse , Craen Margarita , Crock Patricia , Ladjouze Asmahane , Lazea Cecilia , Polak Michel , Savendahl Lars , Touzani Asmae , Amselem Serge

Background: Bi-allelic GHR mutations are classically responsible for Laron syndrome, a severe growth hormone (GH) resistance syndrome. A few GHR missense mutations have also been implicated in mild GH resistance or idiopathic short stature. IGFALS mutations are responsible for recessive or semi-dominant short stature with normal GH provocative test contrasting with extremely low IGF-I levels.Objective and hypotheses: To assess the contribution of GHR and...

hrp0082p1-d3-46 | Bone (1) | ESPE2014

Loss of Function CYP24A1 Mutations in Patients with Hypercalcemia and Low Pth level: an Autosomal Dominant or Recessive Trait?

Molin Arnaud , Baudouin Roseline , Coudray Nadia , Figueres Marie-Lucille , Jones Glennville , Kottler Marie-Laure

Background: Homozygous or compound heterozygous mutations of gene CYP24A1 have recently been reported to cause idiopathic infantile hypercalcemia due to increased intestinal absorption of calcium. However, an autosomal dominant transmission with partial penetrance of the trait was also suggested.Objective and hypotheses: Evaluation of the frequency of CYP24A1 mutation and evaluation of the impact of heterozygous mutation on calcium meta...

hrp0084p2-397 | GH &amp; IGF | ESPE2015

Silver Russell syndrome: A Cause of Partial IGF1 Resistance?

Dufourg Marie-Noelle , Perin Laurence , Houang Muriel , Daubard Marie-Laure , Brioude Frederic , Bouc Yves Le , Netchine Irene

Background: Silver-Russell syndrome (SRS) is characterized by intrauterine and postnatal growth retardation, relative macrocephaly at birth, prominent forehead, severe feeding difficulties and body asymmetry. In around 50%, it is secondary to hypomethylation at the IGF2/H19 imprinted locus on 11p15 (11p15 LOM), and in 10% to a maternal disomy of chromosome 7 (mUPD7). Mechanisms of postnatal growth failure in SRS are not well understood.Objective and hypo...

hrp0086rfc2.7 | Bone &amp; Mineral Metabolism | ESPE2016

Effect of Paternal Loss-of-Function Mutations of GNAS on Growth During the Childhood: A Role for XL

Tran Lea Chantal , Brehin Anne-Claire , Richard Nicolas , Kottler Marie-Laure

Background: Heterozygous GNAS inactivating mutations cause pseudohypoparathyroidism type Ia (PHP-Ia) when maternally inherited and pseudopseudohypoparathyroidism (PPHP)/progressive osseous heteroplasia when paternally inherited. Mutations on the paternal, but not the maternal, GNAS allele are associated with intrauterine growth retardation (IUGR). Moreover, birth weights were lower with paternal GNAS mutations affecting exons 2–13 (including XL and Gαs) than with exo...

hrp0086rfc10.1 | Perinatal Endocrinology | ESPE2016

Paternal Loss-of-Function Mutations of GNAS and Growth Retardation in a Mice Model: A Specific Placental Transcriptomic Signature?

Tran Lea Chantal , Ballandone Celine , Vaiman Daniel , Barbaux Sandrine , Richard Nicolas , Kottler Marie-Laure

Background: GNAS gene is a complex imprinted locus, resulting in the expression of at least four transcripts (XL, NESP55, A/B and Gsα) characterized by their specific exon 1 and common exons 2-13. While Gαs is biallelically expressed in most tissues, XL is only expressed from the paternal allele. Maternally inherited, loss-of-function mutations affecting those GNAS exons that ...