hrp0084p2-480 | Growth | ESPE2015

In Vitro Functional Characterization Of IGFALS Gene Variants Found In ALS Deficient or Idiopathic Short Stature (ISS) Children

Martucci Lucia , Scaglia Paula , Karabatas Liliana , Rey Rodolfo , Domene Horacio , Domene Sabina , Jasper Hector

Background: ALS deficient (ALS-D) patients present severe IGFI and IGFBP3 deficiencies and variable degree of growth retardation. Heterozygous carriers for IGFALS variants, ALS-D relatives or a subset of ISS children, have levels of IGFI, IGFBP3 and ALS intermediate between ALS-D and wildtype (WT) subjects. This supports that IGFALS gene variants may affect ALS synthesis, secretion and/or function and could be responsible for the observed phenotype.<p cla...

hrp0082p1-d1-233 | Thyroid | ESPE2014

TSH Receptor Gene Variants in Pediatric Patients with Non Autoimmune Hyperthyrotropinemia

Scaglia Paula , Keselman Ana , Papendieck Laura Gruneiro , Papendieck Patricia , Bergada Ignacio , Domene Horacio , Chiesa Ana

Context: Heterozygous mutations in TSH recepter (TSHR) have been described associated with mild TSH resistance characterized by non autoimmune hyperthyrotropinemia (NAH). The prevalence of this condition varies in different reports.Objective: To determine the prevalence of TSHR variants in pediatric NAH.Subjects and methods: Thirty-five non obese unrelated children with NAH (18 girls, aged 1–19 years) were enrolled. A...

hrp0082p2-d1-412 | Growth Hormone | ESPE2014

ALS Deficiency due to a Novel and Two Already Described IGFALS Gene Mutations in an Unusual Non Consanguineous Family: Two Compound Heterozygous (Father and Son) and Two Heterozygous Carriers (Brother and Mother)

Scaglia Paula , Keselman Ana , Martucci Lucia , Karabatas Liliana , Ballerini Maria Gabriela , Domene Sabina , Johanna Acosta , Jasper Hector , Domene Horacio

Introduction: Complete ALS deficiency (ALS-D), caused by inactivating mutations in both IGFALS gene alleles, presents severe IGF1 and IGFBP3 deficiencies associated to moderate growth retardation.Aim: To characterize the molecular defect in a family where the index case and his father presented short stature and IGF1 and IGFBP3 deficiencies.Methods: IGF1, IGFBP3, and GH serum levels were determined by CLIA, ALS by ELISA an...

hrp0082p2-d1-410 | Growth Hormone | ESPE2014

GHR Gene Variants within Coding and Intronic Regions in Children with Idiopathic Short Stature

Ballerini Maria Gabriela , Scaglia Paula , Martinez Alicia , Keselman Ana , Braslavsky Debora , Bergada Ignacio , Jasper Hector Guillermo , Ropelato Maria Gabriela , Domene Horacio

Background: Heterozygous GHR gene variants were found in 5–8% of idiopathic short stature (ISS) children. Frequent polymorphisms within GHR coding regions, but not intronic SNPs, have been investigated in ISS.Objectives: To characterize GHR gene variants in ISS children, and to test their influence on height and the peripheral GH/IGF1/IGFBPs system.Methods: GHR gene (coding/intronic flanking...

hrp0084p2-463 | Growth | ESPE2015

Recurrent IGFALS Gene Mutations p.E35Gfs*17 and p.(L409F; A475V): Hot Spot or Founder Effect?

Scaglia Paula , Sala Andrea , Bergada Ignacio , Braslavsky Debora , Keselman Ana , Espinola-Castro Angela , Domene Sabina , Jasper Hector , Corach Daniel , Domene Horacio

Background: Some IGFALS variants have been reported in more than one ALS-deficient family raising the question whether they originated from a single common ancestor allele (founder effect) or alternatively, as independent mutational events (hot spot). Since c.103dupG (p.E35Gfs*17) is located in a stretch of five consecutive guanine residues, where both G-duplication and deletion have been described in several families, we speculate that this region could be a hot spot...

hrp0084p1-93 | Growth | ESPE2015

Severe IGF1 Deficiency and Multi-Organ Autoimmune Disease Associated with Novel Germline STAT3 Mutations

Scaglia Paula , Keselman Ana , Gutierrez Mariana , Domene Sabina , Blanco Miguel , Sanguinetti Nora , Bezrodnik Liliana , Di Giovanni Daniela , Caldirola Maria Soledad , Martucci Lucia , Karabatas Liliana , Kumar Ashish , Jones Nana-Hawa , Hwa Vivian , Revale Santiago , Vazquez Martin , Jasper Hector , Domene Horacio

Background: Primary IGF1 deficiency can result from molecular defects in genes encoding for the GHR, IGF1, STAT5b and ALS. Heterozygous, activating mutations in the STAT3 gene have been recently described in children with severe growth failure associated with a spectrum of early-onset autoimmune disease.Case presentation: We report the molecular diagnosis in two unrelated patients with severe growth failure and IGF1 deficiency: P1, a 3.6 year ol...

hrp0089fc4.1 | GH &amp; IGFs | ESPE2018

Monogenic and Digenic Gene Mutations are Present in Children with Idiopathic Short Stature (ISS)

Sanguineti Nora Maria , Ramirez Laura , Keselman Ana Claudia , Scaglia Paula Alejandra , Ropelato Maria Gabriela , Ballerini Maria Gabriela , Karabatas Liliana , Domene Sabina , Martucci Lucia , Braslavsky Debora , Landi Estefania , Cassinelli Hamilton , Casali Barbara , Rey Graciela Del , Pennisi Patricia , Jasper Hector , Vazquez Martin , Rey Rodolfo , Domene Horacio , Gutierrez Mariana , Bergada Ignacio

Background: Several genetic defects (GHR, SHOX, GHSR, NPR2, IGFALS) have been reported in children classified as ISS. ISS children are GH sufficient and about one third of them show low IGF-I levels, suggesting some degree of GH insensitivity.Objective: To explore potential genetic defects in ISS children suspicious of GH insensitivity, selected by low IGF-I levels and low response to IGF generation test.<...

hrp0089p1-p143 | GH &amp; IGFs P1 | ESPE2018

Severe Pre- and Postnatal Growth Retardation in a Child Harboring a Novel Homozygous IGF1 Gene Mutation

Claudia Keselman Ana , Alejandra Scaglia Paula , Martin Ayelen , Armando Romina , Maria Sanguineti Nora , Gutierrez Mariana , Braslavsky Debora , Gabriela Ballerini Maria , Gabriela Ropelato Maria , Cassinelli Hamilton , Casali Barbara , Del Rey Graciela , Campos Barros Angel , Nevado Blanco Julian , Domene Horacio , Jasper Hector , Arberas Claudia , Rey Rodolfo , Pennisi Patricia , Lapunzina-Badia Pablo , Bergada Ignacio

Background: Human IGF1 gene defects are characterized by intrauterine and postnatal growth retardation, sensorineural deafness, microcephaly and intellectual disability. Seven cases have been reported so far, and the underlying pathophysiology has been characterized in only three.Objective: To describe a patient with severe short stature presenting a novel homozygous IGF1 gene mutation and its underlying pathogenic mechanism.<p clas...

hrp0086p1-p596 | Growth P1 | ESPE2016

Functional in vitro Characterization of Two Novel Germinal STAT3 Mutations Associated with Short Stature, Immunodeficiency and Autoimmune Disease

Gutierrez Mariana , Scaglia Paula , Keselman Ana , Martucci Lucia , Karabatas Liliana , Domene Sabina , Blanco Miguel , Sanguinetti Nora , Bezrodnik Liliana , Di Giovanni Daniela , Caldirola Soledad , Esnaola Azcoiti Maria , Jones Nana-Hawa , Hwa Vivian , Revale Santiago , Vazquez Martin , Jasper Hector , Kumar Ashish , Domene Horacio

Background: We have recently reported the molecular diagnosis of two patients with severe growth failure associated with a spectrum of early-onset autoimmune disease and immunodeficiency. Heterozygous de novo mutations, c.1847_1849delAAG (p.E616del) and c.1276T>C (p.C426R), in the STAT3 gene were found. Functional in vitro studies of these variants are presented.Objective and hypotheses: We...

hrp0084ha2 | A New Syndrome Associated with Mutations in the Gene for Pregnancy-Associated Plasma Protein A2 (PAPP-A2) | ESPE2015

A New Syndrome Associated with Mutations in the Gene for Pregnancy-Associated Plasma Protein A2 (PAPP-A2) Causing Proportionate Short Stature, High Circulating IGF-I, IGFBP-3, and ALS, Mild Microcephaly, thin Long Bones and Decreased Bone Mineral Density in two Unrelated Families

Dauber Andrew , Munoz-Calvo Maria T , Barrios Vicente , Desikan Vardhini , Pozo Jesus , Muzumdar Radhika , Martos-Moreno Gabriel A , Hawkins Federico , Domene Horacio , Jasper Hector G , Kloverpris Soren , Yakar Shoshana , Conover Cheryl A , Kopchick John J , Hwa Vivian , Chowen Julie A , Oxvig Claus , Rosenfeld Ron G , Perez-Jurado Luis A , Argente Jesus

Background: PAPP-A2 is a metalloproteinase that specifically cleaves IGFBPs 3 and 5. Papp-a2 knock-out (KO) mice show a reduction in body size and skeletal abnormalities.Objective and hypotheses: Our objective is to report two affected families from Spain and USA. The Spanish family presents a homozygous frameshift mutation in exon 3 of the PAPP-A2 gene (c.1927_ 1928insAT, p.D643fs25X) resulting in a premature stop codon, with 2 of 4 si...