hrp0092t7 | Top 20 Poster | ESPE2019

Establishing of a Novel NGS Tool for the Diagnosis of X-linked Hypophosphatemia (XLH)

Thiele Susanne , Stubbe Anita , Werner Ralf , Hiort Olaf , Hoeppner Wolfgang

X-linked hypophosphatemia (XLH) is the most common genetic disorder of phosphate homeostasis. It is caused by inactivating mutations in the PHEX gene, which encodes a phosphate regulating endopeptidase predominantly expressed in osteoblasts, osteocytes, and odontoblasts.In children there is a broad phenotypic spectrum of XLH ranging from isolated hypophosphatemia without clinical signs up to severe symptoms, such as rickets, extreme lower limb d...

hrp0089lb-p7 | Late Breaking P1 | ESPE2018

Mutational Analysis of SRD5A2 and AR Genes in Indian Children with 46 XY Disorders of Sex Development

Kumar Anil , Faruq Mohd , Werner Ralf , Sharma Rajni , Jain Vandana

Aim: To study the mutation spectrum in SRD5A2 and AR genes among Indian children with 46 XY disorders of sex development (DSD).Methods: This work is part of an ongoing study at Department of Pediatrics, AIIMS, Delhi, approved by the ethics committee of the Institute. Children with 46 XY DSD in whom endocrine investigations were suggestive of either 5α reductase deficiency or androgen insensitivity syndrome were enrolled for mutatio...

hrp0089p1-p218 | Sex Differentiation, Gonads and Gynaecology or Sex Endocrinology P1 | ESPE2018

Primary Gonadal Dysgenesis in Male 46,XY Patients with NR5A1 Variants Predominantly Affects Sertoli Cell Function

Hoppmann Julia , Werner Ralf , Lunstedt Ralf , Birnbaum Wiebke , Schwab Otfried , Marshall Louise , Wunsch Lutz , Hiort Olaf

Background: Steroidogenic factor 1 (encoded by the NR5A1 gene) is a transcriptional regulator of genes involved in gonadal development and steroidogenesis. Mutations in NR5A1 are associated with a wide phenotypic spectrum in 46,XY individuals ranging from partial/complete gonadal dysgenesis or anorchia, ambiguous genitalia, hypospadias, to infertility. However, little is known about the longitudinal course of endocrine markers for Sertoli and Leydig cell func...

hrp0092rfc10.4 | Sex Differentiation, Gonads and Gynaecology or Sex Endocrinology | ESPE2019

qPCR Screening for Xp21.2 Copy Number Variations in Patients with Elusive Aetiology of 46,XY DSD

Meinel Jakob , Dwivedi Gaurav , Holterhus Paul-Martin , Hiort Olaf , Werner Ralf

Duplications of the dosage sensitive sex locus Xp21.2 have been associated with 46,XY gonadal dysgenesis (GD) for nearly 25 years. In the past, duplications have always included the NR0B1 (nuclear receptor subfamily 0 group B, member 1, also known as DAX1) gene, a known antagonist of SF1 (Steroidogenic Factor 1) dependent SOX9 (SRY Box 9) activation and the GD was attributed to its "double gene dose". However, recent findings have questioned the neces...

hrp0086p1-p365 | Gonads & DSD P1 | ESPE2016

Functional Studies of a New Mutation in the LH/CG Receptor Gene Identified in 2 Sisters with 46,XY DSD

Flieger Susanne , Neuhaus Nina , Strom Tim , Henrichs Ivo , Johren Olaf , Gromoll Jorg , Hiort Olaf , Werner Ralf

Background: Disorders (or differences) of sex development (DSD) are rare congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. The luteinizing hormone/chorionic gonadotropin receptor (LHCGR) is important for male sex development. LHCGR mutations can cause Leydig cell hypoplasia, which is an autosomal recessive disorder.Objective and hypotheses: We found two heterozygous mutations in the LHCGR, a n...

hrp0089p1-p217 | Sex Differentiation, Gonads and Gynaecology or Sex Endocrinology P1 | ESPE2018

Reduced Androgen Receptor Expression in Patients with 45,X/46,XY Mosaicism

Hornig Nadine , Demiri Jeta , Murga Eva , Caliebe Almuth , Schweikert Hans-Udo , Audi Laura , Werner Ralf , Hiort Olaf , Holterhus Paul-Martin

Background: Individuals born with a 45,X/46,XY karyotype can present with diverging phenotypes from normal male, Turner-like to ambiguous genitalia, the latter classically being called mixed gonadal dysgenesis. No correlation between phenotype and degree of mosaicisms in the karyotype could be ascertained so far, making clinical management of these patients difficult.Objective: To understand, if androgen action through the androgen receptor (AR) is compr...

hrp0086p1-p355 | Gonads & DSD P1 | ESPE2016

Mutations at the SF-1 Ligand-Binding Domain Can Lead to Different Effects on DNA Binding: Report of Two Novel Mutations

Fabbri Helena Campos , Werner Ralf , Guerra-Junior Gil , Maciel-Guerra Andrea Trevas , Andrade Juliana Gabriel Ribeiro de , Hiort Olaf , Mello Maricilda Palandi de

Background: Steroidogenic factor-1 (SF-1), denominated as nuclear receptor subfamily five group A member 1 (NR5A1), is an orphan receptor that regulates several steps of adrenal and gonadal development. Mutations in its gene are responsible for different phenotypes of disorders of sex development (DSD).Objective and hypotheses: To study the functional impact of two novel NR5A1 mutations, the p.C247* and p.K396Rfs*34, both identified within the l...

hrp0082lbp-d3-1001 | (1) | ESPE2014

Histological Evaluation of Patients with Partial Gonadal Dysgenesis and NR5A1 Mutations: Review in Leydig and Germ Cell Pattern

de Andrade Juliana Gabriel Ribeiro , Werner Ralf , Fabbri Helena Campos , Guerra-Junior Gil , Maciel-Guerra Andrea Trevas , de Mello Maricilda Palandi , Holl-Ulrich Konstanze , Hiort Olaf

Background: Recent data describe that the gonads of patients with partial gonadal dysgenesis (PGD) and mutation in the NR5A1 gene can present with a different histological pattern.Objective and hypotheses: To evaluate histological aspects of PGD caused by NR5A1 mutations.Method: Five patients with PGD, a history of gonadal biopsy or gonadectomy and confirmed mutation on NR5A1 gene were selected from a Bra...

hrp0082fc6.2 | Gonads & DSD | ESPE2014

Next Generation Sequencing of the Androgen Receptor Gene in Patients With Androgen Insensitivity Syndrome and Controls

Hornig Nadine , Schweikert Hans-Udo , Ukat Martin , Kulle Alexandra , Welzel Maik , Wehner Gaby , Werner Ralf , Hiort Olaf , Drop Stenvert , Cools Martine , de Beaufort Carine , Siebert Reiner , Ammerpohl Ole , Holterhus Paul-Martin

Background: In a large fraction of patients with clinically presumed Androgen Insensitivity Syndrome, no mutation of the Androgen Receptor gene can be detected. However, established Sanger sequencing techniques of the AR gene are often limited to the coding region.Objective and Hypotheses: To set up a next generation sequencing (NGS) approach of the entire AR locus (including UTRs, exons, introns, up- and downstream regions) for a comprehensive ...

hrp0089p1-p216 | Sex Differentiation, Gonads and Gynaecology or Sex Endocrinology P1 | ESPE2018

SDgeneMatch, A New Tool to Aid the Identification of the Genetic Causes of DSD

De Ridder Jeroen , Bashamboo Anu , Baere Elfride De , Krone Nils , Mitchell Rod , Meyts Ewa Rajpert-De , Tobias Ed , Looijenga Leendert , Achermann John , Werner Ralf , Ahmed Faisal , Hiort Olaf , Greenfiled Andy , McElreavey Ken

Currently, the majority of patients with DSD do not have a molecular diagnosis. Although high throughput sequencing is having an impact on the clinical diagnosis of DSD the accurate interpretation genomic datasets of the identification of new gene mutations causing DSD is challenging. This is due to emerging evidence that DSD may be caused by mutations in many different genes and the prevalence of mutations in a single gene may be very low. As larger number of DSD patients are...