hrp0097fc13.2 | Pituitary, neuroendocrinology and puberty 2 | ESPE2023

Targeted gene panel screening in 144 congenital hypopituitarism patients, incorporating 135 known and novel genes implicated in hypopituitarism and/or hypothalamo-pituitary development.

Gregory Louise , Dattani Mehul

Congenital hypopituitarism (CH) is a highly variable disorder affecting 1:3000 - 1:4000 live births, and is characterized by deficiencies in one or more of the 7 pituitary hormones, with growth hormone (GH) being the most frequently-occurring deficiency. It may be associated with a range of syndromic features including visual impairment, midline brain abnormalities and facial clefting. The development of the pituitary gland is closely associated with that of the forebrain and ...

hrp0095p1-353 | Pituitary, Neuroendocrinology and Puberty | ESPE2022

A novel missense variant in the gene encoding Fatty Acid Synthase (FASN) associated with a unique multi-system disorder including hypopituitarism and hypoparathyroidism

Gregory Louise , Eaton Simon , Krywawych Stephen , Rahman Shamima , Dattani Mehul

Whole exome sequencing performed on a male patient with a unique complex phenotype revealed a novel de novo missense variant in FASN (c.6395C>T, p.A2132V), encoding Fatty Acid Synthase. The patient presented with panhypopituitarism (GH, TSH, LH, FSH and ACTH deficiencies), short stature, sensorineural deafness, hypoparathyroidism, retinal dystrophy, and developmental delay. He was 127 cm tall at the age of 21 and failed to respond to GH treatment [IGF-1 ge...

hrp0092fc11.1 | Pituitary, Neuroendocrinology and Puberty Session 2 | ESPE2019

Phenotypic Characterization of a Large Pediatric Cohort of Patients with Genetic Forms of Congenital Hypopituitarism

Cionna Cecilia , Cerbone Manuela , Gregory Louise C , Dattani Mehul T

Background: Genetic variants are identified in a small proportion (~10%) of patients with Congenital Hypopituitarism (CH), with variable associated phenotypes. We aimed to phenotypically characterise a large cohort of patients with genetically proven CH.Patients and methods: 1684 CH patients were screened (Sanger or whole exome sequencing) over a 20-year period (1998-2018) for mutations in genes regulating pitui...

hrp0084fc11.1 | Neuroendocrinology | ESPE2015

Mutations in BRAF are Associated with Septo-Optic Dysplasia and Cardiofaciocutaneous Syndrome

Besser Rachel , Gregory Louise , Davies Justin , Dattani Mehul

Background: Mutations in BRAF are a rare cause of cardiofaciocutaneous syndrome (CFC). Recently, BRAF mutations have been reported in papillary craniopharyngiomas, but have not been described in patients with other hypothalamo-pituitary abnormalities. We describe three patients with CFC and septo-optic dysplasia (SOD) associated with heterozygous BRAF mutations.Cases: Patients presented in childhood with clinical features of ge...

hrp0095p1-143 | Pituitary, Neuroendocrinology and Puberty | ESPE2022

Use of the 100,000 Genomes Project to identify the molecular basis of rare endocrine disorders within a tertiary paediatric endocrinology centre

M McGlacken-Byrne Sinead , Gregory Louise , Roberts Rowenna , Wakeling Emma , Katugampola Harshini , T Dattani Mehul

Introduction: The UK 100,000 Genomes Project (100KGP) recently investigated the genetic basis of rare disease using whole genome sequencing. The genetic aetiology of most rare paediatric endocrine disease remains unexplained.Methods: Children with genetically unexplained rare endocrine disease attending a subspecialist paediatric endocrinology clinic underwent whole genome sequencing as part of the 100KGP. Parental DNA w...

hrp0089p1-p141 | GH & IGFs P1 | ESPE2018

Autosomal Dominant Growth Hormone Deficiency due to a Novel c.178G>A Mutation in the GH1 Gene Causing Instability of the Mutant GH Protein (p.Ala34Thr)

Miller Bradley , Tan Jimmy , Parween Shaheena , Eble Andree , Ternand Christine , Gregory Louise , Dattani Mehul , Pandey Amit

Background: The most frequent cause of familial growth hormone deficiency (GHD) is Type II autosomal dominant GHD (isolated GHD type II) due to several heterozygous GH1 mutations.Method: Genomic DNA from patients with familial GHD was enriched for the coding exons using hybrid capture technology and GH1 was sequenced using Next Generation Sequencing technology. Plasmids containing genes for WT and A34T GH1 were transfected into NCI HEK2...

hrp0082fc14.3 | Puberty | ESPE2014

Novel Genetic Variants in a Cohort of Paediatric and Adolescent Patients with Hypogonadotrophic Hypogonadism and Kallmann Syndrome

Gregory Louise , McCabe Mark , Bancalari Rodrigo , Tziaferi Vaya , Spoudeas Helen , Dattani Mehul

Background: Hypogonadotrophic hypogonadism (HH) is a complex developmental disorder characterized by a reduction in gonadotrophins (LH, FSH) released from the anterior pituitary. LH and FSH stimulate the ovaries or testes to release sex hormones that cause the onset of puberty, therefore delay in onset or complete absence of puberty is seen in the phenotype, often accompanied by short stature and genital abnormalities. When anosmia accompanies HH in the phenotype it is termed ...

hrp0086fc3.1 | Pituitary | ESPE2016

The MAPK Effector BRAF is Essential for the Integrity of Hypothalamic-Pituitary Development and Deregulation of this Pathway Causes Congenital Hypopituitarism

Gregory Louise , Kypranou Nikolina , Besser Rachel , Vignola Lilliana , Temple Karen , Davis Justin , Gevers Evelien , Dattani Mehul , Gaston-Massuet Carles

Background: BRAF is a component of the RAS/MAPK signalling pathway; germline mutations in components of this pathway are associated with congenital abnormalities such as Cardio-Facio-Cutaneous (CFC), Noonan and Costello Syndromes. These syndromes, known as RASopathies, are characterised by variably penetrant central nervous system, cardiac and facial abnormalities. Importantly, short stature and delayed puberty have been associated with these syndromes, as have featur...

hrp0092fc11.2 | Pituitary, Neuroendocrinology and Puberty Session 2 | ESPE2019

A Novel Minor Spliceosome Defect Associated with Growth Hormone Deficiency (GHD) and Primary Ovarian Insufficiency (POI)

Akin Leyla , Gregory Louise , Buonocore Federica , Group GOSgene , Kurtoglu Selim , Kendirci Mustafa , Burçin Gonen Z. , Lovell-Badge Robin , Rizzoti Karine , Dattani Mehul

Objectives: We describe 5 pedigrees with a novel phenotype including GHD associated with primary ovarian insufficiency (POI) and investigate the underlying molecular basis.Patients and Methods: 6 Turkish patients (5F, 1M) born to 5 consanguineous pedigrees with severe GHD were identified. All females had POI; the male had normal puberty. All had severe postnatal growth retardation (height -4.4 to -8.9 SDS at presentation...

hrp0086fc3.4 | Pituitary | ESPE2016

A Novel Mutation in Eukaryotic Translation Initiation Factor 2 Subunit 3 (EIF2S3) is Associated with X-Linked Hypopituitarism and Glucose Dysregulation

Gregory Louise C. , Williams Hywel , Rahman Sophia , Ferreira Carolina B. , Alatzoglou Kyriaki S. , Kapoor Ritika R. , Hussain Khalid , Gaston-Massuet Carles , Kelberman Daniel , Qasim Waseem , Dattani Mehul T.

Background: A mutation in EIF2S3 (NM_001415; Xp22.11) was previously associated with microcephaly and developmental delay in a single pedigree. EIF2S3 encodes the eukaryotic translation initiation factor 2 subunit 3 (eIF2γ), the largest of three EIF2 subunits. EIF2 initiates protein synthesis by forming a ternary complex with GTP and initiator methionyl-tRNA which then binds to the 40S ribosomal subunit, enabling scanning of mRNA from the 5′ end to...