ESPE Abstracts

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...

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...

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...

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...

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...

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 ...

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...

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...

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...

Background: Congenital hypopituitarism (CH), involving deficiencies in one or more anterior pituitary hormones, is rarely observed in combination with severe joint contractures, termed arthrogryposis. Schaaf-Yang syndrome (SHFYNG), which has phenotypic overlap with Prader-Willi syndrome, may be associated with arthrogryposis. L1 syndrome, a group of X-linked disorders including hydrocephalus and spasticity of the lower limbs, may also present with generalized contractures in r...