Endocrine Abstracts

Introduction: Kallmann syndrome (KS) is a developmental disorder characterised by hypogonadotropic hypogonadism and anosmia. Known genetic causes account for up to 30% of patients with KS, with FGFR1 mutations being identified in 10%. FGFR1-related KS has an autosomal dominant inheritance with incomplete penetrance. We present a family with KS due to a novel variably penetrant FGFR1 mutation, where the presenting features included cleft lip/palate and anosmia...

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: Multiple pituitary hormone deficiency (MPHD) and septo-optic dysplasia (SOD) are well known causes of hypopituitarism, but children with optic nerve hypoplasia (ONH) may also be at risk of hormone and neurocognitive disturbances. Clinical and neuroradiological findings of these three related conditions are characterised in this study, aiming to understand their pathophysiology.Design: Data from 140 patients with hypopituitarism (MPHD, SOD) ...

Introduction: Release of GH by the somatotroph cells of the anterior pituitary is stimulated by GHRH. GHRH acts via its transmembrane receptor, GHRHR, a G-protein coupled receptor that stimulates protein kinase A. Recessive mutations in GHRHR are associated with severe isolated GH deficiency (IGHD) with a final height in untreated patients between 130±10 cm (−7.2±1.6 SDS) and 114±0.7 cm (−8.3±0.1 SDS) in males and females respectively.</p...

Introduction: The Gli-family of zinc-finger transcription factors regulates the Sonic Hedgehog (Shh) signalling pathway, critical for normal CNS development. Gli2 is essential for early pituitary and ventral forebrain development in mice, with mutations described in humans with holoprosencephaly (HPE), isolated hypopituitarism (HP) and cranial/midline facial defects. SHH mutations have been associated with phenotypes including HPE but not HP, despite murine studi...

Introduction: The UK 100,000 Genomes Project (100KGP) investigated the genetic basis of rare disease. The molecular drivers of most paediatric pituitary disease remains unknown.Methods: Children with genetically unexplained pituitary disorders attending a tertiary paediatric endocrinology centre were recruited to the 100KGP and underwent whole genome sequencing. Parental DNA was obtained where feasible. Virtual gene panels were applied and bioinformatic ...

Background: LHX4 encodes a member of the LIM-homeodomain transcription factor protein family that is required for development of the pituitary gland. To date, only incompletely penetrant heterozygous mutations in LHX4 have been described in patients with variable combined pituitary hormone deficiencies (CPHD).Objective/hypothesis: To investigate a cohort of patients with congenital hypopituitarism for mutations in LHX4.<p c...

Introduction: Hypogonadotrophic hypogonadism (HH) is a genetically heterogeneous disorder. A number of genes have been implicated in its pathogenesis but, to date, in most cases, the cause remains genetically unknown.Case: A 14-year old male with delayed puberty (G1P2A3, testes two males) and family history of HH was diagnosed with HH following anterior pituitary assessment and an overnight gonadotrophin profile. His baseline gonadotrophins were low (LH,...

Introduction: KAL1 is essential for GnRH neuronal migration and olfactory bulb development, and mutations within this gene have been implicated in 5% of Kallmann syndrome (KS) cases, a disorder characterized by the association of hypogonadotrophic hypogonadism with anosmia. It is the only identified X-linked form of the disorder and as a result only KS males had been screened for mutations until recently, when females exhibiting KS phenotypes were screened and subsequen...

Somatic activating mutations in BRAF, encoding B-Raf, have been described in tumours and recently craniopharyngiomas. Germline mutations in BRAF and other components of the RAS/MAPK pathway are found in RASopathies, whose features include endocrine deficiencies but not craniopharyngiomas. We report three BRAF mutations (two of which are novel) in four children with congenital hypopituitarism. To demonstrate the functional role of the three variants w...