Endocrine Abstracts

Introduction: Congenital central hypothyroidism occurs either as isolated TSH deficiency or in conjunction with other pituitary hormone deficits. Undetected central hypothyroidism is associated with developmental delay in children and adverse cardiometabolic sequelae in adults. Hitherto, mutations in the TRH receptor (TRHR) or TSHβ subunit (TSHB) genes are the only known causes of isolated TSH deficiency.Methods: Using whole exome and candidate gene...

Background: It is well established that subclinical hypothyroidism (SCH) is associated with mild ventricular dysfunction and early cardiovascular disease (CVD), but it is unknown if there is an underlying defect in cardiac bio-energetic function.Objective: To quantify the cardiac phosphocreatine/ATP (PCr/ATP) ratio in SCH, compare with healthy controls (HC) and to measure the effect of 6 months of thyroxine treatment.Method: Cardia...

Whilst the majority of differentiated thyroid cancers (DTC) have oncogenic mutations, a significant minority may be driven by the overexpression of proto-oncogenes. PTTG and PBF are proto-oncogenes which are induced in DTC, elicit tumours in xenograft models and interact in vitro, where PBF shuttles PTTG into the nucleus. However, the relative contributions of each gene to DTC has not been delineated. Here, we constructed a bi-transgenic murine model over-expressing b...

Mice with dominant-negative mutations of thyroid hormone receptor α1 (TRα1) are euthyroid but display growth retardation and delayed bone age as juveniles and increased bone mass during adulthood, indicating impaired skeletal thyroid hormone responsiveness. The first autosomal dominant mutations affecting TRα1 in humans were recently described in two unrelated children and one parent who were euthyroid apart from a low T4:T3 ratio. Consiste...

Familial glucocorticoid deficiency (FGD, OMIM#202200) is a rare autosomal recessive disorder characterised by adrenal resistance to the action of ACTH, with isolated glucocorticoid deficiency. Recently, mutations in NNT, encoding the mitochondrial anti-oxidant nicotinamide nucleotide transhydrogenase have been reported to cause FGD.Our index case, from a highly consanguineous Kashmiri family, was diagnosed with adrenal insufficiency during a sep...

Cushing’s syndrome, which is characterised by excessive circulating glucocorticoid (GC) concentrations, may be due to ACTH-dependent or -independent causes that include anterior pituitary and adrenal cortical tumours, respectively. In the course of our phenotype-driven screens of mouse mutants induced by the chemical mutagen N-ethyl-N-nitrosourea (ENU), we observed a mutant mouse with obesity, hyperglycaemia and low bone mineral density, features that ar...

Glucocorticoid (GC) excess inhibits wound healing (WH) causing increased patient discomfort and infection risk. The GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates local GC availability in tissues including liver, adipose, and muscle. 11β-HSD1 is also expressed in skin, where studies recently demonstrated increased levels in older donors and a reversal of age-induced dermal atrophy in 11β-HSD1-null mice. However, the role o...

Glucocorticoids (GCs) have an important role in inflammation, apoptosis and immunosuppression and are among the most widely prescribed medications in clinical practice. GCs exert their effect by binding to the transcription factor, glucocorticoid receptor (GR). GCs are used in the treatment of acute lymphoblastic leukaemia (ALL) as they induce apoptosis in lymphoid cells, however resistance and side effects still occur frequently. Computational modeling has enormous potential ...