Endocrine Abstracts

ACTH insensitivity or familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder first described in 1959. We demonstrated in 1993 that about 25% of affected patients have nonsense or (more commonly) missense mutations in the ACTH receptor (melanocoprtin 2 receptor, MC2R). Functional analysis of these mutations had been especially difficult until our discovery in 2005 that the receptor requires an essential accessory factor – the melanocortin 2 recepto...

Background: Familial glucocorticoid deficiency (FGD) is characterised by isolated glucocorticoid deficiency, with preserved mineralocorticoid production. FGD type 2 is caused by mutations in MRAP encoding the melanocortin-2 receptor accessory protein. MRAP has a single transmembrane domain essential to its function in trafficking the MC2R/ACTH receptor. 15 mutations in MRAP have been described, five of which are within the canonical donor splice-site of intro...

Background: We recently reported the first human mutation in mini-chromosome maintenance homologue 4 (MCM4) in a cohort of patients with adrenal failure. We now report the endocrine phenotype of 14 patients with MCM4 mutations.Methods: Patients case notes were examined and investigations performed to fully assess adrenal function, pubertal development, gonadal function and growth.Results: 13 of 14 patients have developed isolated g...

GHI is a genetic condition in which patients present with growth failure due to primary IGF1 deficiency caused by a defect in the GH-IGF1 axis. In the last 10 years in the Centre for Endocrinology of WHRI at Barts and the London, 24 causative mutations in genes of the GH–IGF1 axis have been determined in 58 patients (Table 1). STAT5B mutations were responsible in 2 cases, IGFALS in 4 but the majority of defects identified were in GHR. Most mutations identifi...

Background: FGD is an autosomal recessive disorder causing glucocorticoid deficiency. Mutations in the ACTH receptor (MC2R) or the MC2R accessory protein (MRAP) cause FGD types 1 & 2 respectively. All the reported MRAP mutations result in abolition of a functional protein. This is reflected clinically as type 2 patients present early, no patient described to date has presented later than 1.6yrs. In contrast FGD type 1 mutations are usually missense and patients have a medi...

Triple A syndrome (AAAS), a rare and debilitating autosomal recessive disorder. It is characterised by adrenal failure, alacrima and achalasia; ~70% patients develop a neurodegeneration. The AAAS gene encodes ALADIN, a nuclear pore complex (NPC) protein necessary for the selective nuclear import of DNA protective molecules and is important for cellular redox homeostasis. ALADIN’s role is not fully characterised: its discovery at the centrosome and the endoplasmic...

Background: SGPL1 carries out the final degradative step of the sphingolipid pathway, irreversible cleavage of sphingosine-1-phopshate. SGPL1 deficiency is associated with a pathological accumulation of sphingolipid species and a multi-systemic condition incorporating primary adrenal insufficiency (PAI). Sphingolipid intermediates, ceramide and sphingosine are postulated to act as modulators of the steroidogenic pathway, acting as second messengers altering downstream expressi...

Background: Primary adrenal insufficiency (PAI) is a rare, genetically heterogenous condition, characterised by hypocortisolaemia and high plasma ACTH levels in the presence or absence of mineralocorticoid deficiency. PAI can be life-threatening if unrecognised, misdiagnosed or under/untreated. Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive form of PAI characterised by isolated glucocorticoid insufficiency. Mutations in the MC2R/ACTH receptor, ...

Context: Nicotinamide nucleotide transhydrogenase (NNT) is a NADPH-generating mitochondrial proton pump with a central role in mitochondrial antioxidant pathways. Recent studies revealed inactivating NNT mutations in patients with familial glucocorticoid deficiency, indicating a selective susceptibility of the adrenal cortex to NNT deficiency and oxidative stress. Here we explored the potential value of NNT as a therapeutic target in adrenocortical cancer.<p class="abstext...

Background: GH resistance or primary IGF1 deficiency (PIGFD) presents with growth failure, low serum IGF1 and normal/elevated serum GH. PIGFD comprises a spectrum of phenotypic and biochemical abnormalities for which genetic GH–IGF1 axis defects may be causative.Objective: Genotyping of PIGFD patients referred for sequencing of candidate genes.Methods: From 2008 to 2013, 62 patients (42 males and 20 females), median age 6.9 ye...