Endocrine Abstracts

Introduction: GH neurosecretory dysfunction (NSD) refers to children with abnormal auxology, normal GH responses to provocative testing, but with impaired spontaneous GH secretion over 24 h, leading to low IGF1 concentrations. It is thought to be due to abnormal hypothalamic function with aberrant GHRH and somatostatin secretion leading to impaired GH secretion and subsequently suboptimal growth.Methods: We reviewed children admitted for spontaneous GH s...

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...

Introduction: 11-beta-dehydroxysteroid dehydrogenase-1 (11BHSD1) is a bidirectional enzyme which converts inactive cortisone and 11-dehydrocorticosterone to active cortisol and corticosterone and vice-versa. The direction is dependent on NADPH availability and the action of the cofactor enzyme hexose-6-phosphate dehydrogenase (H6PDH). Cortisone reductase deficiency is a rare disorder caused by defects in 11BHSD1 or H6PDH, leading to inability to regenerate act...

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...

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by resistance to the action of ACTH leading to glucocorticoid deficiency with preserved mineralocorticoid and gonadal function. In 1993 we identified mutations in the ACTH receptor (melanocortin 2 receptor; MC2R), although these only explained around 25% of cases. More recently a traditional homozygosity mapping approach identified mutations in a novel gene which we named melan...

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...

Introduction: Non-classical congenital adrenal hyperplasia (NCCAH) is a common autosomal recessive disorder characterized by androgen excess. It classically presents in later life with symptoms of acne, hirsutism, and premature adrenarche. This case illustrates a rare case presentation of NCCAH in early infancy.Clinical case: An 18 day old term male infant was brought to the A&E for 9% weight loss. On review he was mottled, but otherwise examination ...

Introduction: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterised by ACTH resistance and isolated glucocorticoid deficiency. Mutations of ACTH receptor, known as melanocortin-2 receptor (MC2R), and melanocortin-2 receptor accessory protein (MRAP) account for approximately 25 and 15 to 20% of cases respectively. To date there is no strong evidence that heterozygous carriers have abnormal cortisol secretion.Case: We...

Introduction: In recent years a growing number of gene mutations have been identified which cause a myriad of syndromes having adrenal insufficiency as a core characteristic. The evolution of each syndrome is dependent on the variant and the particular gene affected. Common practice is for candidate genes to be sequenced individually, which can be time consuming and is complicated by overlapping clinical phenotypes. The increasing availability and cost effectiveness of whole e...

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...