Endocrine Abstracts

Puberty is a fascinating transition period in the mammalian lifespan, but the biological control of pubertal timing remains poorly understood. Developmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network have been shown to be responsible for disorders of pubertal timing, in a spectrum of conditions ranging from idiopathic hypogonadotropic hypogonadism (IHH) to self-limited delayed puberty. We hypothesized that important regulators of pubertal timin...

Objectives: Abnormal pubertal timing affects >4% of adolescents and is associated with adverse health outcomes. Up to 80% of variation in the timing of pubertal onset is genetically determined. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern, but in the majority the neuroendocrine pathophysiology and genetic regulation remain unclear. Mis-regulation of the embryonic migration of GnRH neurons has been implicated in the pathogenesis of DP (Howar...

Familial glucocorticoid deficiency is an autosomal recessive disorder characterised by resistance to ACTH of the adrenal cortex, leading to isolated glucocorticoid deficiency and life-threatening hypoglycaemia. Half of all cases are caused by mutations in MC2R, MRAP, MCM4 or STAR. Recent work in our group has identified defects in nicotinamide nucleotide transhydrogenase (NNT) to be causal in a further 10% of cases. NNT generates the high con...

The adrenogonadal primordium develops from a thickening of the coelomic epithelium covering the urogenital ridge. After segregation of the primordium into the bipotential gonad and the adrenocortical primordium, the cortex is encapsulated by mesenchymal cells and infiltrated by migrating sympathoadrenal cells, which form the medulla. We have shown that the cell fate regulator sonic hedgehog (Shh) is not required for the formation of the adrenocortical primordium but is require...

Background: Self-limited delayed puberty (DP) often segregates in an autosomal dominant pattern, suggesting that inheritance is conferred by a small number of genes. However, the underlying genetic background is mostly unknown. By comparison, many genes have been identified where loss-of-function mutations lead to hypogonadotropic hypogonadism (HH). Despite likely overlap between the pathophysiology of delayed puberty and conditions of GnRH deficiency, few studies have examine...

Background: Disturbances of pubertal timing affect >4% of the population and are associated with adverse health outcomes. Studies estimate 60–80% of variation in pubertal onset is genetically determined, but few genetic factors are known. We hypothesise that causal variants will be low-frequency, intermediate-impact variants and will be enriched in populations at the extremes of normal pubertal timing. Families with constitutional delay in growth and puberty (CDGP) ha...

Familial glucocorticoid deficiency (FGD;OMIM 202200) results from the inability of the adrenal cortex to produce cortisol in response to ACTH stimulation. Half of all cases are caused by mutations in MC2R, MRAP or STAR. SNP array genotyping of FGD patients of unknown aetiology mapped a disease locus to chromosome 5p13-q12. Targeted exome sequencing of 5p13-q12 in one patient identified a homozygous mutation, p.Ala533Val, in nicotinamide nucleotide transhyd...

Background: Timing of puberty is associated with height, cardiovascular health and cancer risk, with a significant public health impact. Previous studies estimate that 60–80% of variation in the timing of pubertal onset is genetically determined. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern, but the underlying genetic background is unknown.Methods: We performed whole exome sequencing in 111 members of 18 families fro...