Young people presenting with delay in pubertal onset or progression may have one of a spectrum of conditions, with different underlying pathological mechanisms. Whilst environmental factors such as nutrition and emotional well-being can influence the timing of puberty, in the majority of patients presenting with significantly delayed puberty there is a clear family history of delayed or arrested puberty. Pubertal timing is known to be a trait with strong heritability, demonstrating that genetic factors play a key role in determining the timing of puberty. The pace of discovery of gene mutations responsible for delayed or absent puberty in human patients has accelerated in recent years due to next generation sequencing techniques. The identification of causal genetic defects in certain pathways has shed light on the pathogenesis of delayed and disrupted puberty. The development, maturation and function of the gonadotropin releasing hormone (GnRH) system is vital for appropriate timing of pubertal development, and genetic mutations in key regulators of this element of the hypothalamic-pituitary-gonadal (HPG) axis result in a spectrum of conditions ranging from isolated delayed puberty to absent puberty with anosmia. Controlling the activation of this GnRH network, a carefully balanced system of inhibitory and excitatory signals upstream of GnRH secretion are vital for puberty onset and progression, and defects in this system can also lead to delayed puberty. External inputs on the HPG axis, including those linking energy metabolism to the kisspeptin-GnRH system, are also important permissive signals for pubertal development and mutations in genes in these pathways may lead to late onset of puberty associated with changes in body mass. Recent discoveries include mutations in genes responsible for GnRH neuronal migration leading to both isolated (self-limited) delayed puberty and absent puberty (hypogonadotropic hypogonadism or Kallmann syndrome), genes related to the nitric oxide synthesis pathway, and genes which cause a syndrome of delayed puberty with autistic-spectrum disorder or developmental delay. This talk will also consider the utility of genetic testing for diagnosis of the underlying clinical condition in individuals with delayed puberty.
22 Sep 2021 - 26 Sep 2021