Discovery of Novel Genes and Mechanisms in Rare Neuroendocrine Diseases

Research into rare diseases provides an opportunity to improve our understanding of molecular genetic pathways, with the ultimate aim of improving patient care. In a series of extremely rare neuroendocrine diseases, we performed clinical and genetic research across individual kindreds and in large databases. With an international database we demonstrated statistically-significant characteristics of AIP-mutated pituitary adenomas, including young age at onset, large tumour size, familial presentation, and somatostatin analogue resistance. Further work helped to refine the clinical criteria for AIP-related pituitary adenomas and to highlight personalised therapy options based on somatostatin receptor expression. We then performed the first comprehensive study of the characteristics of pituitary gigantism. That project in 208 subjects showed that 50% of pituitary gigantism patients have an identifiable genetic diagnosis. Also, earlier hormonal control led to better outcomes, namely, lower final height. Furthermore, we identified infants with gigantism due to a previously undescribed microduplication in chromosome Xq26.3, a disease we termed X-linked acrogigantism (X-LAG). We identified the gene GPR101 as being responsible for pituitary hypersecretion in X-LAG and characterised the spectrum of disease, including treatment resistance. Subsequently, we showed that duplications including the GPR101 gene alter the local chromatin and disrupt the normal topologically associated domain (TAD). The GPR101 promoter is dysregulated by abnormal ectopic enhancers that drive over-expression and cause X-LAG. In other rare genetic neuroendocrine conditions, we identified a Dutch SDHB founder mutation in apparently-unrelated South African patients with phaeochromocytoma/paraganglioma. The impact is significant as SDHB mutations have incomplete penetrance but high metastatic risk, thereby making management complicated. Other work focused on a novel presentation of pituitary adenomas and phaeochromocytomas in patients with intragenic deletions of the MAX gene. We diagnosed a novel homozygotic LHB gene mutation in patients with hypogonadism, which highlighted a new region that impacted function across all pituitary glycoprotein hormones