Mutations in the 8 haem biosynthetic pathway genes are traditionally known to cause a group of diseases known as porphyria. While Primary Adrenal Insufficiency (PAI), an intrinsic adrenal defect in glucocorticoid synthesis +/- mineralocorticoid synthesis, is linked to mutations in more than 25 genes, in our cohort, most commonly the melanocortin receptor gene (MC2R), its accessory protein (MRAP), steroidogenic enzymes (STAR and CYP11A1), and a gene involved in mitochondrial anti-oxidant defence (NNT). Over the last few decades, there have been tantalising case reports linking porphyria with defects in steroidogenesis.

We identified seven families (11 individuals) with defects in haem biosynthetic enzymes who exhibit flagrant adrenal insufficiency (AI), with or without porphyria. 1) a kindred (n=4) from Egypt with biallelic mutations in protoporphyrinogen oxidase (PPOX) p.(Glu339Lys), who have a spectrum of symptoms ranging from failure to thrive, focal neurology, cutaneous lesions of variegate porphyria along with severe AI. 2) Three kindreds with mutations in coproporphyrinogen oxidase (CPOX), (i) a preterm female of Asian descent homozygous for p.(Pro367Ala) mutation, who presented with anaemia, jaundice, focal neurology and cutaneous manifestations of Hereditary Coproporphyria (HCP) along with AI, (ii) siblings of Kurdish descent homozygous for p.(Ser28*) mutation, the boy had HCP along with AI and Disorder of Sex Development, while the girl has no clinical manifestations of HCP but has severe AI, and (iii) a patient with HCP from France who presented with AI aged 64, this patient had a urinary steroid metabolome that showed elevated levels of 11-deoxycorticosterone and 11-deoxycortisol. 3) Three adult patients with mutations in Hydroxymethylbilane Synthase (HMBS) who presented with AI during acute hepatic porphyria attacks.

This growing evidence suggesting a link between mutations in haem biosynthesis genes and PAI indicates that testing adrenal function in porphyria patients and their families might be warranted. Furthermore, haem biosynthesis genes should be considered for inclusion in genetic testing panels for adrenal insufficiency.

In order to understand the mechanism behind the link in patients, we plan a multicentre study that investigates different aspects of adrenal steroidogenesis biochemically and genetically in porphyria patients and their family members.