Hair loss is common and has many causes, including the recently encountered condition, frontal fibrosing alopecia (FFA). First described in 1994 by Kossard, FFA is an inflammatory and scarring type of hair loss that almost exclusively affects women. Despite a dramatic recent increase in incidence, the aetiopathogenesis of FFA remains unknown, beyond that it is likely to represent a variant of lichen planopilaris. Its pathogenesis is characterized by immune‐mediated follicular destruction at the level of the hair bulge, which leads to a clinical phenotype of progressive frontotemporal hair and eyebrow loss that is often preceded by widespread body‐hair loss. Phenotypic review of 711 UK women with FFA showed that autoimmune disease, thyroid hormone abnormalities and oestrogen deficiency were more prevalent than in the general population. We also undertook genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and performed statistical meta-analysis. We observed genome-wide significant association with FFA at four loci: 6p21.1, 2p22.2, 8q24.22 and 15q2.1. Within 6p21.1, fine-mapping and conditional analysis indicated that the association is driven by allele HLA-B*07:02 (P=9.44×10−117, OR=5.22). At 2p22.2, Bayesian fine-mapping identified a putative causal missense variant in CYP1B1 (P=2.44x10−11, OR=1.65) encoding the homonymous xenobiotic- and hormone-processing enzyme. At 8q24.22, the most likely causal allele is located within ST3GAL1 (P=2.15x10−8, OR=1.34) which has been studied in the context of T cell homeostasis. At the 15q.26.1 locus, the most likely causal variant is in SEMA4B (P=8.12x10−10, OR=1.52) and co-localises with skin eQTLs (Pcoloc=0.99). A global, untargeted, case-control metabolomic study was performed to pursue the mechanistic relevance of CYP1B1, and a case-control gene-environment interaction study is underway to elucidate this further. Transcriptomic analysis of affected scalp tissue highlighted overrepresentation of transcripts pertinent to IFNγ, IL15 and JAK/STAT signalling. These findings characterise FFA as a genetically predisposed complex immuno-inflammatory disorder driven by HLA-B*07:02 and underpinned by causal variation in genes pertinent to T cell homeostasis and hormone and xenobiotic metabolism. The challenge remains, however, to identify at risk individuals, define disease triggers, and optimise preventative or early therapy.
Whole genome sequencing has revolutionised our ability to diagnose genodermatoses, but clinical judgement is still needed to direct investigations, interpret results and counsel patients. This lecture recalls memorable patients where the diagnosis was not straightforward, illustrating important genetic principles.