Key points

Introduction

In discussing the etiology of HS, potential causes can be subdivided into genetic, microbiological, endocrine, and environmental factors such as obesity and smoking. The question, “To what extent is HS caused by genetic factors?” was recently placed in the top 10 most important uncertainties from a short list of 55 HS uncertainties in a Priority Setting Partnership conducted for HS, in which patients with HS, carers, and clinicians agreed mutually important HS research questions. Patients were keen to know the chances of passing on the condition to their children, and clinicians saw the opportunity to develop targeted therapies for HS by identifying the protein products of any relevant gene mutations.

Introduction

In discussing the etiology of HS, potential causes can be subdivided into genetic, microbiological, endocrine, and environmental factors such as obesity and smoking. The question, “To what extent is HS caused by genetic factors?” was recently placed in the top 10 most important uncertainties from a short list of 55 HS uncertainties in a Priority Setting Partnership conducted for HS, in which patients with HS, carers, and clinicians agreed mutually important HS research questions. Patients were keen to know the chances of passing on the condition to their children, and clinicians saw the opportunity to develop targeted therapies for HS by identifying the protein products of any relevant gene mutations.

Contribution of genetics to hidradenitis suppurativa etiology

Any determination of the relative contribution of genetic and environmental factors in disease causation usually incorporates twin studies, to compare disease risk in monozygotic and dizygotic pairs. Unfortunately, twin data are currently lacking in HS. One pair of monozygotic twins was included in an early epidemiology study, and both the women developed HS in the breast region at the beginning of their third decade.

Case series evidence suggests that just more than one-third of patients with HS have a family history of the condition, one of the largest HS case series of 618 French patients reporting another affected family member in 35% of patients. This figure, which relies on patient self-reporting, is probably an underestimate because family members may not discuss the condition between themselves because of embarrassment.

Autosomal dominant inheritance

The timeline of advances in the understanding of the genetics of HS ( Fig. 1 ) begins in 1968 when Knaysi and colleagues noted a family history of HS in 3 of 18 patients who were asked this question, in a case series of patients receiving surgical treatment of HS. Fitzsimmons and colleagues took up the story in 1984, publishing a preliminary report of 3 UK families, including a total of 21 members with HS. All 3 generations of one family were affected. A year later, the same researchers expanded the study to include 23 families with a total of 62 affected individuals. The disease definition used by the study was “recurrent suppurative cicatrizing lesions of apocrine gland bearing areas of the skin, primarily affecting the axillae and anogenital area.” Vertical disease transmission was found involving all 3 generations in 5 families and 2 consecutive generations in 6 families, including male-to-male transmission. The researchers concluded that the pattern of inheritance suggested a single gene disorder inherited as an autosomal dominant trait.

Timeline of advances in the understanding of the genetics of hidradenitis suppurativa.

For an autosomal dominant condition, the frequency of affected first-degree relatives should be 50%; however, in the Fitzsimmons study only 34% were affected. The researchers argued that incomplete penetrance or incomplete case ascertainment may have contributed. In addition, younger unaffected relatives were included who could develop HS later in life, in the context that 16 of the 62 affected probands in the Fitzsimmons study did not develop HS until their fourth decade. In part to address this issue, Von der Werth and colleagues reviewed 14 of the surviving probands in a subsequent study published in 2000. The researchers used a consensus disease definition involving a history of at least 5 painful, erythematous papules, nodules, or abscesses in the axillae or groins or at least 1 active lesion and a history of 3 others. Confirmed cases were individuals who conformed to the disease definition when assessed in person. Probable cases were those who met the definition when assessed by telephone but did not attend in person or individuals who had experienced several flexural skin boils but could not recall a sufficient number to meet the definition. Seven of the probands had a family history of HS, and of their 37 surviving first-degree relatives, 34 were included in the study. Of these, 10 individuals were confirmed to have HS, representing 27% of the total surviving first-degree relatives and including 2 people who had developed HS since the earlier study. Nine probable cases were also identified, producing a potential combined figure for affected first-degree relatives of 51%, with the caveat that about half did not entirely meet the disease definition.

Linkage to chromosome 1

Building on the concept that susceptibility to HS may be underpinned by mutation in a single gene, Gao and colleagues performed a whole-genome scan of individuals in a large Han Chinese family exhibiting autosomal dominant inheritance of HS across 4 generations. A clinical disease definition was used involving “inflammatory papules, painful nodules, pustules, sinuses and abscesses”; affected skin sites included the buttocks, axillae, scalp, face, neck, trunk, and limbs, and disease onset was between 10 and 20 years of age. A total of 9 affected family members and 6 unaffected members older than 10 years contributed to the linkage analysis. The genome-wide scan was performed using 382 fluorescent microsatellite markers and demonstrated linkage to chromosome 1. Subsequently, segregation between affected and unaffected family members of a further 20 microsatellite markers spanning the relevant portion of chromosome 1 was used to narrow down the genetic locus to a 73-Mb region containing approximately 886 genes, 1p21.1–1q25.3.

Discovery of γ-secretase mutations in hidradenitis suppurativa

The combination of a genome-wide linkage scan and subsequent haplotype analysis described earlier was repeated by Wang and colleagues in a further 6 Han Chinese families demonstrating autosomal dominant HS inheritance. Affected family members had skin lesions in both flexural and nonflexural skin sites, and the proband of family 1 also had a squamous cell carcinoma (SCC) of the left axilla. Linkage to chromosome 19q13 was found in families 1 and 2, and haplotype analysis narrowed the target to a 5.5 Mb region containing approximately 200 genes. Sequence analysis of candidate genes demonstrated a frameshift mutation in the PSENEN gene in affected members of family 1, a mutation that was absent in unaffected family members and 200 unrelated Han Chinese control individuals. PSENEN encodes 1 subunit of the γ-secretase protein. A different PSENEN frameshift mutation was present in affected members of family 2. In families 3 to 6, there was no PSENEN mutation, but sequence analysis revealed mutations in either NCSTN or PSEN1 , genes that encode other γ-secretase subunits. The NCSTN gene is located at 1q22–23, within the region identified by Gao and colleagues. Familial HS (acne inversa) is now listed in the Online Mendelian Inheritance in Man catalog under reference 142690 for NCSTN mutations, 613736 for PSENEN mutations, and 613737 for PSEN1 mutations.