Hidradenitis suppurativa (HS) is an inflammatory skin disease that affects roughly 1% of Europeans. It is characterized by painful abscesses, boils, cysts, and malodorous, pus-filled lesions in intertriginous regions (1, 2). It can follow autosomal dominant inheritance in some families, and mutations have been reported (3) in the gamma-secretase genes Presenilin-1 (PSEN1), Presenilin Enhancer-2 (PSENEN), and Nicastrin (NCSTN) in a minority (<7%) of cases. The remaining cohort are presumed to be sporadic or driven by other, as yet unidentified mutations. Nevus comedonicus (NC) is a rare (prevalence 1:45,000–1:100,000) epidermal nevus comprising of a group of dilated hair follicle openings filled with plugs of brownish-black oxidized keratin (4). It is usually localized on the head and neck and was initially described as “localized acne” (5). If it occurs as a part of the nevus comedonicus syndrome (NCS) (6), it can be generalized and form linear streaks. HS-like lesions have been observed in NCS (7). In some cases of NC, a somatic mutation in fibroblast growth factor-receptor gene 2 (FGFR2) has been identified, namely the Ser252Trp missense mutation (5). FGFR2 is expressed in keratinocytes, hair follicles, and sebaceous glands and has been implicated to induce hypercornification and comedogenesis (8). Germline FGFR2 mutations are also associated with acne, as seen in dominant Apert syndrome (9) (also comprising craniosynostosis, epiphyseal closure, and syndactyly) (10, 11). When occurring as a mosaic, the acne lesions follow Blaschko’s lines (12), the pattern of embryological cell development and proliferation. In a recent case, a postzygotic mosaicism was found in exon 4 of FGFR2 (c.758C>G, p.Pro253Arg) in low copy number. A similar mosaicism was also found in two other patients in p.Ser252Trp of exon 4 (8).

A 49-year-old male construction worker presented with a 29-year history of multiple abscesses in his buttock, inguinal, and axillary regions (Figure 1) and a history of severe post-pubertal acne conglobate. His back was studded with innumerable large comedones not unlike those seen in NC, however rather more spread out (Figure 1A), and with significant scarring. His condition had proved resistant to treatment with topical and systemic antibiotics, dapsone, retinoids, including acitretin and isotretinoin, zinc supplements and PUVA. Treatment with infliximab did have an effect on the inflammatory components; however, it was minimal and ultimately unsuccessful. Surgical interventions included excision of the left axilla and shoulder region and a transposition flap and excision of a pilonidal sinus.

The patient is an orphan. It is known that several other people in his family including his father and brother had suffered from the same condition with different intensities; however, there is no contact between the patient and family. Requests to collect samples from family members were denied by the patient. Suspecting a potential genetic origin (13), we therefore performed whole exome sequencing on blood-derived DNA. A search for rare, deleterious mutations revealed that there was no such mutation present in any of the known HS-associated genes. However, a rare missense mutation in the FGFR2 gene was found in exon 5 (c.G492C, p.K164N, see Table 1). This mutation is predicted (14) to have pathological consequence on the protein by several prediction algorithms, namely SIFT (“deleterious,” lowest score 0), PolyPhen (“probably damaging,” highest score 1), LoFtool (“probably damaging,” 0.00179), Condel (“deleterious,” 1.00), CADD (17.05), and SNPs&Go (73% probability). MutPred resulted in 63% probability for “damaging,” and predicted (15) molecular features of the mutation are loss of methylation at K164 (P = 0.0069), loss of ubiquitination at K164 (P = 0.0081), loss of solvent accessibility (P = 0.0371), and loss of MoRF binding (not significant, P = 0.0575) as well as gain of sheet (not significant, P = 0.1451).