Mast cell activation in Dowling–Degos disease

Dear Editor, Dowling–Degos disease (DDD, OMIM 179850) is a rare autosomal‐dominant genodermatosis in the spectrum of reticulate pigmented anomalies that usually presents after puberty. It is characterized by reticulate hyperpigmentation and small brownish papules, located in various regions depending on the mutation. Loss‐of‐function mutations in the genes KRT5, POGLUT1, POFUT1 and PSENEN have been identified in DDD. Patients with KRT5 mutations usually develop their lesions in intertriginous areas, whereas patients with POGLUT1 often show affected extremities. Histology reveals downward elongations of rete ridges with a reticulated or fenestrated pattern, occasional horn cysts and basal hyperpigmentation.1 The phenotype depends on the affected gene.2,3,4,5,6 Hereby, we report on four female patients with DDD with a negative family history. All of them were referred to our outpatient clinic with itchy brownish papules that started developing after puberty. Itch worsened upon heat in one of the patients, Darier sign and serum tryptase levels were negative in all four patients. In patient A, mutational analysis revealed a KRT5 mutation [c.418dupA (p.Ile140AsnfsX39)]. The patient showed disseminated small red‐brownish papules all over the body with predilection of the submammary and axillary folds. In the other three patients, mutations in POGLUT1 were identified. The heterozygous mutation c.1051C>T (p.Gln351*) in patient B resulting in a preliminary stop codon with a shortened protein has recently been described by us.7 Similarly, molecular genetic analyses of DNA from patients C and D revealed heterozygous mutations in POGLUT1 [c.1080dupG (p.Asn361Glufs*5) and c.835C>T (p.R279W), respectively] as previously described by us.3,7 These patients show a more disseminated pattern of reticulate hyperpigmentation and lentigines. It took on average 10 years and evaluation of at least two skin biopsies before the patients received a diagnosis of DDD based on mutational and histological findings. Previous clinical differential diagnoses included mastocytosis, Darier disease, Grover disease and disseminated porokeratosis. Of note, only about half of the previous biopsies showed the characteristic pattern of reticular epithelial hyperplasia when examined retrospectively. Intense pruritus in all four patients and a previous differential diagnosis of mastocytosis prompted us to investigate further the role of mast cells in patients with DDD. Paraffin‐embedded sections of biopsies from lesional skin of the patients with DDD and healthy skin from control participants undergoing reconstructive surgery were stained with a commercially available antibody against tryptase (clone G3, dilution 1 : 50; DCS, Hamburg, Germany). The number of tryptase positive mast cells was quantified double blind as previously described.8 We found that mast cell counts were significantly increased in DDD compared with normal skin (P < 0·005) (Fig. 1). Biopsies were taken from different body areas of the patients with DDD and healthy control participants. Mast cell numbers can vary at different skin sites, thus counts can be slightly influenced by choice of site. (a) Numbers of mast cells are increased in representative skin biopsies of patients with DDD (n = 4) compared with healthy skin (n = 10) (P < 0·005, t‐test two‐sided). Evaluation of skin sections was performed by counting the number of tryptase positive mast cells in five high power fields at 200 × magnification and calculating the mean number of mast cells mm–2 as previously described.8 Data are shown as scatter dot plots and box plots with medians. (b) Mast cells were graded as either not degranulated (ND), moderately degranulated (MD) or extensively degranulated (ED). ND mast cells are decreased and ED mast cells are increased in patients with DDD (n = 4) compared with healthy skin (n = 10) (P < 0·005, t‐test two‐sided). Analysis of mast cell degranulation was performed at 200 × magnification as previously described. Data are shown as box plots with medians. Next, we sought to evaluate degranulation of mast cells. According to the staining pattern we classified mast cells into three groups of either not degranulated, moderately degranulated or extensively degranulated, as previously described8 (Fig. 1). We observed that mast cells in DDD sections were preferentially extensively degranulated, whereas mast cells in normal skin were usually not degranulated, indicating that mast cells are activated in the skin of patients with DDD (Fig. 1). Interestingly, in our four patients the number of mast cells and their degranulation appeared to also correspond to the severity of itching. Patients A and D who had severe pruritus had more extensively degranulated mast cells than patients B and C who showed less pronounced pruritus. Mutations in KRT5 and POGLUT1 are implicated in Notch signalling,3,7 which might influence inflammatory mediators in the mast cells, leading to degranulation and attracting further mast cells to the tissue. In our patients, itching responded well to treatment with H1 antihistamines further strengthening our hypothesis that mast cells play an important role in DDD. However, we are aware that we have only investigated a limited number of patients with this rare disease, therefore restricting our observations on treatment responses. Mast cell stabilizers would be an additional option to treat affected patients. In conclusion, we report four patients with DDD, in whom molecular genetic analysis was crucial for making the diagnosis. This observation confirms that diagnosing this rare disease requires a high degree of experience on behalf of dermatologists as well as dermatopathologists, and also because patients usually develop the disease later in life and may present with a negative family history. Moreover, we showed that cutaneous mast cells are increased and activated in DDD, suggesting their participation in the pathogenesis and their use as a target for novel treatment strategies.