The deregulation of NOTCH pathway, inflammatory cytokines, and keratinization genes in two Dowling-Degos disease patients with hidradenitis suppurativa.

Dowling-Degos disease (DDD) is a rare autosomal-dominant genodermatosis and it has been associated with hidradenitis suppurativa (HS). Deregulation of NOTCH pathway has been linked to the development of HS in DDD context (DDD-HS). However, molecular alterations in DDD-HS, including altered gene expression of NOTCH and downstream effectors that are involved in the follicular differentiation and inflammatory response, are poorly defined. We report two cases of patients diagnosed with DDD-HS, one of those, under Adalimumab treatment. Our results have shown downregulation of NOTCH1/NCSTN pathway, distinct molecular profiles of inflammatory cytokines (IL23A and TNF), and a novel aberrant upregulation of genes involved in the cornified envelope (CE) formation (SPRR1B, SPRR2D, SPRR3, and IVL) in paired HS lesions of two DDD patients.

Familial pseudoxanthoma elasticum associated with multiple comedones.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder characterized by atypical elastic fibers that causes connective tissue abnormalities of the skin, eyes, and heart, among other organs. The disorder is rare, with a classic presentation of yellow-orange cobblestone-like papules on flexural areas, lax skin, ocular degeneration, and moribund vasculature in multiple organs. There is wide variability in the presentation of the affected organs [1]. We present two sisters with classic cutaneous findings of PXE with the additional unusual findings of numerous open comedones on the neck. To our knowledge, this is the first report of numerous open comedones in familial PXE.

Galli-Galli Disease Presenting as a Lentigo-like Eruption: A Further Clinical Feature in the Wide Spectrum of Reticulate Pigment Disorders.

Dear Editor, Reticulate pigmentary disorders (RPD) is a term used to classify a spectrum of several acquired and congenital disorders. Different clinical features can be present, including a reticular pattern and a freckle-like pattern with hyper- or hypo-pigmented macules (1). Dowling-Degos disease (DDD), an autosomal dominant genodermatosis, is the main type of RPD (2). Clinically, DDD presents with pigmented, reticulate, flexural macules and comedo-like papules on the back and neck. Galli-Galli disease (GGD) is a very rare variant of DDD, from which is clinically indistinguishable (3). A 65-year-old Caucasian male patient presented to our Department with a 6-year history of diffuse maculopapular lesions involving the trunk and the extensor and flexor regions of the upper and lower extremities (Figure 1). These lesions were small, monomorphous, erythematous macules and papules, some covered by discrete scales. Numerous brown lentiginous macules were also observed. The patients did not present with comedo-like lesions, reticulate pigmentation, pitted acneiform facial scars, palmar pits, or nail changes. Furthermore, the oral mucosa showed no lesions. The patient's familial history was negative for dermatoses. Laboratory routine tests were all negative. Topical and oral steroids as well as systemic retinoids were unsuccessful. Therefore, a punch biopsy was performed. Histologic examination showed a digitate elongations of rete ridges, with small foci of acantholysis (Figure 2, a). The epidermis showed a finger-like projections extending into the papillary dermis with increased melanin pigment. The epidermis was atrophic above the digitate proliferations and above the acantholytic foci, where necrotic and dyskeratotic keratinocytes also were found (Figure 2, b). In the papillary dermis, a lymphohistiocytic infiltrate with perivascular distribution was detected (Figure 2, a). According to the clinical and histological findings, a final diagnosis of Galli-Galli disease with lentigo-like macular lesions was established. The patients started 25 mg/day acitretin with only partial improvement. GGD is now considered a variant of DDD, from which is clinically indistinguishable (2,3). Several differential diagnosis can be considered, including Darier's and Groover's disease (2-9) (Table 1). Because of the absence of digitate proliferation of the rete ridges and the presence of yellow or brown macules, Darier's disease can be distinguished from GGD. In our patient, the involvement of the lower legs and the presence of unusual brown, lentigo-like macules were accurately evaluated, because of the major diagnostic pitfall with an extensive kind of Grover's-like eruption with lentiginous freckling (6). However, the involvement of sun-shielded areas and the histological presence of a lentiginous elongation of rete ridges led us to a final diagnosis of GGD. Regarding the pathogenesis, the alteration of the keratine 5 gene (12q13.13) may be the main factor in GGD. In GGD, a reduced amount of functional keratin 5 impairs the structure of keratin intermediate filaments (10). As a result, the structure of the epidermis is affected, leading to alterations in desmosomes and hemidesmosomes (2). Regarding the lentigo-like pattern of our patient, the additional diffusion of lentigos over shield-sites and the absence of extreme sun exposure in the patient's history ruled out the ultraviolet radiation as the main etiopathogenetic factor. In this regard, as reported by Girard et al., lentigos could represent a post-inflammatory pigmentation of the papular acantholytic lesions (10). However, as emphasized by Coper et al. (6), the persistence of lentigos for several years would contrast with this hypothesis. It is indeed known that a failure of keratin 5 may disrupt the movement of pigment-carrying melanosomes into keratinocytes. The disruption of melanosome transport is thought to be the cause of the pigmentation abnormalities seen in DDD as well as in GGD. These aspects could explain the elongated rete ridges and the altered pigmentation clinically and pathologically observed in GGD and DDD.

Dowling-Degos disease co-presenting with Darier disease.

We present a case of a patient with long-standing hyperpigmented macules and erythematous papules over his chest, abdomen, back and arms, suggestive of Dowling-Degos disease (DDD). In addition, there were hyperkeratotic papules, alternating red and white nail-bed discolouration, and V-shaped nail notching consistent with Darier disease (DD). Histology showed findings consistent with DDD and DD on separate specimens. The lack of acantholysis in areas of filiform hyperpigmented rete ridges ruled out Galli-Galli disease (GGD). DDD results from mutations in the genes encoding keratin 5 (KRT5), protein O-glucosyltransferase 1 (POGLUT1) or protein O-fucosyltransferase 1 (POFUT1), while DD results from mutations in the ATP2A2 gene. Both genes are present on chromosome 12. In this case, the patient presented with features of both DDD and DD, which suggests that either a cooperating mutation or a mutation in an unrelated gene locus may underlie the findings in this patient.

Hidradenitis suppurrativa (acne inversa) as a systemic disease.

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic follicular occlusive skin disorder characterized by recurrent abscesses, draining sinuses, and scarring, with a multifactorial pathogenesis. The answer to the question whether HS may be considered a systemic disease relies on the presence of accompanying systemic manifestations, on the proof of association with other diseases or conditions, and on the occurrence of systemic implications. We address these questions based on a systemic review of the existing literature. There are several reports in the literature of the coexistence of HS with other diseases, including pyoderma gangrenosum, PASH syndrome, Adamantiades-Behcet's disease, spondylarthropathy, Crohn's disease, SAPHO, pachyonychia congenita, Dowling-Degos disease, and the keratitis-ichthyosis-deafness (KID) syndrome. Case series exist only for Crohn's disease, while most other reports are anecdotal, thus, not providing high-quality scientific evidence. Based on well-designed studies, HS has been associated with the metabolic syndrome and with excess body weight or obesity. The link between HS and systemic associations may be attributed to common genetic or environmental factors or shared inflammatory pathways.