Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4*), c.652C>T (p.Arg218*), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218*) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology.

Pigmented actinic keratosis is one of the simulators of early melanoma in situ from severely sun-damaged skin. Close scrutiny of the hematoxylin and eosin stained section does not always allow an unequivocal diagnosis, because it is sometimes difficult to distinguish pigmented keratinocytes from melanocytes. Immunohistochemical stains, such as S-100 and HMB-45, are used routinely to address this problem. Melan-A, also known as MART-1, is an additional melanocytic marker and has proved to be useful in identifying metastatic tumors of melanocytic origin. The usefulness of this marker to discriminate pigmented actinic keratosis from early melanoma in situ, however, has not yet been a subject of investigation. In this study we evaluated Melan-A expression in ten unequivocal cases of pigmented actinic keratosis and compared the staining pattern with that of S-100, HMB-45, and tyrosinase. In all ten cases the number of cells highlighted with Melan-A was by far larger than those labeled with S-100, HMB-45, and tyrosinase. Four cases showed clusters of Melan-A positive cells being suggestive of melanocytic nests. Even areas of normal skin adjacent to the actinic keratosis featured prominent staining of Melan-A, but only inconsistent labeling of intraepidermal melanocytes with S-100, HMB-45, and tyrosinase. We therefore believe that Melan-A is a more sensitive marker for intraepidermal melanocytes than S-100, HMB-45, and tyrosinase. In addition there may be expression of Melan-A in keratinocytes and nonmelanocytic cells. To avoid an erroneous diagnosis of malignant melanoma one should therefore interpret results obtained from Melan-A stained slides carefully and in the context with other melanocytic markers.

We encountered recently 3 cases with a histopathologic diagnosis of melanoma in situ on sun-damaged skin (male = 2, female = 1; median age: 59 years; range: 52-60 years). The diagnosis was based mainly on the finding of actinic elastosis in the dermis and increased number of melanocytes in the epidermis and was confirmed by strong positivity for Melan-A in single cells and in small nests ("pseudomelanocytic nests"), located at the dermoepidermal junction. Indeed, examination of slides stained with hematoxylin and eosin revealed the presence of marked hyperpigmentation and small nests of partially pigmented cells at the dermoepidermal junction, positive for Melan-A. The histologic and especially the immunohistochemical features were indistinguishable from those of melanoma in situ on chronic sun-damaged skin. In addition, a variably dense lichenoid inflammation was present. Clinicopathologic correlation, however, showed, in all patients, the presence of a lichenoid dermatitis (phototoxic reaction, 1 case; lichen planus pigmentosus, 1 case; and pigmented lichenoid keratosis, 1 case). Our cases clearly show the histopathologic pitfalls represented by lichenoid reactions on chronic sun-damaged skin. Immunohistochemical investigations, especially if performed with Melan-A alone, may lead to confusing and potentially disastrous results. The unexpected staining pattern of Melan-A in cases like ours raises concern about the utility of this antibody in the setting of a lichenoid tissue reaction on chronic sun-damaged skin. It should be underlined that pigmented lesions represent a paradigmatic example of how immunohistochemical results should be interpreted carefully and always in conjunction with histologic and clinical features.

Background: Rudimentary meningocele, a malformation in which meningothelial elements are present in the skin and subcutaneous tissue, has been described in the past under a variety of different terms and has also been referred to as cutaneous meningioma. There has been debate as to whether rudimentary meningocele is an atretic form of meningocele or results from growth of meningeal cells displaced along cutaneous nerves Objective: We reviewed the clinical, histological, and immunohistochemical characteristics of rudimentary meningocele in an attempt to assess the most likely pathologic mechanism for it.Design: Retrospective study.Setting: University hospitals.Patients: Thirteen children with rudimentary meningocele.Main Outcome Measures: Medical records were reviewed and histopathologic examination as well as im-munohistochemistry studies were performed for each case. A panel of immunoperoxidase reagents (EMA, CD31, CD34, CD57, S-100, and CAM 5.2) was used to assess lineage and to confirm the meningothelial nature of these lesions.Results: Recent evidence indicating a multisite closure of the neural tube in humans suggests that classic meningocele and rudimentary meningocele are on a continuous spectrum. Conclusion:Rudimentary meningocele seems to be a remnant of a neural tube defect in which abnormal attachment of the developing neural tube to skin (comparable to that in classic meningocele) could explain the presence of ectopic meningeal tissue. In the majority of cases, no underlying bony defect or communication to the meninges could be detected. However, in light of the probable pathogenesis, imaging studies to exclude any communication to the central nervous system should precede any invasive evaluation or intervention.

We found further evidence to suggest that GGD is indeed a variant of DDD and not a distinct disease entity. Two facts in particular support this conclusion: the same KRT5 mutation was found in patients with GGD and in patients with DDD, and acantholysis seems to be present in a large number of patients who had previously been assigned a diagnosis of DDD.