Acta Dermato-Venereologica 99-1CompleteContent | Page 33

SHORT COMMUNICATION 115 A Postzygotic ATP2A2 Novel Mutation Identified by Next-generation Sequencing in Mosaic Darier Disease Liliana GUERRA 1 , Cristina PEDICELLI 2 , Vittoria PROTO 1 , Angelo Giuseppe CONDORELLI 3 , Cinzia MAZZANTI 2 and Daniele CASTIGLIA 1 1 Laboratory of Molecular and Cell Biology, 2 1 st Dermatology Division, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, and 3 Genetic and Rare Diseases Research Area, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. E-mail: [email protected] Accepted Aug 7, 2018; Epub ahead of print Aug 7, 2018 whereas a loss-of heterozygosity (LOH) in a heterozygous Darier disease (DD) is a rare skin condition with autoso- mal dominant inheritance that manifests in childhood or individual was hypothesized for segmental DD type 2 (10). adolescence (1, 2). It is characterized by keratotic papules Although there is no direct evidence for LOH as a causal that may coalesce into large warty plaques, predominantly event for DD type 2, molecular genetic support has been affecting seborrhoeic areas, such as the forehead, central provided (8). We report here on the molecular basis of the chest, back and scalp borders, usually accompanied by mosaicism in an Italian woman with segmental DD type 1. palmoplantar pits and characteristic nail changes (i.e. longitudinal leukonychia and V-shaped notches at the CASE REPORT distal end of the nail plate) (1, 3). Involvement of in- tertriginous areas and psychiatric symptoms may also A 47-year-old woman presented with keratotic papules on the right side of her trunk, and right arm and leg. The lesions appeared on be present (1, 3). Heat or humidity, excessive sweating, exposure to ultraviolet (UV) light, friction, medications and infections, as well as preg- nancy or delivery, aggravate the disorder (3). Histologically, DD is characterized by loss of adhesion between epidermal cells, termed acantholysis, leading to suprabasal cleavage and abnormal keratinization, which manifests as corps ronds and grains (4). DD is caused by mutations in the ATP2A2 gene, which encodes isoforms of the sarco/en- doplasmic reticulum ATPase type 2 (SERCA2) in keratinocytes and cells from other tissues (5). SERCA2 is a calcium pump incorporated in the endoplasmic reticulum (ER) membrane that regulates Ca 2+ transport from the cyto- plasm into the ER lumen. It is organized in 10 transmembrane helices (M1–M10) intercalated by 5 stalk sectors (S1–S5), and in a cytosol- exposed region comprising the phosphoryla- tion and ATP-binding domains (5). In 2000, genetic mosaicism for mutations in ATP2A2 was demonstrated to cause the segmental form of the disease (6), which is quite rare. Segmental DD can manifest in a mosaic pattern distinctive of 2 disease subtypes: segmental DD type 1, which is characterized by warty papules distributed in a linear pattern on a background of clinically normal skin, and seg- mental DD type 2, in which linear DD lesions Fig. 1. Clinical and histopathological findings. (a, b) Hyperkeratotic papules following the Blaschko’s lines over the right side of the patient’s trunk and her right arm. (a) Note are usually more severe and may manifest early the sharp midline demarcation on the abdomen, clearly visible after sun exposure during after birth, superimposed on a background of the summer, on a background of post-inflammatory hypopigmentation. (c) Hyperkeratotic generalized DD (7, 8). Segmental DD type papules on the right leg during the winter. (d) Hyperkeratosis with parakeratosis, acanthosis 1 was hypothesized to result from a de novo and suprabasal acantholysis in the haematoxylin-eosin staining. Higher magnification shows dyskeratotic cells with a pyknotic nucleus surrounded by a halo, termed corps postzygotic ATP2A2 mutation that occurs ronds, within the spinous layer (d: blue inset, yellow circles), and flattened dyskeratotic during embryogenesis, and a few studies have cells with an elongated nucleus, termed grains, within the parakeratotic horny layer (d: provided genetic proof for this aetiology (4, 9), black inset, green circle). Haematoxylin-eosin staining (d) × 200 (left panel). This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3018 Acta Derm Venereol 2019; 99: 115–116