Akitaka Shibata

PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis

Mutations in patatin-like phospholipase domain-containing 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in differentiated keratinocytes, plays a crucial role in the biosynthesis of ω-O-acylceramide, a lipid component essential for skin barrier. Global or keratinocyte-specific Pnpla1-deficient neonates die due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum, and aberrant keratinocyte differentiation. In Pnpla1−/− epidermis, unique linoleate-containing lipids including acylceramides, acylglucosylceramides and (O-acyl)-ω-hydroxy fatty acids are almost absent with reciprocal increases in their putative precursors, indicating that PNPLA1 catalyses the ω-O-esterification with linoleic acid to form acylceramides. Moreover, acylceramide supplementation partially rescues the altered differentiation of Pnpla1−/− keratinocytes. Our findings provide valuable insight into the skin barrier formation and ichthyosis development, and may contribute to novel therapeutic strategies for treatment of epidermal barrier defects.

High survival rate of harlequin ichthyosis in Japan.

To the Editor: The article, ‘‘Sunscreen use while driving,’’ serves as a valuable reminder of the importance of proper patient education regarding sunscreen use. The authors found that only 26% of the patients surveyed used sunscreen at least half the time while in the car. They drove the importance home by noting that 62% of the nonmelanoma skin cancers in their patients developed on the left side, comparedwith 28% on the right side (P\.03). This is a significant difference to note, especially considering that clear-glass and dark-tinted windows in cars only transmit 62% and 11.4% of ultraviolet (UV) A, respectively. However, it is important to discuss a likely generational gap that exists between the patients they surveyed and current young drivers. The average patient age in the survey was 67.5 years, which means the majority of patients started their main driving years in the early 1960s. This is important since only in 1968, with the production of the American Motors Corporation’s Ambassador, was air conditioning made standard in automobiles. In 1969, only 54% of domestic automobiles were equipped with air conditioning. In addition, 42.4% of adults were smokers in 1965, compared to 20.6% in 2008. Considering both of these factors, it is likely that at least some of the patients surveyed drove with the windows down far more often than current drivers do, resulting in more exposure to UV radiation, particularly UVB, which is blocked by window glass. We thought this generational gap also deserved comment, as it may further have contributed to the effects of driving on UV light exposure and the left-sided dominance of actinic lesions in this US driving population.

Epidemiology, medical genetics, diagnosis and treatment of harlequin ichthyosis in Japan.

Ichthyoses are a group of disorders marked by whitish, brown or dark‐brown scales on the skin of almost the whole body. Harlequin ichthyosis (HI) is the most severe form. Neonatal death from HI was once common. Due to intensive neonatal care and, probably, to the early introduction of oral retinoids, HI outcome has improved. For definitive diagnosis and the exclusion of other disorders, such as lamellar ichthyosis, which also shows a collodion baby phenotype, it is helpful to refer to electron microscopy of abnormal or absent lamellar granules and a heavy accumulation of lipid droplets in the keratinocytes. ATP‐binding cassette transporter A12 (ABCA12) is known as the causative gene of HI. Severe ABCA12 deficiency results in malformation of intercellular lipid layers in the cornified layers and leads to epidermal lipid barrier disruption. In HI patients, at least one mutation on each allele must be a truncation or deletion mutation to cause serious loss of ABCA12 function. Identification of the gene underlying HI has enabled DNA‐based prenatal diagnosis for HI at the earlier stages of pregnancy with low risk. There are no curative treatments for HI. Abca12‐deficient mice were created as a model of HI. Treatment of the model mice with retinoid or steroid has not been successful.

TRPS1 Haploinsufficiency Results in Increased STAT3 and SOX9 mRNA Expression in Hair Follicles in Trichorhinophalangeal Syndrome.

Trichorhinophalangeal syndrome types I and III (TRPS1, OMIM 190350; TRPS3, OMIM 190351) are rare hereditary diseases with autosomal dominant inheritance (1, 2). The first case was reported in 1966 (3). In 2000 the TRPS1 gene was identified as one of its causative genes and mapped to chromosomal region 8q24.1 (1). These syndromes have characteristic sparse and slow-growing hair, craniofacial abnormalities, such as bulbous pear-shaped nose, and skeletal abnormalities (3–5). We report here the effects of TRPS1 protein deficiency in a case of TRPS1.

Urticarial vasculitis and subcutaneous nodules in the extremities seen in a patient with mucopolysaccharidosis II after hematopoietic stem cell therapy

1 Schumann H, Kiritsi D, Pigors M et al. Phenotypic spectrum of epidermolysis bullosa associated with alpha6beta4 integrin mutations. Br J Dermatol 2013; 169: 115–124. 2 Inoue M, Tamai K, Shimizu H et al. A homozygous missense mutation in the cytoplasmic tail of beta4 integrin, G931D, that disrupts hemidesmosome assembly and underlies Non-Herlitz junctional epidermolysis bullosa without pyloric atresia? J Invest Dermatol 2000; 114: 1061–1064. 3 Dang N, Klingberg S, Rubin AI et al. Differential expression of pyloric atresia in junctional epidermolysis bullosa with ITGB4 mutations suggests that pyloric atresia is due to factors other than the mutations and not predictive of a poor outcome: three novel mutations and a review of the literature. Acta Derm Venereol 2008; 88: 438– 448. 4 Yuen WY, Sinke RJ, Jonkman MF. ITGB4-associated non-Herlitz junctional epidermolysis bullosa: report of two new cases carrying two novel ITGB4 mutations. Br J Dermatol 2013; 168: 432–434. 5 Lee M, Chen Q, Wang H et al. ITGB4-associated junctional epidermolysis bullosa without pylori atresia but profound genito-urinary involvement. Acta Derm Venereol 2015; 95: 112–113.

Cross-sectional survey on disease severity in Japanese patients with harlequin ichthyosis/ichthyosis: Syndromic forms and quality-of-life analysis in a subgroup

BACKGROUND Congenital ichthyoses (CIs) adversely affect quality of life (QOL) in patients. However, the effects of CIs on patient QOL have not been studied sufficiently. OBJECTIVE To investigate the association between disease severity and QOL in patients with harlequin ichthyosis (HI) and ichthyosis: syndromic forms (ISFs) METHODS: Clinical information of patients with HI and ISFs from 2010 to 2015 were obtained from 100 dermatology departments/divisions of principal institutes/hospitals throughout Japan. We examined the relationship between disease severity and QOL in patients with HI and ISFs. Patients who were aged 8 years or older and participated in a multicenter retrospective questionnaire survey in Japan were assessed by dermatology life quality index (DLQI, range of 0-30) and clinical ichthyosis score (range of 0-100). RESULTS Netherton syndrome patients had a significantly higher risk of allergy to food or environmental allergens than patients with other phenotypes. Keratitis-ichthyosis-deafness (KID) syndrome patients showed a significantly higher risk of skin infections than patients with other phenotypes. Complete data on DLQI were obtained from 13 patients, whose median age was 21 (8-71) years. Nine patients were male, and 4 were female. Systemic retinoids were administrated to 2 of the 3 HI patients. The Spearmans correlation coefficient between the clinical ichthyosis score and DLQI was 0.611 (P < 0.05). CONCLUSION We confirmed that Netherton syndrome and KID syndrome patients have a higher risk of allergy to food or environmental allergens and of skin infections, respectively. QOL impairment correlates with disease severity in HI and ISFs patients.

Dyshidrosiform pemphigoid restricted to the soles

Dyshidrosiform pemphigoid restricted to the soles Dyshidrosiform pemphigoid (DP) is a rare dermatosis characterized by persistent, localized vesicles, or bullae that are largely limited to the soles and/or palms. DP is regarded as a variant of localized bullous pemphigoid (BP). We herein report a case of DP presenting with vesicles and bullae localized on the soles. An 88-year-old woman was referred to our hospital for multiple erythematous papules and pruritus on the trunk and extremities for 6 months. A skin biopsy specimen from the left upper arm showed features of chronic dermatitis. Five months later, she had exacerbated pruritus and eruptions on the bilateral soles. Physical examination revealed multiple vesicles, hemorrhagic bullae, and erosions on the soles but no other skin symptoms (Fig. 1a). She did not have a coagulopathy or any episode of a trauma in the soles. She had taken no anticoagulant. Despite administration of oral antihistamines and topical steroid ointments (betamethasone butyrate propionate 0.05%), the eruptions were worse 1 week later. Laboratory examination demonstrated eosinophilia (white blood cell count of 5,800/ll, with 21.2% eosinophils) and elevated serum IgE (1,916 IU/ml). Enzyme-linked immunosorbent assay (ELISA) for anti-BP180 antibody was 190 U/ml (normal range: <9). ELISA for anti-desmoglein 1 and 3 antibodies was negative. A biopsy specimen from the vesicle on the right sole showed abundant dermal hemorrhage and an intraepidermal vesicle with eosinophilic infiltration in the vesicle and the upper dermis, but no subepidermal bulla was shown (Fig. 1b,c). Direct immunofluorescence of the specimen revealed linear deposits of IgG and C3 at the basement membrane zone (Fig. 1d,e). Therefore, we made the final diagnosis of DP. We treated her with oral prednisolone at 0.3 mg/kg/day considering her old age and limited lesional areas, and the cutaneous lesions promptly diminished in 10 days. We gradually reduced the dose of oral prednisolone and finally ceased that medication 2 months after the first prednisolone administration, and anti-

Eosinophilic annular erythema localized on the neck

673 6. Savage KJ, Harris NL, Vose JM, et al. ALK-anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008; 111: 5496-504. 7. Vasmatzis G, Johnson SH, Knudson RA, et al. Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood 2012; 120: 2280-9. 8. Parrilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood 2014; 124: 1473-80. 9. Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet 2017. Ahead of print.