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 Spearman's 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.

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.

Toll-like receptor 4 antagonist TAK-242 inhibits autoinflammatory symptoms in DITRA.

BACKGROUND: IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), and loss-of-function mutations in IL36RN define a recessively inherited autoinflammatory disease named "deficiency of IL-36Ra" (DITRA). DITRA causes systemic autoinflammatory diseases, including generalized pustular psoriasis (GPP), an occasionally life-threatening disease that is characterized by widespread sterile pustules on the skin, fever and other systemic symptoms. GPP can present at any age, and provocative factors include various infections, medicines and pregnancy. OBJECTIVE: We aimed to elucidate the role of toll-like receptor 4 (TLR4) signaling in DITRA and to innovate an efficient treatment for DITRA. METHODS: We generated Il36rn-/- mice and treated them with TLR4 agonist to establish DITRA model mice. Furthermore, we administrated TLR4 antagonist TAK-242 to the model mice to inhibit the DITRA symptoms. RESULT: Il36rn-/- mice treated by TLR4 agonist showed autoinflammatory symptoms in skin, articulation and liver. Thus, we established model mice for DITRA or GPP that show cutaneous, articular, and hepatic autoinflammatory symptoms typical of DITRA or GPP: sterile pustules on the skin, liver abscesses and enthesitis of the hind paws. Additionally, these symptoms were canceled by TAK-242 administration. We demonstrated the inhibitory effects of the TLR4 antagonist TAK-242 on the autoinflammatory symptoms exhibited by the DITRA models. CONCLUSION: We suggested that blockage of TLR4 signaling is a promising treatment for DITRA and GPP.

Apparent homozygosity due to compound heterozygosity of one point mutation and an overlapping exon deletion mutation in ABCA12: A genetic diagnostic pitfall.

BACKGROUND: Harlequin ichthyosis (HI), one of the most severe genetic skin disorders, is autosomal recessively inherited. Mutations in ABCA12, which encodes ATP-binding cassette transporter A12 (ABCA12), are known to be the cause of HI. It is very difficult to make precise genetic diagnosis when an exon deletion mutation overlaps the site of another causative point mutation. This combination of mutations may lead us to conclude incorrectly that the patient has the point mutation homozygously, a phenomenon called "apparent homozygosity". OBJECTIVE: To demonstrate that the present HI patient has apparent homozygosity in ABCA12 mutations. METHODS: We performed direct sequencing of gDNA in the entire coding region, including exon-intron boundaries, of ABCA12 in the HI patient and her parents. To further elucidate the mutations in the patient, parental mutation segregation study was done and SNP analysis was conducted on the region flanking ABCA12 in the patients and her parents. Quantitative PCR of gDNA in exon 11 of ABCA12 was also performed. Direct sequencing of cDNA from exon 9 to exon 13 and of gDNA between intron 9 and intron 11 of ABCA12 was done in the HI patient and her parents. RESULTS: Direct sequencing of gDNA in the entire coding region, including exon-intron boundaries, of ABCA12 seemed to indicate that the patient had the novel homozygous nonsense mutation c.1216A>T (p.Lys406X) in exon 11. However, mutation segregation analysis, SNP analysis, qRTPCR of gDNA in exon 11 of ABCA12 and direct sequencing of cDNA from exon 9 to exon 12 of ABCA12 and of gDNA between intron 9 and intron 11 of ABCA12 in the HI patient and her parents demonstrated that the present patient was compound heterozygous for two ABCA12 mutations: c.1216A>T (p.Lys406X) in exon 11 and g.111346_113217del1872 (p.Leu355_Lys428del, Gln354fs7*) which was overlapping exon deletion mutations involving exons 10 and 11. CONCLUSION: When direct sequencing indicates that a patient from a non-consanguineous family has an apparently homozygous non-founder point mutation, the homozygosity may be "apparent homozygosity", and we should keep in mind the possibility of overlapping exon deletion mutation.

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.

Hydroxyurea-induced amyopathic dermatomyositis presenting with heliotrope erythema.

Hydroxyurea (HU) is a chemotherapeutic agent used for the treatment of myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, and essential thrombocytosis. We describe a 69-year-old man who had essential thrombocytosis and developed amyopathic dermatomyositis after long-term HU therapy. He presented with Gottron papules and heliotrope erythema. The former has been described in all cases of HU-induced dermatomyositis; the latter has been seen in a few cases of that disorder.