Vinzenz Oji

Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia

Focal dermal hypoplasia (FDH) is an X-linked dominant multisystem birth defect affecting tissues of ectodermal and mesodermal origin. Using a stepwise approach of (i) genetic mapping of FDH, (ii) high-resolution comparative genome hybridization to seek deletions in candidate chromosome areas and (iii) point mutation analysis in candidate genes, we identified PORCN, encoding a putative O-acyltransferase and potentially crucial for cellular export of Wnt signaling proteins, as the gene mutated in FDH. The findings implicate FDH as a developmental disorder caused by a deficiency in PORCN.

Loss of Corneodesmosin Leads to Severe Skin Barrier Defect, Pruritus, and Atopy: Unraveling the Peeling Skin Disease

Generalized peeling skin disease is an autosomal-recessive ichthyosiform erythroderma characterized by lifelong patchy peeling of the skin. After genome-wide linkage analysis, we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin. In contrast to hypotrichosis simplex, which can be associated with specific dominant CDSN mutations, peeling skin disease is characterized by a complete loss of CDSN expression. The skin phenotype is consistent with a recent murine Cdsn knockout model. Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule. Therefore, peeling skin disease will represent a new model disorder for atopic diseases, similarly to Netherton syndrome and ichthyosis vulgaris in the recent past.

Molecular Analysis of 250 Patients with Autosomal Recessive Congenital Ichthyosis: Evidence for Mutation Hotspots in ALOXE3 and Allelic Heterogeneity in ALOX12B

In recent years several new genes for autosomal recessive congenital ichthyosis (ARCI) have been identified. However, little is known about the molecular epidemiology and pathophysiology of this genetically and clinically heterogeneous group of severe disorders of keratinization. ARCI is characterized by intense scaling of the whole integument often associated with erythema. We and others have shown that mutations in ALOX12B and ALOXE3, coding for the lipoxygenases 12R-LOX and eLOX-3 predominantly synthesized in the epidermis, can underlie this rare condition. Here we have surveyed a large group of 250 patients with ARCI for mutations in these two genes. We have identified 11 different previously unreported mutations in ALOX12B and ALOXE3 in 21 ARCI patients from 19 unrelated families and demonstrated that mutations in the two genes are the second most common cause for ARCI in this cohort of patients. Examination of the molecular data revealed allelic heterogeneity for ALOX12B and two mutational hotspots in ALOXE3. Functional analysis of all missense mutations and a splice site mutation demonstrated that complete loss of function of the enzymes underlies the phenotype. Our findings further establish the pivotal role of the 12-lipoxygenase pathway during epidermal differentiation.

Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length.

The barrier function of the human epidermis is supposed to be governed by lipid composition and organization in the stratum corneum. Disorders of keratinization, namely ichthyoses, are typically associated with disturbed barrier activity. Using autozygosity mapping and exome sequencing, we have identified a homozygous missense mutation in CERS3 in patients with congenital ichthyosis characterized by collodion membranes at birth, generalized scaling of the skin, and mild erythroderma. We demonstrate that the mutation inactivates ceramide synthase 3 (CerS3), which is synthesized in skin and testis, in an assay of N-acylation with C26-CoA, both in patient keratinocytes and using recombinant mutant proteins. Moreover, we show a specific loss of ceramides with very long acyl chains from C26 up to C34 in terminally differentiating patient keratinocytes, which is in line with findings from a recent CerS3-deficient mouse model. Analysis of reconstructed patient skin reveals disturbance of epidermal differentiation with an earlier maturation and an impairment of epidermal barrier function. Our findings demonstrate that synthesis of very long chain ceramides by CerS3 is a crucial early step for the skin barrier formation and link disorders presenting with congenital ichthyosis to defects in sphingolipid metabolism and the epidermal lipid architecture.

Ichthyosis: clinical manifestations and practical treatment options.

Ichthyoses constitute a large group of cornification disorders that affect the entire integument. The skin is characterized by visible scaling and in many cases by inflammation, for example, in bullous/keratinopathic ichthyosis or Netherton syndrome. From the viewpoint of classification it is useful to distinguish non-syndromic from syndromic types of ichthyosis. Ichthyosis vulgaris and recessive X-linked ichthyosis are common disorders - often of delayed onset, in contrast to congenital ichthyoses, which belong to the group of rare diseases and present at birth with either the features of collodion membrane or congenital ichthyosiform erythroderma. The diagnostic steps are based on clinical data, analyses such as the steroid sulfatase activity test, skin biopsies, and genetic results. However, the dramatic increase in knowledge about the pathophysiology of these conditions has not led to a curative therapy so far. The therapeutic management is multidisciplinary and involves ichthyosis patient organizations in many countries. The mainstay of treatment remains with moisturizing creams containing, for example, urea, lactic acid and other humectants and keratolytics, regular bathing, and mechanical scale removal. Patients with lamellar ichthyosis or ichthyosiform erythroderma in particular profit from oral therapy with retinoids or retinoic acid metabolism-blocking agents.

Nonsyndromic types of ichthyoses - an update.

Ichthyoses are genetically determined Mendelian disorders of cornification (MEDOC) that are characterized by universal scaling. Today we distinguish between non‐syndromic and syndromic forms. Ichthyosis vulgaris is the most frequent type (prevalence 1:100) and is caused by autosomal semi‐dominant filaggrin mutations. It is associated with a higher risk for the development of atopic diseases, such as atopic eczema and allergic rhinitis. Recessive X‐linked ichthyosis (RXLI) occurs almost exclusively in boys; in Germany it has a prevalence of around 1:4,000. It is caused by steroid sulfatase deficiency and is often associated with further clinical problems, such as cryptorchidism (∼20%) or social communication deficits, such as attention deficit hyperactivity syndrome (40%) or autism (25%). Autosomal recessive congenital ichthyosis (ARCI) is genetically very heterogeneous and 8 different genes have been identified so far. The most frequent cause of ARCI is a transglutaminase 1 deficiency (prevalence 1:200, 000). Mutations in keratin genes are the cause of the keratinopathic ichthyoses, such as epidermolytic ichthyosis. They manifest at birth and often feature episodes of blistering. Most of these types are inherited as autosomal dominant traits, but autosomal recessive forms have also been described on occasion.

Topical pimecrolimus : a novel therapeutic option for Netherton syndrome

SIR, Netherton syndrome (NS) is an autosomal recessive ichthyosis characterized by the triad of congenital ichthyosiform erythroderma (CIE) or ichthyosis linearis circumflexa (ILC), trichorrhexis invaginata or other hair shaft anomalies, and severe atopic diathesis. Its incidence has been estimated at one in 200 000; none the less, NS may account for up to 18% of all cases of infantile erythroderma. It also features associated symptoms such as neonatal dehydration, failure to thrive and recurrent infections. The disease is caused by mutations in the SPINK5 gene resulting in a lack of the serine protease inhibitor LEKTI and a dysregulation of epidermal proteolysis. So far, no effective therapy is available. Chronic inflammation of the skin is a major clinical problem and thus NS is an excellent target for treatment approaches using topical immunomodulators. In the past, patients with NS have been treated successfully with tacrolimus, but significant absorption due to the impaired epidermal barrier prevents widespread application of this drug in NS. We describe a boy with NS who was successfully treated with pimecrolimus cream 1% without serious side-effects and without developing significant systemic absorption of pimecrolimus over a period of 3 months. In August 2000, a 10-year-old boy with severely inflamed skin was referred as an emergency patient to the dermatology department. He was the second child of healthy nonconsanguineous parents of Bosnian origin. His general state of health was reduced. Except for a generalized redness and scaling of the skin resembling scalded skin, the perinatal ⁄neonatal period had been without complications. Episodic flares of erythroderma were accompanied by severe pruritus and scaling and were resistant to various therapeutic agents such as corticosteroids, antihistamines, urea and tar ointments. Furthermore, in infancy he developed allergic rhinitis and grew poorly. Bone age analysis revealed a retardation of 1 year. His skin changes had previously been considered as atopic dermatitis. When first seen by us, physical examination revealed erythema with fine ichthyotic scales over the entire body with additional polycyclic scaling and erythematous plaques bordered by double-edged scales. These skin lesions were consistent with the morphological signs of CIE and superimposing ILC. The hair was rough. Blood tests showed IgE levels of > 2000 IU mL (normal < 100), specific IgE antibodies to several aeroallergens, eosinophils 12Æ9% (normal 1–6%) and eosinophil cationic protein 74 lg L (normal < 24). Culture from dermal swaps was positive for Staphylococcus aureus + enterotoxin C. Microscopic hair analysis revealed trichorrhexis invaginata. Hence we established the diagnosis of NS complicated by S. aureus superinfection. Systemic flucloxacillin and the use of topical antiseptic agents gave rapid resolution of infected areas. Treatment at home was continued with calcipotriol 0Æ05 mg, urea 10% cream and mild skin barrier-maintaining products. However, it was not possible to reduce the number of flares of erythroderma in the following 21⁄2 years despite using a broad arsenal of topical and systemic drugs including corticosteroids. In January 2002, marked clinical improvement was produced by a 3-week topical treatment of ~ 18% body surface area (BSA) with tacrolimus 0Æ03%, but the treatment was discontinued because systemic tacrolimus levels increased from <1Æ5 to 2Æ5 ng mL (systemic adverse effects have been reported in organ transplant recipients at ‡ 5 ng mL). In March 2003, we successfully started treatment with pimecrolimus cream 1% applied twice daily on 99% BSA in combination with bland ointments (Fig. 1). Within 4 weeks the Netherton Area and Severity Assessment (NASA) score was reduced to ~ 75% of the initial value and was maintained for 3 months. This score, requiring validation in further studies, was developed as an equivalent to the Eczema Area and Severity Index (EASI) score for atopic dermatitis, replacing the symptom ‘excoriation’ (EASI) by the symptom ‘scaling’ (NASA). The blood pimecrolimus concentration was assessed on five different occasions in the course of 3 months, and always remained below 2Æ4 ng mL. There was no difference in blood levels before and 1–2 h after application. No systemic adverse effects were reported in patients with psoriasis with blood pimecrolimus levels of 10–15 ng mL. In October 2003 the pimecrolimus 1% cream was still well tolerated. Flares of erythroderma were reduced. Pimecrolimus cream 1% is steroid-free and has immunomodulating properties similar to tacrolimus, but exhibits a different lipophilicity distribution, providing an effective and safe treatment for inflammatory skin diseases. Generally, in NS the risk of systemic exposure from percutaneous drug absorption due to the impaired epidermal barrier is of serious concern. However, this clinical case demonstrates that treatment of 99% BSA with pimecrolimus does not result in an increase in blood levels of pimecrolimus. Therefore, we propose pimecrolimus cream 1% as a new anti-inflammatory treatment in patients with NS. Further clinical studies are necessary in order

Expanding the keratin mutation database: novel and recurrent mutations and genotype–phenotype correlations in 28 patients with epidermolytic ichthyosis

Background  Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes. In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation. The presence of palmoplantar keratoderma suggests KRT1 mutations, whereas KRT10 mutations in most instances give rise to the nonpalmoplantar variants.

Palmoplantar Pustular Psoriasis Is Associated with Missense Variants in CARD14, but Not with Loss-of-Function Mutations in IL36RN in European Patients

Cite this article as: Rotraut Mössner, Yvonne Frambach, Dagmar WilsmannTheis, Sabine Löhr, Arnd Jacobi, Ansgar Weyergraf, Michael Müller, Sandra Philipp, Regina Renner, Heiko Traupe, Harald Burkhardt, Külli Kingo, Sulev Kõks, Steffen Uebe, Michael Sticherling, Heinrich Sticht, Vinzenz Oji, Ulrike Hüffmeier, Palmoplantar Pustular Psoriasis is Associated with Missense Variants in CARD14, but not with loSs-of-Function Mutations in IL36RN in European Patients, Journal of Investigative Dermatology accepted article preview 19 May 2015; doi: 10.1038/jid.2015.186.

Acral Peeling Skin Syndrome with TGM5 Gene Mutations May Resemble Epidermolysis Bullosa Simplex in Young Individuals

TO THE EDITOR The acral peeling skin syndrome (APSS) is a rare autosomal recessive condition characterized by superficial painless peeling of the skin predominantly on the dorsal aspects of hands and feet (Shwayder et al., 1997; Cassidy et al., 2005). The condition is usually aggravated by heat, humidity, and exposure to water. Microscopically, the cleavage level is located in the upper epidermis, between the stratum granulosum and the stratum corneum (Garcia et al., 2005). Only 15 patients with APSS have been reported since 1997 (Shwayder et al., 1997; Brusasco et al., 1998; Hashimoto et al., 2000; Cassidy et al., 2005; Garcia et al., 2005; Kharfi et al., 2009; Oumakhir et al., 2009; Wakade et al., 2009) (Table 1). In several of them, in addition to superficial peeling, acral blisters were also described (Wakade et al., 2009). The genetic basis of the disease was determined in only three families, in whom two different missense mutations in the TGM5 gene encoding transglutaminase 5 (TGase 5) were disclosed (Table 1) (Cassidy et al., 2005; Kharfi et al., 2009). It remains unclear whether the other patients have mutations in the same gene, or whether APSS is clinically and genetically heterogeneous (Cassidy et al., 2005). In this study, we investigated nine unrelated patients, eight children and one adult, clinically suspected to have epidermolysis bullosa simplex (EBS) because of acral skin blistering. The patients and/or diagnostic samples were referred to the Epidermolysis bullosa Center of the University Medical Center Freiburg (Volz et al., 2007) for molecular diagnostics of EBS. EDTA-blood and skin samples were obtained after informed consent of the patients and, if available, of family members. EDTAblood samples of 50 clinically unaffected Central European individuals were used as controls. The study was conducted according to the Declaration of Helsinki Principles. Immunofluorescence staining of skin cryosections was performed using a panel of antibodies to components of the epidermal basement membrane zone (Kern et al., 2006), as well as antibodies to loricrin (Abcam, Cambridge, UK), filaggrin (clone 15C10; Novocastra, Newcastle, UK), involucrin (clone SY5; Sigma, Taufkirchen, Germany), cytokeratin 10 (clone DE-K10; Dako, Glostrup, Denmark), TGase 1 (clone B.C1; Biomedical Technologies, Madrid Spain), TGase 3 (Jackson Immunoresearch Laboratories, West Grove, PA), and TGase 5 (Novus Biologicals, Littleton, CO). Genomic DNA was extracted from EDTA-blood using the QiAmp DNA mini kit (Qiagen, Hilden, Germany). Amplification of all KRT5 (NC_000012.11, National Center for Biotechnology Information (NCBI)), KRT14 (NC_000017.10, NCBI), and TGM5 (NC_000015.9, NCBI) exons and exon–intron boundaries, and sequencing were performed as described (Schuilenga-Hut et al., 2003; Wood et al., 2003; Cassidy et al., 2005). Mutations were confirmed by resequencing. The mutation c.763T4C was verified in 100 control chromosomes by Abbreviations: APSS, acral peeling skin syndrome; EBS, epidermolysis bullosa simplex; TGase, transglutaminase