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Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity.Epidemiological data from different countries have been published, but none are available from Germany.In this population-based cross-sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories and patient organization.Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries.Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision-making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.

ImportanceUncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far.ObjectiveTo elucidate the genetic spectrum of UHS.Design, Setting, and ParticipantsThis cohort study includes 107 unrelated index patients with a suspected diagnosis of UHS and family members who were recruited worldwide from January 2013 to December 2021. Participants of all ages, races, and ethnicities were recruited at referral centers or were enrolled on their own initiative following personal contact with the authors. Genetic analyses were conducted in Germany from January 2014 to December 2021.Main Outcomes and MeasuresClinical photographs, Sanger or whole-exome sequencing and array-based genotyping of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling. Descriptive statistics, such as frequency counts, were used to describe the distribution of identified pathogenic variants and genotypes.ResultsThe genetic characteristics of patients with UHS were established in 80 of 107 (74.8%) index patients (82 [76.6%] female) who carried biallelic pathogenic variants in PADI3, TGM3, or TCHH (ie, genes that encode functionally related hair shaft proteins). Molecular genetic findings from 11 of these 80 individuals were previously published. In 76 (71.0%) individuals, the UHS phenotype were associated with pathogenic variants in PADI3. The 2 most commonly observed PADI3 variants account for 73 (48.0%) and 57 (37.5%) of the 152 variant PADI3 alleles in total, respectively. Two individuals carried pathogenic variants in TGM3, and 2 others carried pathogenic variants in TCHH. Haplotype analyses suggested a founder effect for the 4 most commonly observed pathogenic variants in the PADI3 gene.Conclusions and RelevanceThis cohort study extends and gives an overview of the genetic variant spectrum of UHS based on molecular genetic analyses of the largest worldwide collective of affected individuals, to our knowledge. Formerly, a diagnosis of UHS could only be made by physical examination of the patient and confirmed by microscopical examination of the hair shaft. The discovery of pathogenic variants in PADI3, TCHH, and TGM3 may open a new avenue for clinicians and affected individuals by introducing molecular diagnostics for UHS.

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.

We evaluated the presence of tight junction (TJ) remnants in the stratum corneum (SC) of in vitro reconstructed human epidermis and human skin explants subjected or not to an aggressive topical treatment with beta-lipohydroxy salicylic acid (LSA) for 24 h. LSA-treated samples showed an increased presence of TJ remnants in the two lowermost layers of the SC, as quantified with standard electron microscopy. The topical aggression-induced overexpression of TJ-like cell–cell envelope fusions may influence SC functions: (1) directly, through an enhanced cohesion, and (2) indirectly, by impeding accessibility of peripheral corneodesmosomes to extracellular hydrolytic enzymes and, thus, slowing down desquamation. Observations of ichthyotic epidermis in peeling skin disease (PSD; corneodesmosin deficiency; two cases) and ichthyosis hypotrichosis sclerosing cholangitis syndrome (IHSC/NISCH; absence of claudin-1; two cases) also demonstrated increased persistence of TJ-like intercellular fusions in pathological SC and contributed to the interpretation of the diseases’ pathological mechanisms.

BACKGROUND Peeling skin syndrome type 1 (PSS1) is a rare and severe autosomal recessive form of congenital ichthyosis. Patients are affected by pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin. The disease is caused by nonsense mutations or complete deletion of the CDSN gene encoding for corneodesmosin (CDSN). PSS1 severely impairs quality of life and therapeutic approaches are totally unsatisfactory. OBJECTIVES The objective of this study was to develop the first steps towards a specific protein replacement therapy for CDSN deficiency. Using this approach, we aimed to restore the lack of CDSN and improve cell-cell cohesion in the transition area of the stratum granulosum (SG) to the stratum corneum. METHODS Human CDSN was recombinantly expressed in Escherichia coli. A liposome-based carrier system, prepared with a cationic lipopeptide to mediate the transport to the outer membrane of keratinocytes, was developed. This formulation was chosen for CDSN delivery into the skin. The liposomal carrier system was characterized with respect to size, stability and toxicity. Furthermore, the interaction with primary keratinocytes and human epidermal equivalents was investigated. RESULTS The liposomes showed an accumulation at the membranes of keratinocytes. CDSN-deficient epidermal equivalents that were treated with liposomal encapsulated CDSN demonstrated presence of CDSN in the SG. Finally, the penetration assay and histological examinations revealed an improved epidermal integrity for CDSN-deficient epidermal equivalents, if they were treated with liposomal encapsulated CDSN. CONCLUSIONS This study presents the first preclinical in vitro experiments for a future specific protein replacement therapy for patients affected by PSS1.

Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa‐Like Domain‐Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. One patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype–phenotype correlations.

These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert-based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis.What's already known about this topic?Various symptomatic treatment options exist for congenital ichthyoses, but there are no European guidelines.What does this study add?These European guidelines for the management of congenital ichthyosis may help to improve outcomes and quality of life for patients.Linked Comment: Akiyama. Br J Dermatol 2019; 180:449-450. Plain language summary available online

The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: TGM1, ALOX12B, ALOXE3, NIPAL4, CYP4F22, ABCA12, PNPLA1, CERS3, SDR9C7, and SULT2B1. The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype, most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3. We investigated the spectrum of mutations in ALOX12B and ALOXE3 in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations.

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%–41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E−08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E−09); this effect was stronger when including IL36RN mutations (1.48E−13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP’s pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.

is missing (Short communication)

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare disorders of keratinization characterized by generalized abnormal scaling of the skin. Ten genes are currently known to be associated with ARCI: TGM1, ALOXE3, ALOX12B, NIPAL4 (ICHTHYIN), ABCA12, CYP4F22, PNPLA1, CERS3, SDR9C7, and SULT2B1. Over a period of 22 years, we have studied a large patient cohort from 770 families with a clinical diagnosis of ARCI. Since the first report that mutations in the gene CYP4F22 are causative for ARCI in 2006, we have identified 54 families with pathogenic mutations in CYP4F22 including 23 previously unreported mutations. In this report, we provide an up-to-date overview of all published and novel CYP4F22 mutations and point out possible mutation hot spots. We discuss the molecular and clinical findings, the genotype-phenotype correlations and consequences on genetic testing.

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Background Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous group of rare Mendelian skin disorders characterized by cornification and differentiation defects of keratinocytes. Mutations in nine genes including PNPLA1 are known to cause non-syndromic forms of ARCI. To date, only ten distinct pathogenic mutations in PNPLA1 have been reported. Objectives To identify new causative PNPLA1 mutations, we screened genetically unresolved cases including our ARCI collection comprising more than 700 families. Here, we report on 16 novel mutations present in patients from 17 families. Methods The screening for mutations was performed either by direct Sanger sequencing or in combination with a multi gene panel, followed by sequence and mutation analysis. Results While all previously reported mutations and most of our novel mutations are located within the core patatin domain, here we report on five novel PNPLA1 mutations, which are downstream of this domain. Thus, as recently described for PNPLA2, we hypothesize that a region larger than core domain is required for full enzymatic activity of PNPLA1 in human skin barrier formation. Conclusions We estimate the frequency of PNPLA1 mutations amongst ARCI patients to around 3%. Most of our patients were born as collodion babies and showed a relatively mild ichthyosis phenotype. In four unrelated patients we observed a cyclic scaling course, which seems to be a potential phenotype variation in a small percentage of patients with PNPLA1 mutations. The variability of the clinical manifestations as well as the lack of typical clinical features are specific for patients with PNPLA1 mutations, and emphasize the importance of DNA sequencing for differential diagnosis of ARCIs. This article is protected by copyright. All rights reserved.

The impact of steroid sulfatase (STS) activity in the circulating levels of both sulfated and unconjugated steroids is only partially known. In addition, the sulfated steroid pathway, a parallel pathway to the one for unconjugated steroids, which uses the same enzymes, has never been characterized in detail before. Patients with steroid sulfatase deficiency (STSD) are unable to enzymatically convert sulfated steroids into their unconjugated forms, and are a good model to elucidate how STS affects steroid biosynthesis and to study the metabolism of sulfated steroids. We quantified unconjugated and sulfated steroids in STSD serum, and compared these results with data obtained from serum of healthy controls. Most sulfated steroids were increased in STSD. However, androstenediol-3-sulfate and epiandrosterone sulfate showed similar levels in both groups, and the concentrations of androsterone sulfate were notably lower. Hydroxylated forms of DHEAS and of pregnenolone sulfate were found to be increased in STSD, suggesting a mechanism to improve the excretion of sulfated steroids. STSD testosterone concentrations were normal, but cholesterol and DHEA were significantly decreased. Additionally, serum bile acids were three-fold higher in STSD. Correlations between concentrations of steroids in each group indicate that 17α-hydroxy-pregnenolone-3-sulfate in men is mainly biosynthesized from the precursor pregnenolone sulfate and androstenediol-3-sulfate from DHEAS. These findings confirm the coexistence of two steroidogenic pathways: one for unconjugated steroids and another one for sulfated steroids. Each pathway is responsible for the synthesis of specific steroids. The equal levels of testosterone, and the reduced level of unconjugated precursors in STSD, support that testosterone is primarily synthesized from sulfated steroids. In consequence, testosterone synthesis in STSD relies on an enzyme with sulfatase activity other than STS. This study reveals that STS is a key player of steroid biosynthesis regulating the availability of circulating cholesterol.

X-linked ichthyosis (XLI) is a keratinization disorder caused by deficient activity of steroidsulfatase. In contrast, ichthyosis vulgaris is due to semidominant mutations of the filaggrin gene ( FLG ). In view of phenotypic variations of these ichthyoses we speculated that XLI may be influenced by additional FLG mutations in a significant number of patients. We characterized a group of 51 patients with XLI and systematically analyzed them for additional FLG mutations (R501X, 2282del4, R2447X, S3247X). The study was complemented by morphological analyses. Full FLG sequencing for rare mutations was performed in special cases. Interestingly, prevalence of FLG mutations was significantly increased compared to a population-based control cohort of 1,377 individuals (17.6% vs. 8.4%, p=0.038). Palmoplantar hyperlinearity was significantly associated with the FLG mutation status. Ichthyosis severity score seemed to be increased in XLI with FLG mutations, but the difference was not significant (p=0.124). To our surprise, percentages of atopic manifestations were highly prevalent in both subgroups, 40% and 33% in XLI without and with filaggrin deficiency, respectively. Of note, reduction of filaggrin staining or keratohyalin could not be explained by FLG mutations in all patients. However, we conclude that FLG mutations represent a significant genetic modifier of XLI. [196 words]

Ichthyoses comprise a heterogeneous group of hereditary disorders of keratinization characterized by a highly varied clinical picture. A distinction is made between common hereditary ichthyoses (ichthyosis vulgaris and X-linked ichthyosis), which usually manifest themselves in the first year of life, and rare, sometimes severe congenital ichthyoses. Patients with very mild symptoms often do not even realize they have ichthyosis. The diagnosis is usually based on clinical evaluation. Molecular genetic testing as well as histological and electron microscopic studies may aid in confirming the diagnosis. Mapping a family tree is also diagnostically useful. Besides skin manifestations, important aspects of the clinical examination and history include disease onset, presence of a collodion membrane at birth as well as the presence of hair anomalies and extracutaneous signs and symptoms. Rigorous hydration of the skin (several times a day) and balneotherapy are the mainstay of ichthyosis treatment. For patients with severe disease, systemic acitretin treatment should be considered on a case-by-case basis. While ichthyoses are generally limited to the skin, there are syndromic forms that may affect other organs and that require interdisciplinarity cooperation. Although ichthyoses remain incurable, they can be managed well with symptomatic treatment. However, such treatment is frequently time consuming and expensive. In the future, novel therapeutic approaches might include enzyme replacement and gene therapies as well as antiinflammatory drugs.

The proteinase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), which forms part of the caspase recruitment domain-containing protein 11-B-cell lymphoma 10-MALT1 signalosome complex, plays a direct role in nuclear factor kappa B activation. Here, we describe the case of a female infant with severe immune dysregulation leading to recurrent systemic infections, failure to thrive and severe crises of ichthyosiform erythroderma with high levels of serum IgE. Hence, initial symptoms indicated Netherton syndrome or Omenn syndrome. Surprisingly, sequence analyses of SPINK5 and RAG1/RAG2, respectively, excluded these diseases. During the hospital stay the patient's health deteriorated, despite intensive care therapy, and she died. In order to delineate the diagnosis, whole-exome sequencing was performed. Two compound heterozygous mutations in MALT1 were found and verified by Sanger sequencing (exon 2 c.245T>C, exon 2 c.310dup), which led to a MALT1 deficiency at the protein level. Based on these results, an immunological analysis was performed, as was immunofluorescence staining of key skin proteins, to confirm a diagnosis of MALT1 deficiency. This case report provides a closer description of the clinical and histological skin phenotype of MALT1 deficiency, and we conclude that MALT1 deficiency must be considered a possible differential diagnosis of Netherton and Omenn syndromes. What's already known about this topic? Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) deficiency is a combined immunodeficiency. MALT1 is part of the caspase recruitment domain-containing protein 11-B-cell lymphoma 10-MALT1 signalosome complex, which is essential for nuclear factor kappa B activation. Current publications describe a phenotype of recurrent systemic infections; only in a few cases has an inflammatory involvement of the integument been described. What does this study add? A closer description of the cutaneous phenotype of MALT1 deficiency in a patient with two novel MALT1 mutations. Immune mapping of follicular epidermis shows lympho-epithelial Kazal-type-related inhibitor is reduced in MALT1 deficiency and absent on interfollicular staining. Clinically, MALT1 deficiency mimics Netherton syndrome and Omenn syndrome, and should be considered a differential diagnosis.

Background Transglutaminase (TG)1 plays a key role in the formation of the cornified envelope and thus in the maintenance of the epidermal barrier. Patients with Netherton syndrome (LEKTI deficiency) have increased activity of both TG1 and serin proteases. Objectives To determine whether there is a functional biochemical link between TG1 and LEKTI and whether LEKTI domains could possibly serve as substrates for TG1. Methods We analysed the protein sequence of LEKTI for possible TG1 recognition sites using bioinformatics. Synthetic peptides and recombinant LEKTI domains D6, D7 and D8+9 were examined in vitro and in situ for possible substrate specificity. The recombinant LEKTI domains were studied for inhibitory activity in a kallikrein (KLK)5 activity test. Results We identified possible TG1 consensus sequences in LEKTI domains D6, D7 and D8+9, pointing to a novel biological link between these two proteins. Indeed, synthesized short peptides from these consensus sequences were incorporated into the TG1 activity zone of the epidermis. In vitro the entire recombinant domains of LEKTI showed substrate specificity for TG1, which was again confirmed in situ. The inhibitory activity of the recombinant LEKTI domains was confirmed by a KLK5 inhibition test. The strongest inhibition was observed for domains D8+9. Conclusions There are specific domains of LEKTI that are recognized and processed by TG1. LEKTI domains D6, D7 and D8+9 contribute to the formation and protection of the cornified envelope. These results impact the development of protein replacement therapy approaches for Netherton syndrome. What's already known about this topic? LEKTI and transglutaminase (TG)1 are key proteins involved in the terminal differentiation of the epidermis. Lack of LEKTI causes Netherton syndrome; TG1 deficiency causes lamellar ichthyosis. The serine protease inhibitor LEKTI is processed into different functional units. Among different target proteases, kallikrein (KLK)5 appears to be a key player in disease pathology. It has been demonstrated that LEKTI domain 6 inhibits KLK5 and KLK7; LEKTI domains 8-11 also inhibit KLK14. What does this study add? The single LEKTI domains 6, 7 and the functional unit of domains 8 and 9 contain recognition motifs for TG1. We show that these domains and unit are crosslinked into the epidermis by TG1. Functional analyses of the recombinant LEKTI domains revealed that LEKTI D8+9 has the strongest inhibitory effect on KLK5. What is the translational message? The novel functional link between LEKTI and TG1 should be taken into account when considering the development of a targeted topical protein therapy for Netherton syndrome. The unit of domains D8+9 may be sufficient for this purpose.

Bathing suit ichthyosis (BSI) is a rare variant of autosomal recessive congenital ichthyosis (ARCI) due to transglutaminase-1 gene (TGM1) mutations leading to a temperature sensitive phenotype. It is characterized by dark-grey or brownish scaling restricted to the “bathing suit” areas. We report two Indian girls with bathing suit ichthyosis and mutations in TGM1 (patient 1: homozygous for c.1147G>A; patient 2: compound heterozygous for c.832G>A, c.919C>G).

Data on vitamin D status of patients with inherited ichthyosis in Europe is scarce and unspecific concerning the genetic subtype. This study determined serum levels of 25-hydroxyvitamin D3 (25(OH)D3) in 87 patients with ichthyosis; 69 patients were additionally analysed for parathyroid hormone. Vitamin D deficiency was pronounced in keratinopathic ichthyosis (n = 17; median 25(OH)D3: 10.5 ng/ml), harlequin ichthyosis (n = 2;7.0 ng/ml) and rare syndromic subtypes (n = 3; 7.0 ng/ml). Vitamin D levels were reduced in TG1-proficient lamellar ichthyosis (n = 15; 8.9 ng/ml), TG1-deficient lamellar ichthyosis (n = 12; 11.7 ng/ml), congenital ichthyosiform erythroderma (n = 13; 12.4 ng/ml), Netherton syndrome (n = 7; 10.7 ng/ml) and X-linked ichthyosis (n = 8; 13.9 ng/ml). In ichthyosis vulgaris 25(OH)D3 levels were higher (n = 10; 19.7 ng/ml). Parathyroid hormone was elevated in 12 patients. Low 25(OH)D3 levels were associated with high severity of scaling (p = 0.03) implicating scaling as a risk factor for vitamin D deficiency. Thus, this study supports our recent guidelines for ichthyoses, which recommend screening for and substituting of vitamin D deficiency., This study was supported by the Selbsthilfe Ichthyose e.V., the Medical Faculty of the University of Münster (OJI120817 & OJ111409) and of the German Research Foundation (DFG OJ 53/3-1). It is part of the medical thesis of Mi-Ran Kim. The work was supported by the Selbsthilfe Ichthyose e.V., the Medical Faculty of the University of Muenster (OJI120817 & OJ111409) and by the German Research Foundation (DFG OJ 53/3-1). Furthermore, we cooperated with members of the European Reference Network (ERN, subgroup ERN-skin). The cohort of this paper was also part of a project funded by the programme “Innovative Medizinische Forschung” (IMF); project number: SÜ212007.

Introduction Le syndrome de Dorfman-Chanarin (DC) est une forme rare d’ichtyose syndromique autosomique recessive du a des mutations du gene ABHD5, responsables d’une accumulation de lipides dans plusieurs organes. Il n’existe dans la litterature que 3 petites series (3, 6 et 15 cas) sans suivi, et tres peu de donnees sur la tolerance de l’acitretine. Nous rapportons une serie de 21 patients avec suivi prolonge. Materiel et methodes Il s’agit d’une etude retrospective realisee en conformite avec la reglementation (engagement MR004), avec le reseau national et europeen ERN-Skin. Etaient inclus tous les patients presentant un syndrome de DC confirme sur le plan moleculaire. Resultats Un total de 21 patients (P) etaient inclus : 10 femmes et 11 hommes, âge median au diagnostic : 4 ans. L’evaluation etait realisee a un âge median de 18 ans (3–58). La mediane de suivi etait de 6 ans (1–23). Concernant les signes cutanes, ils etaient presents a la naissance pour 19P, incluant 3 cas de bebe collodion. L’ichtyose etait moderee a severe (16P), sous la forme de squames fines (16P) et blanches (9P), erytheme leger a modere (17P), hyperkeratose legere a moderee (12P), prurit modere a severe (7P), ectropion (10P). Concernant les anomalies extra cutanees : atteinte hepatique (hepatomegalie et cytolyse (mediane a 2 N (2–7)) chez 14P/18. Sept avaient un suivi hepatique > 5 ans : aggravation chez 2P, stabilite ou amelioration chez 3P. Atteinte musculaire clinique chez 2P/21, CPK augmentees chez 14P/16 (mediane : 2 N (1–6)), anomalies ophtalmologiques pour 8P/19 et anomalies neurologiques chez 4P/19. Sur le plan therapeutique, 6P ont recu de l’acitretine (dose maximale mediane 0,35 mg/kg/j (0,3–1), duree mediane 9 ans (1–12)). Bonne tolerance clinique, stabilite du bilan hepatique sauf pour 1P (aggravation de la cytolyse). L’analyse moleculaire du gene ABHD5 montrait 12 mutations (9 a l’etat homozygote, 3 heterozygote composites) dont 5 nouvelles : 2 mutations entrainant un decalage du cadre de lecture, 1 mutation au niveau d’un site d’epissage et 2 larges deletions emportant l’exon 1 ou 4. Discussion Notre serie est la 1re europeenne, comporte le plus grand nombre de patients et un suivi prolonge. Le phenotype cutane est comparable a celui rapporte dans la litterature. L’incidence des complications est comparable sauf les complications neurologiques qui sont moins frequentes. Sur le plan hepatique, l’evolution est favorable avec le plus souvent une stabilite voire une amelioration. Le traitement oral par retinoides est souvent juge contre-indique par l’atteinte hepatique (seuls 4 patients ont ete traites par acitretine dans la litterature), avec un suivi limite. Notre etude montre que l’acitretine semble presenter un bon rapport benefice/risque. Nous rapportons egalement 5 nouvelles mutations. Conclusion Nous apportons des donnees nouvelles utiles pour la prise en charge des patients avec un DC.

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Steroids are primarily present in human fluids in their sulfated forms. Profiling of these compounds is important from both diagnostic and physiological points of view. Here, we present a novel method for the quantification of 11 intact steroid sulfates in human serum by LC-MS/MS. The compounds analyzed in our method, some of which are quantified for the first time in blood, include cholesterol sulfate, pregnenolone sulfate, 17-hydroxy-pregnenolone sulfate, 16-α-hydroxy-dehydroepiandrosterone sulfate, dehydroepiandrosterone sulfate, androstenediol sulfate, androsterone sulfate, epiandrosterone sulfate, testosterone sulfate, epitestosterone sulfate, and dihydrotestosterone sulfate. The assay was conceived to quantify sulfated steroids in a broad range of concentrations, requiring only 300 μl of serum. The method has been validated and its performance was studied at three quality controls, selected for each compound according to its physiological concentration. The assay showed good linearity (R2 > 0.99) and recovery for all the compounds, with limits of quantification ranging between 1 and 80 ng/ml. Averaged intra-day and between-day precisions (coefficient of variation) and accuracies (relative errors) were below 10%. The method has been successfully applied to study the sulfated steroidome in diseases such as steroid sulfatase deficiency, proving its diagnostic value. This is, to our best knowledge, the most comprehensive method available for the quantification of sulfated steroids in human blood.

Neonatologen und Kinderarzte benotigen ein Basiswissen uber das Bild der zwei haufigsten Ichthyosen, um seltene kongenitale Formen abzugrenzen. Dieser Artikel wird Ihnen dabei helfen, die beiden Formen zu unterscheiden und therapeutische Kniffe anzuwenden.

Steroid sulfatase (STS) deficiency is the underlying cause of the skin condition known as recessive X-linked ichthyosis (RXLI). RXLI patients show scales on their skin caused by high concentrations of cholesterol sulfate (CS), as they are not capable of releasing the sulfate group from its structure to obtain free cholesterol. CS has been reported, so far, as the sole sulfated steroid with increased concentrations in the blood of RXLI patients. A non-targeted LC-MS approach in negative mode detection (LC-MS precursor ion scan mode) was applied to serum samples of 12 RXLI patients and 19 healthy males. We found that CS was not the only sulfated compound consistently elevated in RXLI patients, because a group of compounds with a m/z of 481 was found in high concentrations too. Further LC-MS/MS demonstrated that the main contributor to the m/z 481 signal in RXLI serum is 27-hydroxycholesterol-3-sulfate (27OHC3S). Accordingly, a new method for 27OHC3S quantification in the context of RXLI has been developed and validated. Other hydroxycholesterol sulfate compounds were elevated as well in RXLI patients.