Developing a protocol to identify and prioritize research questions for psoriasis: a James Lind Alliance Priority Setting Partnership

Psoriasis is a common condition that affects over two million people in the UK and causes red, flaky patches of skin which can sometimes feel sore or itchy. People with psoriasis can be affected by their disease physically, emotionally and socially. There are many unanswered questions about psoriasis. To find out what the most important questions are, a Psoriasis Priority Setting Partnership PSP is being carried out now. The PSP involves patients, families, carers and healthcare professionals working together to follow a process outlined by the James Lind Alliance. The first step is for all groups with an interest in psoriasis to complete a survey about what they think the important research questions are. Survey responses are then checked against existing evidence. Questions raised in the surveys, but which have already previously been answered, will be shared with relevant organisations who may consider how this information can be better shared with clinicians, patients and their families. Questions raised in the surveys, which have not already been answered will be compiled into a list. This list will be sent round to stakeholders in a second survey where they will be ordered by importance. At a final workshop, a ‘top ten’ list of unanswered questions will be agreed by patients, their carers and health professionals. This ‘top ten’ list will be shared widely with psoriasis researchers and funders, to encourage research that focuses on tackling the key issues which really matter to patients, families, carers and healthcare professionals.     

Autosomal-dominant lamellar ichthyosis: Ultrastructural characteristics of a new type of congenital ichthyosis

Summary Recently, autosomal-dominant lamellar ichthyosis (ADLI) has been shown to be a new genetic trait with clinical and histologic features similar to those of autosomal-recessive lamellar ichthyosis. In two patients affected with ADLI, the malpighian keratinocytes showed ultrastructural signs of increased cellular metabolism. The tonofilaments and keratohyaline granules were regular in structure and number. However, as a distinctive ultrastructural feature, a prominent transforming zone was found between the granular and horny layers. Moreover, a normal keratin pattern and only a limited number of lipid inclusions were observed in the stratum corneum. Thus, ADLI can be distinguished from the autosomal-recessive forms of lamellar ichthyosis, permitting a correct diagnosis when genetic counselling has to be given in sporadic cases.     

The clinical spectrum of congenital ichthyosis in Sweden: a review of 127 cases

Congenital ichthyosis comprises a rare group of usually monogenetic diseases that present at birth as a collodion phenotype or as variable degrees of ichtHyosiform erythroderma, with or without superficial blisters. Depending on which gene mutation causes the disease, the skin problems later in life may range from a severe lamellar or bullous ichthyosis to mild or only focally expressed hyperkeratotic lesions. It is obviously important, but sometimes painstakingly difficult, to make a correct diagnosis already in infancy. Fortunately, recent advances in our understanding of the molecular genetics of ichthyosis have led to several new diagnostic tools that are continuously being updated. Based on this development, and on our own 5 years of experience in a national genodermatosis centre, we describe 127 cases of congenital ichthyosis examined in childhood or adulthood. Applying a combination of phenotypic and genotypic criteria, the patients were classified into three main groups: 1) Bullous ichthyosis (epidermolytic hyperkeratosis) and related disorders due to keratin mutations (n = 21); 2) Non-bullous ichthyosiform erythroderma and lamellar ichthyosis mainly due to transglutaminase 1 mutations (n = 80); 3) Syndromic ichthyosis, i.e. systemic (multi-organ) diseases due to many different causes (n = 26). Each group could be further stratified into 4-11 entities using mutation analysis, electron microscopy of epidermis and various other techniques. Our findings are discussed in relation to recent data in the literature emphasizing the clinical usefulness of various diagnostic procedures for ichthyosis.     

Rapid detection of homozygous mutations in congenital recessive ichthyosis

Congenital recessive ichthyoses (CRI) form a remarkably heterogeneous group of diseases, resulting from mutations in at least eight distinct genes, six of which have been identified so far. In the present study we ascertained two CRI families of Iranian and Druze origins. Exploiting the high degree of consanguinity characterizing these populations, we typed all family members for microsatellite markers spanning the major CRI chromosomal loci and used homozygosity mapping to identify candidate genes for subsequent mutational analysis. This strategy led to the rapid identification of two novel homozygous CRI-causing mutations in TGM1 (c.2058delC) and FLJ39501 (p.W521X). The present data demonstrate that the molecular analyses of CRI in consanguineous families can be readily completed in less than 96 h at relatively low costs.     

Recurrent terbinafine resistant Trichophyton rubrum infection in a child with congenital ichthyosis

Dermatophytosis in children caused by Trichophyton rubrum is preferably treated with topical or systemic terbinafine. We report the first case of terbinafine resistance in a child with recurrent T. rubrum dermatophytosis and congenital ichthyosiform erythroderma.     

The Eczema Priority Setting Partnership: a collaboration between patients,carers, clinicians and researchers to identify and prioritize important research questions for the treatment of eczema

Background Eczema is a common condition, yet there are uncertainties regarding many frequently used treatments. Knowing which of these uncertainties matter to patients and clinicians is important, because they are likely to have different priorities from those of researchers and funders. Objectives To identify the uncertainties in eczema treatment that are important to patients who have eczema, their carers and the healthcare professionals (HCPs) who treat them. Methods An eczema Priority Setting Partnership was established, including patients, HCPs and researchers. Eczema treatment uncertainties were gathered from patients and clinicians, and then prioritized in a transparent process, using a methodology advocated by the James Lind Alliance. Results In the consultation stage 493 participants (including 341 patients/carers) made 1070 submissions, of which 718 were uncertainties relating to the treatment of eczema. Treatment uncertainties with more than one submission were grouped into 52 ‘indicative uncertainties’, which were then ranked by 514 participants (including 399 patients/carers). The top 14 treatment uncertainties were prioritized for research. The first four were common to patients/carers and HCPs (shared uncertainties): (i) the best and safest way of using topical steroids (including frequency of application, potency, length of time, alternation with other topical treatments and age limits); (ii) the long‐term safety of topical steroids; (iii) the role of food allergy tests; and (iv) the most effective and safe emollients in treating eczema. The remaining 10 of the top 14 uncertainties comprised the next five highest ranked uncertainties for patients and the next five highest ranked uncertainties for HCPs. At a workshop involving 40 participants (patients, HCPs and researchers), shared uncertainties were formulated into possible research questions. Conclusions The top 14 treatment uncertainties around the treatment of eczema provide guidance for researchers and funding bodies to ensure that future research answers questions that are important to both clinicians and patients.     

The sound of silence: autosomal recessive congenital ichthyosis caused by a synonymous mutation in ABCA12

Autosomal recessive congenital ichthyosis refers to a heterogeneous group of cornification disorders of major impact on patients’ life. The disease has been linked so far to mutations in 8 distinct genes. We report a consanguineous family of Arab Muslim origin with several members displaying a severe form of congenital ichthyosiform erythroderma. Using a panel of polymorphic microsatellite markers, we identified a region of homozygosity shared by all patients on 2q34, in a region harbouring the ABCA12 gene. Direct sequencing of genomic DNA derived from a patient failed to reveal any obviously pathogenic change in the coding sequence of this gene. In contrast, cDNA sequence analysis revealed the existence of a 163‐bp‐long deletion in exon 24, thus pointing to a splicing defect. Careful reanalysis of the genomic DNA sequence revealed apart from several known single‐nucleotide polymorphisms, a hitherto unreported homozygous synonymous mutation in exon 24 (c.3456G>A; p.S1152S), which was found to lead to the formation of a novel splicing acceptor site. Synonymous mutations have been shown to uncommonly cause inherited disorders in humans. Here, we present the first example of a congenital form of ichthyosis resulting from such a genetic defect.     

Evidence of a marked 25-hydroxyvitamin D deficiency in patients with congenital ichthyosis

BACKGROUND: Vitamin D is essential for bone mineralization, and its deficiency may be the cause of skeletal fractures and osteomalacia. Geographical or ethnic factors may modulate the cutaneous synthesis of vitamin D. We hypothesized that major changes in keratinization may similarly alter the cutaneous synthesis of vitamin D. OBJECTIVES: To explore calciotrophic hormones, parameters of bone remodelling and bone mineral density (BMD) in nine patients with non-bullous congenital ichthyosis. PATIENTS AND METHODS: Six patients were European, three were North African. Four had received acitretin over a long period of time. A complete biological investigation, including serum and urinary calcium and phosphorus, calciotrophic hormones [intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25-(OH)D) and 1,25-dihydroxyvitamin D (1,25-(OH)2D)], bone formation and resorption markers, was performed on all patients during the winter season and repeated among four patients after summer. BMD was measured in all patients. RESULTS: All patients had a marked 25-(OH)D deficiency, clearly below the deficiency threshold of 25 nmol/L. Patients from North Africa had a greater deficiency than European patients, perhaps because of the difference in skin pigmentation. iPTH remained normal in European patients but was elevated among the North Africans. After sun exposure, an improvement in vitamin status was visible in only one patient. Bone formation and resorption markers remained normal. Femoral neck osteodensitometry indicated values near the osteopaenic threshold in two young North African females. No deleterious effect of retinoids on vitamin D metabolism was observed. CONCLUSION: Patients, and in particular pigmented patients, with congenital ichthyosis present a severe deficiency in vitamin D. Care provided to protect the skeletal future of these patients involves measuring BMD and prescribing supplementation.     

Novel mutation in NIPAL4 in a Romanian family with autosomal recessive congenital ichthyosis

Autosomal recessive congenital ichthyosis (ARCI), a severe and highly clinically heterogeneous group of mendelian disorders of cornification, is the result of mutations in at least nine genes regulating the epidermal barrier functionality. NIPAL4 is the second most frequently mutated ARCI gene. We report two adult patients from a nonconsanguineous family of Romanian origin, who had lamellar ichthyosis. A positive in situ transglutaminase 1 activity assay excluded a putative TGM1 mutation. NIPAL4 sequencing revealed in both patients a new homozygous missense mutation, c.403A>C, affecting a highly conserved amino acid (p. Ser135Arg) and predicted to be deleterious according to in silico analysis. In addition to the ARCI features, the patients had caries and partial edentation. Although delay in dental treatment led to caries progression and extraction of secondary teeth, this finding raises the possibility of a deficiency in enamel mineralization due to NIPAL4 dysfunction as an Mg²⁺ transporter. Evaluating new patients with ARCI provides fruitful clinical and molecular findings.     

Heterogeneity in autosomal recessive ichthyosis. Clinical and biochemical differentiation of lamellar ichthyosis and nonbullous congenital ichthyosiform erythroderma

Nonbullous congenital ichthyosiform erythroderma (CIE) and classic lamellar ichthyosis (LI) can be distinguished by clinical, histopathologic, and biochemical findings reported herein. Whereas all patients with CIE (n = 12) had fine white scales, they were heterogeneous with respect to degree of erythroderma, ectropion, and prognosis. In contrast, all patients with LI (n = 6) had large, dark, platelike scales, severe ectropion that showed no improvement with age, and minimal erythroderma. Although the stratum corneum of patients with LI was two to three times thicker than that of those with CIE, the latter group demonstrated more acanthosis, parakeratosis, hypergranulosis, and less prominent dermal capillaries. Studies of scale-lipid content have indicated biochemical correlates of this clinical heterogeneity. These clinical, histologic, and biochemical findings provide useful guidelines to differentiate CIE from LI and strongly suggest that autosomal recessive primary ichthyosis comprises two distinct diseases.     

常染色体隐性遗传性鱼鳞病一家系表型、基因型与皮损超微结构研究

目的 探讨常染色体隐性遗传性鱼鳞病家系临床表型、基因型及超微结构。方法 观察常染色体隐性遗传性鱼鳞病患者临床表现。用PCR扩增TGM1基因15个外显子及其邻近剪切位点,双向直接测序;取先证者背部皮损做透射电镜观察,记录电镜表现特征。结果 先证者临床表现介于板层状鱼鳞病及非大疱性鱼鳞病样红皮病之间,其弟弟为火棉胶婴儿。先证者、其弟及父亲3号外显子第551位碱基胞嘧啶（C）→胸腺嘧啶（T）,其编码的第143位氨基酸由精氨酸变为半胱氨酸（R143C）;先证者、其弟及母亲4号外显子第759位胞嘧啶（C）→胸腺嘧啶（T）,使第212位氨基酸由丝氨酸转变为苯丙氨酸（S212F）。电镜观察发现,先证者皮损不仅有Ⅱ型结构表现,也同时存在Ⅲ型结构特征。结论 该家系患者携带复合杂合突变,R143C属于热点区,S212F为新发现的位点。携带TGM1基因突变的先证者皮损电镜表现为Ⅱ型,但同时发现有Ⅲ型结构存在。