Interventions for congenital ichthyosis

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of topical and systemic interventions for congenital ichthyosis.

Background

Description of the condition

Please see Table 1 for an explanation of the terms and abbreviations we have used.

Table 1.

Glossary of terms used

Term	Explanation
Alopecia	Loss of hair
Autosomal recessive congenital ichthyosis (ARCI)	A non‐syndromic ichthyosis
Autosomal dominant inheritance	The disease is manifested if the abnormal gene from any 1 parent is inherited
Autosomal recessive inheritance	The disease is manifested if only the abnormal gene is inherited from both the parents
Bullous	Involving blisters of the skin larger than 5 mm
Cerebellar ataxia	Unsteadiness due to disease of the cerebellum
Cholangitis	Inflammation of the bile ducts
Congenital ichthyosiform erythroderma (CIE)	Ichthyosis similar to LI but milder
Collodion baby	Babies born with a shiny, waxy outer layer to the skin
Conradi‐Hünermann‐Happle	Mutation in the emopamil binding protein (EBP) gene associated with growth deficiency and ichthyosis
Cornification	The conversion of epithelial cells into a horny material
Ectropion	The eyelids are turned outwards
Epidermolysis	Loosening of the upper layer of the skin causing detachment or blisters
Erythroderma	Inflammation of skin with redness and scaling
Filaggrin	Filament‐associated protein that binds to keratin fibres in the skin cells
Flexural creases	Skin lines at the foldings of joints (technically, at the junction of opposing flexural surfaces)
Harlequin ichthyosis (HI)	Ichthyosis with deep fissured red skin with pattern mimicking costumes of harlequin clowns
Hyperkeratosis	Thickened stratum corneum (see Scaling) without visible scaling. Gives skin surface a hardened texture
Hypotrichosis	Presence of less than normal amount of hair
IBIDS syndrome	IBIDS is the acronym for ichthyosis, brittle hair, impaired intelligence, and decreased fertility, where the patient presents with dry, scaly skin (ichthyosis), brittle hair, impaired physical and mental development, decreased fertility, and short stature
Hypoplasia	Underdevelopment; incomplete development
Hygroscopic	Substances that absorb moisture
Ichthyosis vulgaris (IV)	A common form of ichthyosis
Keratitis ichthyosis deafness (KID) syndrome	Abnormalities noticed: eye problems; dry, scaly skin; and hearing loss
Keratinisation	Process by which keratin is deposited in cells
Keratinopathic	Diseases that arise due to fault in the keratin (the subcellular structures inside the skin cells)
Keratosis pilaris	Skin disorder presenting as small red bumps in the upper arms, thighs, and buttock region
Palmomplantar keratoderma	Abnormal thickening of the skin of the palms and soles
PUVA	Psoralen with UVA (ultraviolet A) treatment
Lamellar ichthyosis (LI)	The development of large plate‐like scales with shallow fissures, mosaic pattern
Mendelian disorders of cornification (MeDOC)	This is synonymous with inherited ichthyoses and refers to conditions with visible scaling or hyperkeratosis of the skin
Netherton syndrome	Mutation in the SPINK5 gene causing skin inflammation, itch, and dehydration
Recessive X‐linked ichthyosis (RXLI)	A syndromic form of ichthyosis
Refsum disease	Ichthyosis with retinitis pigmentosa, peripheral neuropathy, and cerebellar ataxia
Retinitis pigmentosa	An inherited degenerative eye disorder that can be caused by abnormalities of the retinal pigment epithelium
Scaling	Thickening of the stratum corneum (outermost protective cornified layer of the skin) with visible flakes on the skin surface
Sjögren‐Larsson syndrome	Mutation in the gene on chromosome 17 causing mental retardation, ichthyosis, and spastic paraplegia
Transepidermal water loss (TEWL)	Physiological water loss through the epidermis; as a person has no control over it, it is called 'insensible water loss'
Trichothiodystrophy	Sparse, brittle hair with an unusually low sulphur content
Ultraviolet B (UVB)	Ultraviolet B
Xerosis	Abnormal dryness of the skin

Introduction

Congenital ichthyosis is an inherited disorder of the skin whereby the skin is dry and scaly (Figure 1). The skin symptoms can range from mild to severe and have a major impact on a person's quality of life. The altered skin appearance may be associated with pain, itch, and smell due to infection and might worsen in relation to environmental changes, such as episodes of heat intolerance. Skin pain may lead to impaired mobility, and itch may severely affect sleep. Ichthyoses, like other skin diseases, can have psychological effects due to limiting social relationships. People with ichthyoses find that additional housework is involved because of excessive shedding of scaly skin (Mazereeuw‐Hautier 2012). In families with children who have ichthyosis, the main topics of complaint expressed by parents were difficulties finding babysitters, organisation of holidays, restrictions in terms of leisure, and society's perception of their children's condition (Dufresne 2013).

Figure 1.

A 38‐year‐old man with congenital ichthyosis vulgaris, resistant to acitretin but with b) remarkable effect of heliotherapy (light therapy) at the Dead Sea, Israel. Photographs before (a) and after (b) a few weeks of heliotherapy with almost complete clearing of scaling and hyperkeratosis

Copyright© [2014] [Bispebjerg University Hospital, Department of Dermatology, Denmark]: reproduced with permission

Chronic symptomatic treatment with daily applications of creams can be time‐consuming and also expensive because of the cost of these remedies. People with congenital ichthyosis generally have a high disease burden, with estimated annual costs comparable to those of cutaneous lymphoma (Schmuth 2013).

Terminology

Classification of inherited ichthyoses is clinically based. An international consensus report divides the ichthyoses into non‐syndromic (only affecting skin) and syndromic (affecting the skin and other organs) (Oji 2009).

• Non‐syndromic ichthyoses

• • common ichthyoses: ichthyosis vulgaris (IV) and recessive X‐linked ichthyosis (RXLI) (non‐syndromic presentation)

  • autosomal recessive congenital ichthyosis (ARCI): harlequin ichthyosis (HI), lamellar ichthyosis (LI), and congenital ichthyosiform erythroderma (CIE)

  • keratinopathic ichthyosis (KPI): epidermolytic ichthyosis (EI) and superficial epidermolytic ichthyosis (SEI)

  • other forms

• Syndromic ichthyoses

• • X‐linked ichthyosis syndromes: RXLI (syndromic presentation) and Conradi‐Hünermann‐Happle syndrome

  • autosomal ichthyosis syndromes: with hair abnormalities, Netherton syndrome, ichthyosis hypotrichosis syndrome, ichthyosis hypotrichosis‐sclerosing cholangitis syndrome, and trichothiodystrophy

  • with neurological signs: Sjögren‐Larsson syndrome and Refsum syndrome

  • others forms

Epidemiology

The incidence of moderate to severe ichthyosis in the US has been estimated to be 67 per million based on claims and discharge codes (Milstone 2012), and the prevalence of ARCI has been estimated at 16 per million (Hernandez‐Martin 2012). Recessive X‐linked ichthyosis has an estimated incidence in the UK of 162 per million males (Wells 1966).

Aetiology and pathogenesis

The congenital ichthyoses comprise an etiologically heterogeneous group of Mendelian (genetic) disorders of cornification (MeDOC) of the skin characterised by hyperkeratosis and scaling. Mutations in various genes responsible for keratinocyte differentiation and epidermal barrier function cause a limited disease. Skin barrier impairment is a constant feature of ichthyoses. Scaling may vary from mild to severe and present in different locations, e.g. with or without involvement of palmoplantar skin (DiGiovanna 1994), or as xerosis (abnormal dryness of the skin). Ichthyoses may also involve bullous phenotypes that may be focal or more generalised and syndromic forms involving internal organs (Vahlquist 2003).

Ichthyosis vulgaris is an autosomal dominant disease caused by mutations in the filaggrin gene (Smith 2006). Recessive X‐linked ichthyosis arises because of a mutation in the steroid sulphatase gene (Webster 1978). Lamellar ichthyosis is a disorder of cornification (final stage of skin cell maturation) probably due to a defect in the transglutaminase‐1 pathway (Akiyama 2001). Mutations in the genes for lipoxygenase, ichthyin, and transglutaminase are implicated in congenital ichthyosiform erythroderma (CIE). Keratinopathic ichthyoses are caused by keratin mutations. See Oji 2009 for specific gene mutations in other MeDOCs.

Clinical presentation

In ichthyosis vulgaris, the skin is usually dry and scaly in the early days of life, but onset may be delayed. Scale is more prominent on extensor surfaces but not in flexural creases. Associated features are pronounced skin lines on the palms and soles and keratosis pilaris (Mevorah 1985).

Harlequin ichthyosis is a severe variant wherein the baby presents with thick scales and deep skin fissures, along with difficulty in breathing and feeding. It is associated with high mortality, although the survival rate is increasing (Rajpopat 2011).

Most severely affected infants with lamellar ichthyosis present at birth as collodion babies. This waxy layer of skin is shed within the first month of life, leading to large, dark brown adherent scales. Associated features are palmoplantar keratoderma, scarring alopecia, hypoplasia of aural and nasal cartilages, and ectropion. Intellectual ability is normal. Congenital ichthyosiform erythroderma and LI may be indistinguishable at birth, but CIE evolves into generalised erythroderma with fine white scales, although the erythema may vary, with less severe symptoms, and may improve at puberty (Rimoin 2012).

Keratinopathic ichthyoses (KPI) have a wide spectrum of manifestations and severity ranging from mild scale to hyperkeratotic plaques and blistering, with variable regional involvement. Among the KPI, epidermolytic ichthyosis presents with large erosions and erythroderma at birth, later replaced by generalised hyperkeratosis, which has a predilection for frictional areas and palmoplantar keratoderma. Superficial epidermolytic ichthyosis also presents with blistering and erythroderma, but fine moulting characterises it in later life (Oji 2009).

Syndromic ichthyoses are a heterogenous group of usually recessive inheritance with extracutaneous features, common among them being Netherton syndrome, Sjögren–Larsson syndrome, and Conradi‐Hünermann‐Happle syndrome. Hair abnormalities and neurological signs are prominent in syndromic ichthyoses, although several other extracutaneous associations are reported.

Description of the intervention

Interventions for congenital ichthyoses may be systemic (taken orally) or topical (applied to the skin). Systemic interventions include oral retinoids (e.g. 13‐cis‐retinoic acid, acitretin, etretinate, alitretinoin) and retinoic acid metabolism‐blocking agents (e.g. liarozole, rambazole). Topical interventions may consist of emollient creams (liquid paraffin), keratolytic agents (salicylic acid), and topical formulations of retinoic acid derivatives (retinoic acid, tazarotene) or vitamin D2/D3 (calcipotriol).

How the intervention might work

Emollient creams containing one or more lipid components are used to restore the skin barrier and improve hydration, both of which are compromised in ichthyoses. Topical treatment may improve xerosis and barrier function of the skin and help to decrease itch.

Keratolytic agents, such as urea and lactic acid, dissolve the scales and have hygroscopic properties. Topical formulations of retinoic acid derivatives, e.g. adapalene and tazarotene, might normalise keratinisation.

Oral retinoids, which are vitamin A derivatives, regulate cell differentiation, proliferation, and apoptosis and thus accelerate the shedding of excessive scales and decrease hyperkeratosis, resulting in normalisation of the epidermis (Vahlquist 2008).

Why it is important to do this review

Substantial research progress has been made regarding inherited cutaneous keratin disorders. Our Cochrane review will aim to help clinicians and people with the condition identify benefits and optimal regimens of interventions for the treatment of ichthyoses. We also hope to highlight areas where further research may be best directed for the treatment of this disease.

Objectives

To assess the effects of topical and systemic interventions for congenital ichthyosis.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) and non‐RCTs.

Because of the rarity of the disease, it is unlikely that many RCTs have been performed. Moreover, we are concerned about the possibility that both beneficial and harmful effects of treatments for congenital ichthyosis may not be investigated adequately in RCTs. For instance, a given side‐effect may be rare enough not to be captured by RCTs (rarity of events of interest). We expect RCTs of only two intervention arms.

Therefore, should the goal of the review not be met by reviewing RCTs only, we will attempt to systematically review the findings of non‐randomised studies. With this aim, we will consider cohort studies (i.e. a defined group of participants are followed‐up over time to assess the association between different treatments and prespecified outcomes) and case‐control studies (i.e. studies comparing patients with a specific outcome of interest with patients without that outcome to assess the association between the outcome (e.g. toxicity) and a given treatment).

We will only include non‐randomised studies (NRS) where randomised trials are not found to be available. As the review is updated and if randomised trials become available, we may no longer use NRS. Where we include both NRS and randomised trials in the review, we will present these separately (Chapter 13.2, Higgins 2011).

Types of participants

People of all ages with congenital ichthyoses (IV, RXLI, non‐bullous ichthyosiform erythroderma, LI, HI, bullous ichthyosiform erythroderma, ichthyosis bullosa of Siemens, ichthyosis hystrix), ichthyosiform syndromes (Netherton syndrome, Sjögren‐Larsson syndrome, neutral lipid storage disease, Refsum disease, multiple sulphatase deficiency syndrome, X‐linked dominant ichthyosis, and others), and congenital ichthyosis variants.

Types of interventions

Any topical interventions (e.g. glycerol; paraffin; tar; urea; pimecrolimus; liarozole; N‐acetylcysteine; tazarotene; cholesterol; corticosteroid; or light therapy (PUVA, UVB) or others, such as heliotherapy) or systemic interventions (e.g. retinoids) compared to placebo or other active intervention.

Types of outcome measures

Primary outcomes

• Pruritus (visual analogue scale).

• Changes in scaling, roughness, cracks, and erythema.

• Dermatology quality of life index.

Secondary outcomes

• Safety and tolerability of the drugs.

• Transepidermal water loss (TEWL).

• Health‐related quality of life (HRQoL) measured by validated instruments, e.g. HRQoL (Guillemin 1993) or 36‐Item Short Form Health Survey (SF‐36) (Anderson 1993).

Timings of our outcomes

We will set no time frame for the outcome assessments.

Search methods for identification of studies

We aim to identify all relevant RCTs, cohort, and case‐control studies, regardless of language or publication status (published, unpublished, in press, or in progress).

Electronic searches

We will search the following databases for relevant trials:

• the Cochrane Skin Group Specialised Register;

• the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library;

• MEDLINE via OVID (from 1946);

• Embase via OVID (from 1974); and

• LILACS (Latin American and Caribbean Health Science Information database, from 1982).

We have devised a draft search strategy for RCTs, cohort, and case‐control studies for MEDLINE (OVID), which is displayed in Appendix 1. This will be used as the basis for search strategies for the other databases listed.

Searching other resources

Trials registers

We will search the following trials registers.

• The metaRegister of Controlled Trials (www.controlled‐trials.com).

• The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov).

• The Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).

• The World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch).

• The EU Clinical Trials Register (www.clinicaltrialsregister.eu).

References to further studies

We will check the bibliographies of pertinent systematic reviews, as well as the included and excluded studies, for further references to relevant trials.

Adverse effects

We will not perform a separate search for adverse effects of the target intervention. However, we will examine data on adverse effects from the included studies we identify.

Data collection and analysis

We plan to include at least one 'Summary of Findings' table in our review. In this, we will summarise the primary outcomes for the most important comparison. If we feel there are several major comparisons or that our findings need to be summarised for different populations, we will include further 'Summary of Findings' tables.

Selection of studies

Two review authors (PD and VTP) will independently inspect the results obtained through the search strategy by assessing titles and abstracts. We will not be blinded to study information with regard to investigators, location, etc. and will remove duplicate records of the same study and obviously irrelevant reports.

We will independently assess full‐text reports for compliance with our eligibility criteria. We will seek to contact the investigators to clarify study eligibility, elucidate missing data, or if results in an abstract are not confirmed by subsequent publications.

When we make decisions on study inclusion, if there are disagreements on whether or not we should include a study, a discussion will follow, and if disagreement persists, the third and fourth review author will examine the report and decide. We will make a list of excluded studies in the review with reasons for exclusion.

We will identify and link together possible multiple reports of the same study. Specific criteria for comparing reports will be author names, location and setting, specific details of the interventions, number of participants and baseline data, and date and duration of the study. When we cannot clarify uncertainties, it may be necessary to communicate with the authors of the reports.

We intend to complete a PRISMA (Prefered Reporting Items for Systematic Reviews and Meta‐analyses) flowchart (Liberati 2009).

Data extraction and management

Two authors (PD and VTP) will independently extract data from study publications. We will design data collection forms carefully to target our objectives, and we will pilot the form using two journal articles. We will extract the following specific data items from the included studies:

• source (publication source identification (ID), study ID, country, year of publication, author ID, and contact details);

• methods (study design, duration, blinding, generation of sequence, allocation sequence concealment, concerns regarding bias (e.g. selection, confounding and measurement biases, including loss to follow up));

• participants (number, age, sex);

• diagnostic criteria for ichthyosis;

• intervention (total number of intervention groups, regimen (dose, frequency, duration));

• other intervention details, e.g. integrity (compliance and follow‐up);

• outcomes (definition, measurement scale with upper and lower limit and whether a high or low score is a positive outcome): For each outcome of interest, we will note the following: sample size, participants lost to follow up, summary data, and estimate of effect (mean difference (MD), standard deviation (SD), and P value); and

• results (number of participants in each intervention group).

We will also record the following information: declaration of interest, funding source, key conclusions, what correspondence with study authors we required and what the result of this might be, and our decisions as review authors (confirmation of eligibility or reason for exclusion).

We will maintain a copy of the original extracted data. If there are disagreements, we will discuss these and resolve them. If we do not reach consensus, the third and fourth review authors will be consulted. We do not expect any problems concerning this issue.

Assessment of study quality

Two authors will independently assess the methodological quality of the RCTs and observational studies included through the initial screening. For non‐randomised studies, we will collect data as we will for RCTs (i.e. details of study, study population, sample size recruited, sample size analysed, and so on). In particular, we will collect information regarding what the investigators did in each study following the Non‐Randomised Studies Methods Group (NRSMG) methodology (Chapter 13.2, Higgins 2011). We will give special attention to the collection of data on confounding factors, group comparability, and data that will enable us to judge risk of selection bias (due to differences between individuals in different intervention groups) and measurement bias (i.e. studies that do not explicitly report having had a protocol) (Table 13.2.a, Chapter 13.2, Higgins 2011).

We will use the following quality assessment tools to assess the methodological quality of both randomised controlled trials and observational studies included in the review. For example, we will assess the RCTs for quality of randomisation, use of blinding, quantification of withdrawals, concealment of intervention allocation, and monitoring of protocol adherence. We propose to score RCTs on a scale of zero to five, with one point allocated for each methodological area addressed (Moher 1998; Moher 1999). We will include in an analysis the studies that obtain a score of four or higher in this scale (Canonico 2008).

We will derive tools to assess the quality of the observational studies (cohort and case‐control) using the published recommendations (Stroup 2000), including the studies of high methodological quality.

Assessment of risk of bias in included studies

Two review authors will independently assess each included study using The Cochrane Collaboration's tool for assessing risk of bias (Chapter 8, Higgins 2011). This tool addresses six specific domains, namely, sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other issues (e.g. baseline imbalance). Baseline imbalance will often occur because of factors such as errors in the randomisation method, poor allocation concealment, and postrandomisation exclusions; these are factors that we will evaluate via 'Risk of bias' assessment criteria (Chapter 8.14.1.2, Higgins 2011). We will assess blinding and completeness of outcome data for each outcome separately. We will complete a 'Risk of bias' table for each eligible study. All review authors will discuss any disagreement to achieve consensus.

We will present our assessment of risk of bias, including data on the variation of duration of study follow up and loss to follow up, using a 'Risk of bias' summary figure, which presents all of the judgements in a cross‐tabulation of study by entry. This display of internal validity indicates the weight the reader may give the results of each study.

Measures of treatment effect

The primary and secondary outcomes will comprise continuous data for which we will record the mean difference (MD) and standard deviation (SD). When needed, we will try to obtain missing information or clarify statistical procedures by correspondence with the original study authors. If the measurement scales are not the same across the trials, we will use the standardised mean difference as a summary statistic.

Unit of analysis issues

The unit of analysis will be the participant, that is, the unit randomised in the eligible trials.

Dealing with missing data

As part of the quality assessment procedure of RCT and cohort observational studies, we will identify studies with losses to follow up (missing data). Examination of losses to follow up in RCT and cohort designs will consider relative losses per treatment versus placebo (or exposure versus unexposed) groups.

Assessment of heterogeneity

We will visually inspect the forest plots to evaluate the consistency of intervention effects across the trials.

We will also apply a statistical test to quantify inconsistency across studies (I² statistic). The value of the I² statistic (the proportion of variation between studies not due to chance) ranges from 0% to 100%. We will interpret findings according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions: Thresholds for the interpretation of I² statistic (Chapter 9, Higgins 2011). If we identify substantial statistical heterogeneity (I² statistic > 50%), strategies for addressing this will be as follows: We will check the data again and explore the heterogeneity, as one explanation could be groups of participants with different ages and skin pigmentation (Ioannidis 2008).

Assessment of reporting biases

We will create a funnel plot of intervention effect against the standard error of the intervention effect to assess whether there might be reporting bias. If we include more than 10 studies, we will carry out a test for funnel plot asymmetry. If there is asymmetry or evidence of small study effects, we will consider possible explanations, such as publication bias, selective outcome reporting, poor methodological design, inadequate analysis, true heterogeneity, or chance (Chapter 10, Higgins 2011).

Data synthesis

The primary aim is to perform meta‐analyses to summarise the effectiveness of different treatments for congenital ichthyoses.

We plan to use random‐effects modelling for continuous outcomes on the basis that it assumes that treatment effects are not identical in all studies. A fixed‐effect model assumes that the treatment effect is the same in each study and that differences in results are due only to chance. As stated above, we will quantify heterogeneity among studies using the I² inconsistency statistic, which is a measure of inter‐study variability. If inter‐study variability is low (I² statistic < 30%), the fixed‐effect and random‐effects models will yield very similar results (Chapter 9, Higgins 2011).

For the outcome 'Health‐related quality of life (HRQoL)', we anticipate the use of different validated quality of life instruments. If data are normally distributed, we will take a standardised mean difference approach. In this instance, we will use standard deviations to standardise the mean differences to a single scale as well as the calculations of study weights.

If studies present continuous data as both log‐transformed and untransformed data, such data cannot be mixed in a meta‐analysis, and we will present a narrative synthesis.

Special issues with non‐randomised studies

We expect that heterogeneity for non‐randomised studies will be greater than that for RCTs. Therefore, it is likely that we will not be able to perform meta‐analysis to pool data deriving from non‐randomised studies; moreover, although we might pool together summary data from non‐randomised studies (provided that the study design is similar), we will not pool these data with those from RCTs. Finally, the systematic review of non‐randomised studies will enable us to provide readers with a summary table collecting the main evidence from these studies, including their main limitations (e.g. risk of bias).

Subgroup analysis and investigation of heterogeneity

If heterogeneity exists, we will consider analysis of subsets of studies where participants are included on the basis of age, for example, being younger than 18 years or 18 or over. We will also consider subset analysis by disease type (if available).

Sensitivity analysis

We will conduct sensitivity analyses to explore the impact of excluding trials of poor quality as identified by The Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011) on risk estimates.

We will conduct analyses on all included studies that achieve acceptable study quality, and we will repeat 1) excluding studies with losses to follow up, to assess the robustness of the results and potential impacts of losses to follow up; and 2) including studies based on full‐set analyses (intention‐to‐treat) versus complete case analyses (on treatment) (Chapter 16.2.3, Higgins 2011).

Appendices

Appendix 1. MEDLINE (OVID) draft search strategy

1. exp "Ichthyosis Bullosa of Siemens"/ or exp Ichthyosis, X‐Linked/ or exp Ichthyosis/ or exp Ichthyosis Vulgaris/ or exp Ichthyosis, Lamellar/ 2. exp Ichthyosiform Erythroderma, Congenital/ or exp Hyperkeratosis, Epidermolytic/ 3. exp Sjogren‐Larsson Syndrome/ 4. exp Refsum Disease/ 5. exp Kallmann Syndrome/ 6. neutral lipid storage disease.mp. 7. kid syndrome.mp. 8. Keratitis, ichthyosis, deafness syndrome.mp. 9. child syndrome.ti,ab. 10. (Congenital hemidysplasia with ichthyosiform erythroderma and limb defects).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] 11. tay syndrome.mp. or Trichothiodystrophy Syndromes/ 12. ibids syndrome.ti,ab. 13. (Ichthyosis follicularis, alopecia, and photophobia syndrome).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] 14. ichthyosis follicularis.mp. 15. ifap syndrome.ti,ab. 16. neu laxova syndrome.mp. 17. ichthyos$.mp. 18. Sjogren Larsson Syndrome.mp. 19. refsum$ disease.mp. 20. netherton$ syndrome.mp. 21. kallmann$ syndrome.mp. 22. or/1‐21 23. randomized controlled trial.pt. 24. controlled clinical trial.pt. 25. randomized.ab. 26. placebo.ab. 27. clinical trials as topic.sh. 28. randomly.ab. 29. trial.ti. 30. 23 or 24 or 25 or 26 or 27 or 28 or 29 31. exp animals/ not humans.sh. 32. 30 not 31 33. (observational adj (study or studies)).tw. 34. (cohort adj (study or studies)).tw. 35. exp Cohort Studies/ 36. exp Case‐Control Studies/ 37. case control.tw. 38. cross sectional.tw. 39. Cross‐Sectional Studies/ 40. Epidemiologic Studies/ 41. cohort analy$.tw. 42. (follow up adj (study or studies)).tw. 43. longitudinal.tw. 44. retrospective.tw. 45. 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 46. 32 or 45 47. 22 and 46

What's new

Date	Event	Description
29 September 2017	Amended	The authors have relinquished responsibility for this protocol. It was published several years ago, and Cochrane Skin have decided to withdraw it (Managing Editor, Cochrane Skin).

Contributions of authors

PD was the contact person with the editorial base. PD and VTP co‐ordinated the contributions from the co‐authors and wrote the final draft of the protocol. SM and JD worked on the methods sections. PD and VTP drafted the clinical sections of the background and responded to the clinical comments of the referees. SM and JD responded to the methodology and statistics comments of the referees. PD, VTP, JD, SM, and AM contributed to writing the protocol. AM was the consumer co‐author and checked the protocol for readability and clarity. He also ensured that the outcomes are relevant to consumers. PD, VTP, JD, SM, and AM are the guarantors of the final review.

Disclaimer The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health, UK.

Sources of support

Internal sources

• No sources of support supplied

External sources

• The National Institute for Health Research (NIHR), UK.

  The NIHR, UK, is the largest single funder of the Cochrane Skin Group.

Declarations of interest

Patricia L Danielsen: Nothing to declare. Vetrichevvel Thirthar Palanivelu: Nothing to declare. Aqif S Mukhtar: Nothing to declare. Janine M Duke: Nothing to declare. Simone Mocellin: Nothing to declare.

Notes

The authors have relinquished responsibility for this protocol. It was published several years ago, and Cochrane Skin have decided to withdraw it (Managing Editor, Cochrane Skin).

Withdrawn from publication for reasons stated in the review