Management of congenital ichthyoses: European guidelines of care, part two.

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.

Management of congenital ichthyoses: European guidelines of care, part one.

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. They summarize evidence and expert-based recommendations and are intended to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part one, covering topical therapies, systemic therapies, psychosocial management, communicating the diagnosis and genetic counselling.

Ichthyosis bullosa of Siemens--a disease involving keratin 2e.

Ichthyosis bullosa of Siemens (IBS) is a congenital bullous ichthyosis without erythroderma. In contrast to bullous congenital ichthyosiform erythroderma (BCIE), there is a relatively mild involvement of the skin and epidermolytic hyperkeratosis (EHK) is restricted to the upper suprabasal layers of the epidermis. Tonofilament aggregation was observed by EM in suprabasal cells from affected patients in the two families under study, indicative of a keratin abnormality. Keratin 2e is a differentiation specific type II keratin expressed suprabasally in the epidermis. Part of the K2e gene was amplified by polymerase chain reaction using genomic DNA from affected and unaffected individuals from two IBS families. Direct sequencing of polymerase chain reaction products revealed a point mutation in the highly conserved helix termination motif, producing the protein sequence change LLEGEE-LLEGKE. This mutation was found in all affected members of a five-generation kindred and also in a sporadic case in a second unrelated family. No mutation was seen in unaffected individuals. The mutation destroys a MnlI restriction site, which allowed exclusion of the mutation from a population of 50 unaffected unrelated individuals by restriction fragment analysis of K2e PCR products. This is the sixth keratin gene found to be involved in an inherited epidermal disorder.

Mutations in the rod 1A domain of keratins 1 and 10 in bullous congenital ichthyosiform erythroderma (BCIE).

Bullous congenital ichthyosiform erythroderma is a human hereditary skin disorder in which suprabasal keratinocytes rupture. Recent reports have implicated keratins K1 and K10 in this disease. Here we describe four diverse keratin mutations that are all significantly associated with this disease. Two of these are in the helix 1A subdomain of the type II keratin 1, giving a serine-to-proline substitution in codon 185 and an asparagine-to-serine substitution in codon 187. In the analogous region of type I keratin 10, an arginine-to-proline and an arginine-to-serine transition in codon 156 have been identified. All four mutations create restriction fragment length polymorphisms that were used exclude the mutations from 120 normal chromosomes. Insertional polymorphism (in the V2 subdomains of the non-helical tails of K1 and K10) was excluded as the cause of the phenotypic heterogeneity observed within one family.

Cytokine expression in psoriatic skin lesions during PUVA therapy.

To determine whether an improvement in skin lesions as a result of PUVA therapy may be correlated with changes in cytokine patterns, RT-PCR amplification was used to compare the levels of IL-2, IL-6, IL-8, IL-10, TNF-alpha and IFN-gamma cytokine mRNA expression in serial biopsies from three chronic plaque psoriatic patients. In each case, 3-mm punch biopsies were taken from lesional skin before and during 2-28 days of treatment with PUVA. Total mRNA was extracted from each biopsy, cDNA synthesized, and then amplified by 35 cycles of PCR using cytokine-specific primers. The specificity of the PCR products was confirmed by the Southern blot technique. Substantial levels of specific mRNA for each of the cytokines studied was present in the lesions prior to treatment. In two of the three patients who responded well to PUVA, a reduction in all the cytokines including IL-10 was observed compared with baseline levels. In contrast, PUVA proved to be ineffective in clearing the psoriasis of the third patient whose skin lesions worsened during the course of treatment. This was accompanied by an increase in IFN-gamma but not of the other cytokines investigated, above the pretreatment level. This study showed an association between PUVA-induced resolution and decreases in the levels of various cytokines highly expressed in psoriatic lesions.

Quantification of stratum corneum ceramides and lipid envelope ceramides in the hereditary ichthyoses.

Ceramides (sphingolipids) are the main polar lipids of the stratum corneum and play an important role in skin barrier function, cell adhesion and epidermal differentiation. In view of the function of ceramides in normal skin, this study aimed to assess their levels in patients with various types of hereditary ichthyosis, in which epidermal homeostasis is markedly abnormal. Stratum corneum samples were collected from 80 patients and 23 normal controls, and the intercellular and lipid envelope ceramides were analysed by high-performance thin-layer chromatography. The covalently bound ceramides (ceramides A and B) of the lipid envelope were present in all patients studied, and showed no significant differences from control samples. Total ceramides (ceramides 1-6) were decreased in bullous ichthyosiform erythroderma, which is presumably a secondary phenomenon similar to that seen in patients with atopic dermatitis. Patients with non-erythrodermic lamellar ichthyosis showed a marked decrease in levels of the important acylceramide, ceramide 1, whereas those with other types of autosomal recessive ichthyosis (limited lamellar ichthyosis and non-bullous ichthyosiform erythroderma) had mean levels similar to the controls. Ceramide 1 deficiency may therefore define a subgroup within the autosomal recessive ichthyoses. Sjögren-Larsson syndrome (SLS) shows a deficiency of both acyl-ceramides (ceramides 1 and 6), which would seem likely to disrupt the normal skin barrier function. Furthermore, glucosylceramides (cerebrosides) are known to be deficient in the neural tissue of patients with SLS. The relationship of these ceramide abnormalities to the underlying fatty alcohol oxidoreductase defect remains uncertain, but they may provide an interesting link between the nerve damage and cutaneous abnormalities seen in this rare neurodermatosis.

The quantification of free sphingosine in the stratum corneum of patients with hereditary ichthyosis.

Sphingosine is a long-chain base which provides the back-bone of all sphingolipid molecules. Free sphingosine is found in normal epidermis, especially in the stratum corneum. As a free molecule it may modify epidermal cell proliferation and differentiation through its inhibition of protein kinase C. Using a thin-layer chromatography technique we have demonstrated in vitro that the erythrodermic ichthyoses show significantly lower levels of stratum corneum sphingosine than the non-erythrodermic types. The exact in vivo significance of this finding is unclear, but free sphingosine may have an important role in determining the inflammatory component of the hereditary ichthyoses.

Papules and pustules of the elbows and knees: an uncommon clinical sign of dermatomyositis in oriental children.

We report two children with dermatomyositis in whom the initial manifestation was a papular eruption on the extensor surfaces of the elbows and knees. In each there was a follicular component to the eruption and one child had pustular lesions. The extensor eruption predated the onset of muscle weakness by 1 year in the first child and by 2 years in the second. Both children had Vietnamese parents. There is some evidence in the literature that Oriental patients may be predisposed to this type of eruption.

An unusual presentation of diffuse granuloma annulare in an HIV-positive patient - immunohistochemical evidence of predominant CD8 lymphocytes.

Over the past decade there have been several reports in the literature of atypical forms of granuloma annulare (GA) occurring in HIV positive patients. We now report a case of diffuse granuloma annulare in an HIV positive patient with unusual clinical and immunohistological features. Our patient presented with a persistent extensive macular erythematous eruption on his face and upper trunk with bizarre sparing around the nipples and axillae. The histology showed an interstitial pattern of GA, with a predominance of CD8 positive cells, in contrast to the usual CD4 positive infiltrate typically seen in GA.

Golf tee hairs in Netherton disease.

We present a case of Netherton disease, where the hairs lacked the characteristic microscopic feature of trichorrhexis invaginata. In its place were certain hairs with a golf tee morphology. These represent the proximal half of the invaginate node seen in typical Netherton disease. Scanning electron microscopy demonstrated the three-dimensional quality of this abnormality, which is subtle when assessed by light microscopy alone. We describe this sign so that it might be recognized when seen in isolation, as here, and allow the diagnosis of Netherton disease to be confirmed.

A clinical and genetic study of X-linked recessive ichthyosis and contiguous gene defects.

X-linked recessive ichthyosis (XLI) is caused by a deletion, or mutation, of the steroid sulphatase gene on the distal short arm of the X chromosome (Xp22.3). This region of the X chromosome is particularly susceptible to deletions. Such deletions can occasionally extend to involve neighbouring genes, causing a contiguous gene defect. Therefore, XLI may be associated with Kallmann's syndrome (KS), mental retardation, X-linked recessive chondrodysplasia punctata and short stature. We have reviewed 33 patients with XLI. Nine showed evidence of contiguous gene defects. A further four had neurological deficit sustained at the time of birth. This study highlights the importance of screening patients with X-linked recessive ichthyosis for neighbouring genetic disorders and, in particular, the early identification of KS, as delay in diagnosis may lead to infertility and osteoporosis. Parents should be warned about possible obstetric complications due to prolonged labour in future pregnancies.

Restrictive dermopathy: a disorder of fibroblasts.

Restrictive dermopathy is a rare, lethal genodermatosis, characterized by a thin, tightly adherent skin which causes a dysmorphic facies, arthrogryposis and respiratory insufficiency. The recorded cases to date show a remarkable phenotypic similarity. Thinning of the dermis and the arrangement of collagen in parallel bundles appear to be constant findings. We have found many dead and degenerating fibroblasts in the dermis on ultrastructural examination, and have demonstrated their poor growth in vitro. Studies of collagen from a skin sample showed a marked increase in mature cross-links, indicating a decrease in skin collagen turnover. These findings suggest a primary disorder of fibroblasts, and may explain the apparent arrest in growth and differentiation of the skin which appears to be important in the pathogenesis of this rare condition.

Lichen planus pemphigoides in a child--immunopathological findings.

Lichen planus pemphigoides is a rare immuno-bullous disorder which usually affects adults. It is extremely uncommon in children. Previous cases have been described in a 10-year-old girl and in two 16-year-old adolescents. A case of lichen planus pemphigoides in an 11-year-old Afro-Caribbean boy is reported and the immunopathological findings are discussed.

Linear IgA disease and ulcerative colitis.

Seventy adult patients with linear IgA disease were studied. Five (7.1%) also suffered from ulcerative colitis (the prevalence of ulcerative colitis in the U.K. is 0.05%). A further three patients with this association, from other British centres were also reviewed. In all cases, ulcerative colitis preceded the onset of skin disease, by a median of 6.5 years. The reason for this association remains unclear but the abnormalities in colonic mucosal B cells and mucosal IgA1 production reported in patients with ulcerative colitis may be important in the subsequent development of IgA1 mediated linear IgA disease.

Bone changes and their significance in children with ichthyosis on long-term etretinate therapy.

Anxiety about the use of etretinate in children has been provoked by several reports describing skeletal abnormalities during long-term therapy. However, we have observed no evidence of skeletal toxicity in 42 children treated over an 11-year period. Radiological screening before and during treatment has failed to reveal abnormalities that would influence our decision to commence or to continue etretinate administration. We recommend that children who are to be treated with etretinate should have a baseline selective skeletal survey, with follow-up radiology restricted to those with pretreatment radiological abnormalities and those who develop musculo-skeletal symptoms. In addition we advise that dosage should not exceed 1 mg/kg/day. If these guidelines are followed, we believe that long-term therapy with etretinate can be given to children, with an acceptable margin of safety.