Chapter 1 Introduction

Ichthyosis Vulgaris is one of the more commonly seen types of ichthyosis. Sometimes called Common Ichthyosis (vulgar means common in Latin), it appears in approximately 1 in 250 individuals. Ichthyosis vulgaris often goes undiagnosed because people who have it think they have simple dry skin and never seek treatment. Hereditary ichthyosis vulgaris and acquired ichthyosis vulgaris, members of a group of cutaneous disorders of keratinization, appear similar both clinically and histologically. The term ichthyosis is derived from the ancient Greek root ichthys, meaning fish. Although the resemblance is rather fanciful, it nevertheless conveys the characteristic features of these diseases. References to ichthyosis have been found in ancient medical texts aged more than 2000 years. Robert Wilan first made the most accurate description of ichthyosis in the English literature in 1808. Later modifications classified the diseases into hereditary and acquired forms.1 In ichthyosis vulgaris, the skin cells are produced at a normal rate, but they do not separate normally at the surface of the stratum corneum (the outermost layer of skin) and are not shed as quickly as they should be. The result is a buildup of scales. Usually only a portion of the body may be involved (scaling is most common and most severe over the lower legs), and the scale is usually fine and white. Scaling on the torso is usually less severe and the face is usually unaffected. When the face is affected, the scaling is usually limited to the forehead and cheeks.1 Babies with ichthyosis vulgaris often appear normal when they are born, but then the skin abnormalities will almost always show up by their first birthday. Ichthyosis vulgaris may improve in certain climates, during the summer and with age. Hereditary ichthyosis vulgaris is an autosomal dominant genetic disorder first evident in early childhood. It is the most common form of ichthyosis, accounting for more than 95% of ichthyosis cases. It is caused by altered profilaggrin expression leading to

scaling and desquamation. Visible scales are retained for longer periods and sloughed off in clumps. Hereditary ichthyosis is also associated with atopy. The protein filaggrin is important in maintaining effective skin barrier function. Loss-of-function mutations in the profilaggrin gene (FLG) are evident in up to 10% of the population, causing ichthyosis vulgaris and representing a major risk factor for the development of atopic dermatitis. 1 Acquired ichthyosis, usually appearing for the first time in adulthood, is a nonhereditary condition associated with internal disease. Acquired ichthyosis is rare and must be viewed as a marker of systemic disease, including malignancy. Cases have been attributed to the use of certain medications.

Chapter 2

Content

1. Etiology Ichthyosis is a hereditary disorder of keratinization. It occurs in two forms: - Autosomally dominant ichthyosis is the most frequent and less severe form. - Hereditary ichthyosis vulgaris is an autosomal dominant genetic disorder first evident in early childhood. It is caused by altered profilaggrin expression leading to scaling and desquamation. Visible scales are retained for longer periods and sloughed off in clumps. Hereditary ichthyosis is also associated with atopy. The protein filaggrin is important in maintaining effective skin barrier function. It represents the least severe defect in the synthesis of profilaggrin and filaggrin, exhibiting a very dry skin with powdery scales, in some cases occurring with thicker, dark grey to greenish scales or follicular elevations. The hollows of the joints remain unaffected; the furrows of the hands increase in both number and depth. Loss-of-function mutations in the profilaggrin gene (FLG) are evident in up to 10% of the population, causing ichthyosis vulgaris and representing a major risk factor for the development of atopic dermatitis.1 - Acquired ichthyosis, usually appearing for the first time in adulthood, is a nonhereditary condition associated with internal disease. Acquired ichthyosis is rare and must be viewed as a marker of systemic disease, including malignancy. Cases have been attributed to the use of certain medications.1

2. Pathogenesis Ichthyosis vulgaris is classified as a retention hyperkeratosis.

Immunohistochemical staining revealed that filaggrin was absent in the epidermis of severely affected individuals and reduced in intensity in the less severely affected family members compared with healthy controls and unaffected family members. More recent studies showed that profilaggrin mRNA levels were

significantly reduced in the epidermis in ichthyosis vulgaris, presumably due to a defect in post-transcriptional control. The only known molecular marker affected by hereditary ichthyosis vulgaris is profilaggrin, a high molecular weight filaggrin precursor. Profilaggrin, synthesized in the granular layer of the epidermis, is a major component of keratohyalin granules. Through various posttranslational modifications, profilaggrin is converted to filaggrin, which aggregates keratin intermediate filaments in the lower stratum corneum. Filaggrin is proteolyzed and metabolized, producing free amino acids that may play a critical role as waterbinding compounds in the upper stratum corneum. Normal cycles of skin hydration and dehydration contribute to normal desquamation. These cycles are disrupted in ichthyosis vulgaris.2 Normal expression of the profilaggrin gene can be first detected in the granular layer. In ichthyosis vulgaris, the expression of profilaggrin is absent or reduced in the epidermis. This biochemical abnormality correlates with the decreased numbers of keratohyalin granules and the clinical severity of the condition. Analyses of cultured keratinocytes have shown reduced profilaggrin mRNA. Compared with normal amounts, one study found only 50% of the profilaggrin mRNA and 10% of the profilaggrin protein present. Research has shown that defective posttranscriptional regulation leads to decreased stability of profilaggrin mRNA.2 The profilaggrin gene is part of a cluster of genes on 1q21 that encodes for structural proteins expressed in terminally differentiating epidermis. This complex, called the epidermal differentiation complex, involves many genes involved in this process. An adjacent region on 1q22 may also be involved. The underlying molecular mechanisms contributing to the pathophysiology of this disease have not yet been determined. Studies are currently underway in humans and mouse models.2 An association exists between filaggrin null mutations of ichthyosis vulgaris and atopic dermatitis. Two common filaggrin (FLG) null mutations cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. Comprehensive analysis of the gene encoding filaggrin uncovered prevalent and

rare mutations in ichthyosis vulgaris and atopic eczema. These common European mutations are ancestral variants carried on conserved haplotypes. Fifteen variants were described, including 7 that are prevalent, all being either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis.3 The flaky tail phenotype is caused by a single autosomal recessive mutation that maps to mouse chromosome 3, close to the genes encoding mouse loricrin and profilaggrin. Linkage analysis in humans suggested linkage of ichthyosis vulgaris to chromosome 1q22 in two Chinese families. Another study reported linkage of a clinical subtype of ichthyosis vulgaris with an absent granular epidermal layer to the chromosomal region containing the EDC protein filaggrin. Filaggrin mutations p.R501X and c.2282del4 were analyzed in patients with ichthyosis vulgaris. Homozygotes and compound heterozygotes may be severely affected, whereas heterozygotes showed mild disease or were asymptomatic, suggesting semidominant inheritance with incomplete penetrance in heterozygotes. The presence of FLG mutations in 15 of 21 ichthyosis vulgaris patients were studied with a marked generalized scaling phenotype, including 8 affected members of a 4-generation family. In this group, heterozygous patients for p.R501X and c.2282del4 also displayed a pronounced phenotype. Filaggrin mutation c.3321delA was identified in a Korean patient with ichthyosis vulgaris and atopic dermatitis. Mutations R501X and 2282del4 represent the most frequent genetic cause in German ichthyosis vulgaris patients, but are probably population and family specific. 3 Thus, variation in the FLG gene has long been suspected as a major reason for ichthyosis vulgaris. Yet, the unusual and complex structure of the EDC protein filagrin in general and the human FLG gene in particular has long prevented the identification of causative mutations (Fig. 1). The FLG gene consists of three exons. Exon 1 (15 bp) encodes only untranslated sequence and exon 2 (159 bp) contains the translation initiation codon, while exon 3 (12-14 kb) contains the Nterminal domain and 10-12 copies of a 1-kb sequence that encode the

proteolytically cleaved parts of filaggrin. It has proved quite difficult to amplify the entire 12-14-kb sequence as well as to develop specific primers within the highly homologous structure of 10-12 identical repeats.2 Nevertheless, Smith et al. recently managed to develop long-range polymerase chain reaction conditions to amplify the entire exon 3 and, although they were unable to sequence the fragment completely, they identified two mutations in the first repeat of exon 3 in 14 families with ichthyosis vulgaris: R501X and 2282del4. Both mutations result in formation of a premature stop codon and complete loss of filaggrin peptide production. Analysis of the pedigrees indicated that these mutations are semidominant with individuals homozygous for either mutation or compound heterozygous being severely affected while heterozygotes were only mildly affected. Two heterozygous individuals did not show any clinical symptoms, suggesting incomplete penetrance. The combined allele frequency of the two mutations was estimated as 4% in populations of European ancestry. In a second report, six Irish families with ichthyosis vulgaris were screened for mutations in the FLG gene. In all six families, the severely affected index patients were homozygous or compound heterozygous for FLG mutations and the semidominant mode of inheritance was confirmed. In one family, a third FLG mutation, 3702delG, was identified in the third repeat block that, in compound heterozygous state with R501X, produced an indistinguishable severe phenotype of ichthyosis vulgaris. Yet, in contrast to the previously reported mutations, the 3702delG mutation was found to be very rare (undetectable in about 400 population controls). A third recent report found the R501X and 2282del4 mutations in 15 of 21 patients with a severe ichthyosis vulgaris phenotype. Yet, in this group of patients not only homozygous or compound heterozygous individuals were severely affected but also heterozygous individuals, and six patients with a severe phenotype did not harbour either of these two mutations, raising the question of whether or not additional allelic or nonallelic mutations might be detectable in these patients.[31] Very recently, the first analysis of FLG loss-of-function mutations in a non-European cohort was published. Evaluation of the R501X and 2282del4 mutations in Japanese individuals showed that they were absent in both

families with ichthyosis vulgaris and healthy controls. Subsequently, sequencing of the FLG gene in four Japanese families with ichthyosis vulgaris revealed two novel mutations (3321delA and S2554X). Both mutations result in formation of a premature stop codon, and skin biopsies from affected family members demonstrated that keratohyaline granules were greatly reduced in quantity. 4

Figure 1. FLG mutation detection and confirmation. (a) Schematic diagram of FLG, (b) long-range PCR product from genomic DNA covering exon 3, (c) normal aequence from fillagrin repeat 1 in exon 3, (d) heterozygous transition mutation 1501C, (e) heterozygous mutation resulting in a nonsense codon, (f) corfirmation of mutation R501X, (g) normal sequence, (h) overlapping peak owning heterozygous deletion mutation, 2282del4

Figures 2. Fillagrin deficiency and mechanism of possible disease

Mutations in the gene encoding filaggrin have been identified as the cause of ichthyosis vulgaris and shown to be major predisposing factors for atopic dermatitis both in European and Japanese populations. Mutations at any site within FLG appear to cause significant effects, possibly accounting for the lack of genotype-phenotype correlation observed in patients with FLG mutations.

3. Clinical feature

- ichthyosis vulgaris is characterized by fine white scale covering the entire body and pronounced skin dryness. The scale can be centrally attached with superficial fissuring at the edges. - The scale are more prominent and coarser at the lower extremities and at the extensor surfaces. The axillary and gluteal folds are usually not involved, and the elbow and knee flexures as well as the diaper area (in chidren) are most often spared. Hyperkeratosis of the palm and soles usually coexist. Hypohidrosis (decreased sweating) may occur, because of the involvement of the adnexal structures of the skin, with subsequent heart intolerance.5 - The scales increase in severity and extent with cold and dry weather and ameliorate in warm, humid climates6 - Several conditions, including keratosis pilaris and atopic dermatitis, are more frequent in patient with ichthyosis vulgaris. - Autosomal co-dominant ichthyosis vulgaris usually appears within the first year of life. Pruritus, palmar and plantar hyperlinearity, atopic dermatitis, and keratosis pilaris are often seen in ichthyosis vulgaris.5 - Multiple sulfatase deficiency and Ref-sum disease are syndromes associated with ichthyosis vulgaris

- Several joint disorders associating with ichthyosis have been reported such as digital contracture with palmop- lantar keratoderma - Atopic manifestations (eg, asthma, eczema, hay fever)

4. Diagnosis - Usually the diagnosis is made based on the clinical findings. The existence of associated conditions such as hyperlinear palms and soles associated with atopy, or keratosis pilaris5 - Family history and family pedigree point to a dominant mode of inheritance - Biopsies from involved areas show moderate hyperkeratosis with a markedly reduced or absent granular layer. The thickness of spinous layer is normal. The findings are distinctive but not pathognominic. Examination with electron microscopy reveals irregular (fragmented or spongy) keratohyalin granules7 - Mild forms can be confused with xerosis (dry skin), while severe forms in males are difficult to distinguish from x-linked ichthyosis. Other inherited forms of ichthyosis as well as acquired ichthyosis are also included in the differential diagnosis.4 - Histological finding : hyperkeratosis, diminished granular layer, thinned epidermis, diminished rete pattern, small skip areas 1 or 2 cells wide in which granular cell is totally absent. No epidermolysis.3

5. Differential diagnosis - asteatotic eczema - atopic dermatitis - contact dermatitis, allergic, irritant - drug eruptions - ichthyosis fetalis - ichthyosis lamellar - ichthyosis X-linked - impetigo

Ichthyosis vulgaris

x-linked ichthyosis

Bullous congenital ichthyosifor m erythroderm a (BCIE)

Lamellar ichthyosis

Harlequin ichthyosis

Frequenc y

Common

uncommon XR

rare AD

rare AR

Very rare AR

Inheritanc SD

e pattern Age onset Skin symptom (site)

(semidominan t) At birth or At birth or At birth early birth Extrimities, abdomen), intertriginous surface Abdomen trunk (back > back, intertriginous sites, = after early birth > Whole body Whole body Whole body after At birth

of Babyhood, infancies

sites, extensor extensor flexor surface (form) Fine scales Large,

> flexor surface dark Severe hyperkeratos is Flushing, fine Markedly or dark brown thick (NBCIE) large (lamellar ichthyosis) hyperkeratosi deep fissures, ectropion Severe hyper or keratosis scales s,

brown scales

Pathology Hyperkeratosi s, granular layer

Hyperkeratos normal granular cell layer

Degeneratio cell layer

Hyperkeratosi (with without parakeratosis)

thinned is

almost n ofgranular s

Causative gene

Filaggrin (FLG)

Steroid sulfatase

Keratin 1 or Transglumina 10 se 1 in some cases

ABCA 12

6. Therapy

Hereditary ichthyosis vulgaris is a chronic disorder that may improve with age but often requires continuous therapy. The severity of acquired ichthyosis usually depends on the status of the underlying systemic condition. The main approach to treatment of both conditions includes hydration of the skin and application of an ointment to prevent evaporation. Hydration promotes desquamation by increasing hydrolytic enzyme activity and the susceptibility to mechanical forces. Pliability of the stratum corneum is also improved. Note the following: Topical retinoids are helpful for some patients. Alpha-hydroxy acids (eg, lactic, glycolic, or pyruvic acids) are effective for hydrating the skin. They work by causing disaggregation of corneocytes in the lower levels of the newly forming stratum corneum. Lactic acid is available as a 12% ammonium lactate lotion, or it can be compounded by prescription in a concentration of 5-10% in a suitable vehicle. Twice-daily applications have shown to be superior to petrolatum-based creams for controlling of ichthyosis vulgaris. 6 Removal of scales can be aided by keratolytics (eg, salicylic acid), which induce corneocyte disaggregation in the upper stratum corneum. A commercially available 6% salicylic acid gel can be used on limited areas. Given the emerging evidence implicating fillagrin deficiency in the pathogenesis of ichthyosis, treatment aimed at restoration of the barrier function has been advocated in ichthyosis and related barrier defect diseases. The newest, EpiCeram (Promius) is formulated with a 3:1:1 ratio of ceramides, cholesterol, and free fatty acids intended to optimize the repair of barrier of function. EpiCeram contains the ceramide hydroxypropyl bispalmitamide MEA. Within the normal epidermal membrane lamellar component, ceramides account for more than 50 percent (by weight) of all lipids and help structure and maintain the water permeability barrier function of the skin. The formulation also contains cholesterol; lipids (capric acid and linoleic acid); the emollients petrolatum and squalane; and the humectant glycerin. Evidence shows that topical application of

ceramides, cholesterol, and lipids in a ratio of 3:1:1 results in replenishment of physiologic lipids, leading to improved barrier function in AD8 Over-the-counter products often contain urea or propylene glycol. Moisturizers containing urea in lower strengths (10-20%) produce a more pliable stratum corneum by acting as a humectant. Propylene glycol draws water through the stratum corneum by establishing a water gradient. Thick skin is then shed following hydration. Propylene glycol is a common vehicle in both prescription and over-the-counter preparations. 9 Topical retinoids (eg, tretinoin) may be beneficial. They reduce cohesiveness of epithelial cells, stimulate mitosis and turnover, and suppress keratin synthesis. Tazarotene, a topical receptor-selective retinoid, has also been effective in one small trial. 10 Ichthyosis vulgaris is not responsive to steroids, but a mild topical steroid may be useful for pruritus. Acquired ichthyosis vulgaris generally tends to improve with treatment of the underlying systemic condition.

7. Prevention a. Take long soaking baths to soften the skin. Then use a rough-textured sponge, such as a loofa sponge, to remove the thickened scales. b. Choose mild soaps that have added oils and fats. Avoid deodorant and antibacterial soaps, which are especially harsh on dry skin. c. After showering or bathing, gently pat or blot your skin dry with a towel so that some moisture remains on the skin. d. Apply moisturizer or lubricating cream while your skin is still moist from bathing. Choose a moisturizer that contains urea or propylene glycol chemicals that help keep your skin moist. Petroleum jelly is another good choice. Cover the treated areas with plastic wrap to keep the petroleum jelly

from staining clothes and furniture.9 e. Apply an over-the-counter product that contains urea, lactic acid or a low concentration of salicylic acid twice daily. Mild acidic compounds help your skin shed its dead skin cells. Urea helps bind moisture to your skin.4 f. Use a portable home humidifier or one attached to your furnace to add moisture to the air inside your home.

Chapter 3 Conclusion

Ichthyosis Vulgaris is considered one of the five main types of ichthyosis (the others being Lamellar Ichthyosis, Congenital Ichthyosiform Erythroderma, X-linked Ichthyosis and Epidermolytic Hyperkeratosis). Most varieties of ichthyosis affect only one person in several thousand or tens of thousands. Ichthyosis vulgaris, sometimes called common ichthyosis (vulgar means common in Latin), is the exception. It appears in approximately one person in every 250 to 300. The name is rarer than the disorder itself, which often goes undiagnosed because people who have it think that they have simple dry skin and never seek treatment. In ichthyosis vulgaris, the skin cells are produced at a normal rate, but they do not separate normally at the surface of the stratum corneum (the outermost layer of skin) and are not shed as quickly as they should be. The result is a build-up of scale. Only a portion of the body may be involved, but scaling is most common and most severe over the lower legs. The scale is usually fine and white. Scaling on the torso is less severe and the face is usually unaffected. If the face is affected, the scaling is usually limited to the forehead and cheeks. Often, the skin on the palms of the hands and the soles of the feet is thickened and may have exaggerated lines. Babies with ichthyosis vulgaris often appear normal when they are born, but the skin abnormalities will almost always begin to show up by their first birthday. Ichthyosis vulgaris sometimes improves in certain climates or during the summer.

Ichthyosis vulgaris also intends to improve with age. Ichthyosis vulgaris was thought be caused by an autosomal dominant gene. If a person inherited the gene for ichthyosis vulgaris, the gene overshadowed the gene for normal skin and the person displayed the disease. However, researchers recently discovered that the disorder is semi-dominant. Profilaggrin (a protein that makes up most of the granules in the granular layer in the epidermis) was reduced or absent from the skin or people with vulgaris. Severely affected individuals have mutations in both copies of the profilaggrin gene, while people with only one copy of the mutated gene usually have a very mild skin problem. Ichthyosis vulgaris is treated topically with moisturizers containing urea or glycerol. Lotions containing alpha-hydroxy acids may help. (For more information on which products contain these ingredients, refer to the Foundations Skin Care Products.) However, some individuals with ichthyosis vulgaris also experience atopic dermatitis (red, itchy patches of skin) and the alpha-hydroxy acids may irritate their skin.

Reference :

1.

Necmettin Akdeniz, MD. A Case Report of Ichthyosis Vulgaris with Arthropathy and Ophthalmic Findings. J Turk Acad Dermatol 2011; 5 (3): 1153c3

2.

Alan D. Irvine, M.D., W.H. Irwin McLean, Ph.D., D.Sc. Filaggrin Mutations Associated with Skin and Allergic Diseases. N Engl J Med 2011;365:1315-27

3.

Colin N A Palmer. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature genetic. 2006 ; doi:10.1038/ng1767

4.

Frances JD Smith. Loss of function mutation in the gene encoding filaggrin cause ichthyosis vulgaris. 2006; doi:10.1038/ng1743

5. 6.

Alan Irvine. The gene for ichthyosis vulgaris is finally found. ISG. 2006 Bremmer SF. Clinical detection of ichthyosis vulgaris in an atopic dermatitis clinic: implications for allergic respiratory disease and prognosis. J Am Acad Dermatol. 2008 Jul;59(1):72-8

7.

Cuevas-Covarrubias SA. Accuracy of the clinical diagnosis of recessive X-linked ichthyosis vs ichthyosis vulgaris. J Dermatol. 2000 Aug;25(8):556-7.

8.

Smith F, et al. Mutations in Gene Cause Ichthyosis Vulgaris. Nature Genetics 2004;38(3):337-342.

9.

BARRIE JAY, R. K. BLACH. OCULAR MANIFESTATIONS OF ICHTHYOSIS. Brit.J.Ophthal.(1998)52,217

10.

J.G.KOPPE,A.MARINKOVIC-ILSEN.X-linkedichthyosis. Archives of Disease in Childhood, 1999, 53, 803-806