Ichthyosis a keratinization disorder, the skin becomes dry and scaly, might like fish appearance. The keratinization process cells in the stratum corneum are changing shape and number of cells. The process of epidermal differentiation is abnormal due to mutations of certain genes in various types of ichthyoses. Etiology genes identified as important in ichthyosis has increased. These genes cause changes in barrier function in the stratum corneum. The most common ichthyosis is ichthyosis vulgaris and has a fairly good prognosis. The rare and highest severity ichthyosis is harlequin ichthyosis and has a poor prognosis because of its high morbidity rate [1].

Ichthyosis has various types, but the common ones are Harlequin Ichthyosis (HI), Lamellar Ichthyosis (LI), Congenital Ichthrodermic Erythroderma (CIE), Epidermolytic Hyperkeratosis (EHK), X-Linked Recessive Ichthyosis (RXLI) to the mildest form is Ichthyosis   Vulgaris (IV), as well as Siemens Bullous Ichthyosis (SEI). In general, the clinical diagnosis can distinguish the various types of ichthyoses, however, a histopathological diagnostic examination is needed to confirm the diagnosis [2].

Histopathological examination showed a varied picture according to the type of ichthyosis, which was dominated by thickening of the stratum corneum, thinning of the stratum granulosum and the presence of perivascular lymphohistiocytic infiltrates and protein in the dermis layer. Histopathological examination can help make the diagnosis as early as possible so that it can accelerate the administration of therapy so as to improve quality of life and reduce mortality and morbidity due to ichthyosis [3].

Treatment that can be done in cases of ichthyosis is symptomatic treatment to reduce disturbing complaints. Topical keratolytic drugs to reduce the thickening of epidermal cells. Meanwhile, symptomatic drugs can be in the form of emollients due to dry skin and antihistamines if there are complaints of itching. Patients should also be educated about the conditions causing ichthyosis, the routine medications that should be given and the factors that can make it worse [4].

Etiology and Pathogenesis

In some of these disorders, the gene defect becomes a key component of the process that causes ichthyosis. The etiology of ichthyosis is not known to date, but recent research has reached an understanding of the molecular basis of the human epidermal keratinization process and the causes of ichthyosis [5,6].

In 1978, the disorder causing RXLI was identified as a steroid sulfatase deficiency caused by a genetic defect in the steroid sulfatase gene. In 1992, mutations in the Keratin 1 (KRT1) and keratin 10 (KRT10) genes were detected as the cause of EHK. Mutation of the Transglutaminase (TGase) 1 (TGM1) gene was identified as the cause of LI in 1995, mutations in several other genes have also been identified in severe autosomal recessive hereditary ichthyosis in 2005, mutations in the ABCA12 gene causing HI. In 2006, a null mutation in the filaggrin coding gene (FLG) was detected as a defect causing IV [7,8].

To date, the number of genes identified and shown to cause ichthyosis in human patients has reached eleven. Barriers function in the stratum corneum as an underlying pathogenetic mechanism. The skin barrier in the stratum corneum can occur in three main components, namely the intercellular lipid layer, cornified cells and keratin / filaggrin degradation products. In 2009, the first ichthyosis consensus conference was held to establish a consensus on the nomenclature and classification of inherited ichthyosis and an international consensus on the classification of inherited ichthyosis was achieved [2,10].

The end product of the fully differentiated epidermis is the stratum corneum, which is composed of terminal keratinocytes called corneocytes, which are surrounded by an intercellular matrix. Corneocytes are enriched by protein, while the intercellular cellular matrix consists of a hydrophobic membrane enriched with keratin lipids. Corneocytes are thought to have good water resistance and retention properties in the stratum corneum, while their intercellular matrix has permeability barriers to water loss. The normal stratum corneum is desquamated regularly and is not visible. The process of epidermal differentiation is complex and not fully understood. This disorder can be caused by many aspects and stages of this process can cause disruption of the stratum corneum and abnormal scales [2,11].

Clinical Manifestations, Investigations and Classification of Ichthyosis

The clinical manifestations of ichthyosis vary according to the type. The specific diagnosis of an individual with ichthyosis can help predict the prognosis. Age at onset, presence of colodion membrane at birth, quality of scales, presence or absence of erythroderma, abnormalities of other skin parts (palms and feet, ectropion, eclabium) and adnexal structures (alopecia, hair follicles, or hair shaft abnormalities) and associations other organ systems are useful in differentiating forms of ichthyosis. Hyperkeratosis that occurs can be different in each type of ichthyosis. Family history can clarify the hereditary pattern of ichthyosis [1,3].

Table 1: Essential Components of The Stratum Corneum Barrier and Causative Molecules/Genes in Ichthyosis [9]

Table 2: Types and Characteristics of Hereditary Ichthyosis [8]

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; EHK, epidermolytic hyperkeratosis; SEI, Siemens bullous ichthyosis; IH, histric ichthyosis of Curth and Macklin; EV, erythrokeratoderma variabilis; CIE, congenital ectocystic erythroderma; LI, lamellar ichthyosis; HI, Harlequin ichthyosis; RXLI, X-linked recessive ichthyosis; IV, ichthyosis vulgaris

Table 3: Summary Profiles of Several Types of Ichthyoses and Differential Diagnosis [8,12,13]

The diagnosis of ichthyosis is carried out based on history, physical examination, laboratory examination and a multidisciplinary approach. The current laboratory examination which is the gold standard in diagnosing ichthyosis is histopathological examination. In addition, immunohistology, hair analysis, electron microscope examination, skin biopsy (measuring enzyme activity), measuring the activity of steroids sulfatase and other metabolites using peripheral blood (EDTA) and molecular genetic studies [4,8].

Currently there are more than 20 variants of ichthyosis. In general, ichthyosis is divided into hereditary ichthyosis and acquired ichthyosis. Hereditary ichthyosis itself is divided into 2 major groups, namely syndromic hereditary ichthyosis and non-syndromic hereditary ichthyosis [3,4]. Based on the inheritance pattern, ichthyosis is divided into 3, namely autosomal dominant (for example ichthyosis vulgaris-IV), autosomal recessive and x-linked recessive (for example lamellar ichthyosis and non-bullous congenital ichtyosiform erythroderma-NClE) [12].

Based on the degree of severity, ichthyosis is divided into the most severe forms, namely Harlequin Ichthyosis (HI), Lamellar Ichthyosis (LI), Congenital Ichthroderma (CIE), Epidermolytic Hyperkeratosis (EHK), Recessive X-Linked Ichthyosis (RXLI) to the lightest form are ichthyosis vulgaris (IV) and Siemens bullous ichthyosis (SEI). 3Common types of hereditary ichthyosis based on hereditary patterns and clinical findings are listed in Table 2. 

Acquired ichthyosis usually appears for the first time in adulthood, often a condition associated with systemic disease. Acquired ichthyosis is rare and should be watched out as a marker of systemic disease, including malignancy. The cause is usually associated with the use of certain drugs [3].

Management of Ichthyosis

Currently, the management of hereditary ichthyosis is symptomatic and focuses on hydration, lubrication and keratolysis [3]. Iktiotic skin, although thicker than normal skin, has decreased barrier function and increased trans epidermal fluid loss, so that hydration efforts, such as use of moisturizers and long showers, can smoothen skin surface. Areas of hyperkeratosis that are well hydrated can be easier to treat using a mild abrasive agent (sponge, bath wool, stones, etc.). The use of oils while bathing or lubricants such as body lotions, creams, oils, ointments, or vaseline can prolong hydration and smoothness [14,15].

Keratolytic agents are used to increase desquamation of corneocytes so as to remove scales and dilute hyperkeratosis in the stratum corneum. The keratolytic agent used can contain urea, salicylic acid, or hydroxy acid. Urea works by its ability to bind water. Propylene glycol has been shown to be effective in removing scales. Occlusion can help improve skin hydration and facilitate the de-exclusion process, as well as enhance the effects of keratolytic agents. Topical retinoin or vitamin D preparations can also be used, but can be irritating in some patients. It should be noted that impaired skin barrier function in ichthyosis should be considered in the use of topical preparations over large areas, such as the use of topical salicylic acid which can cause significant absorption which can lead to intoxication (nausea, tinnitus, spasms, hallucinations) to death [16].

In addition, giving to children also has a greater risk because they have a larger body surface area than adults so that the likelihood of systemic toxicity with topical drug administration is greater. 

Another risk to children is that in some types of ichthyoses, nutritional requirements can be very high and inadequate nutrition can lead to growth failure. Some patients with ichthyosis (especially lamellar erythroderma and congenital ichthrodermic erythroderma) experience decreased sweating with heat intolerance, which is why it is important for parents to be aware of signs such as flushing and lethargy, especially during summer and physical exercise. Avoidance of hot environments and reduce and prevent evaporation and cool the body can minimize heat stress [17,18]. 

Systemic retinoin therapy with isotreonin (0.5-2 mg/ kg/day) and acitretin (25-50 mg/day) can provide substantial clinical improvement in many types of ichthyoses, particularly lamellar ichthroderma, congenital ichthroderma and variabilis erythrokeratoderma. The decision to give systemic retinoin therapy must be considered carefully, because after starting therapy, long-term therapy is needed to get the benefit of continuous therapy. Treatment of Harlequin ichthyosis uses systemic retinoin during infancy can save lives by increasing the desquamation of constricting membranes [19-21].

Currently there are more than 20 variants of ichthyosis based on ethiology. In general, ichthyosis is divided into hereditary ichthyosis and acquired ichthyosis. Hereditary ichthyosis itself is divided into 2 major groups, namely syndromic hereditary ichthyosis and non-syndromic hereditary ichthyosis.

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