Hereditary and Acquired Ichthyosis Vulgaris

Updated: Jul 19, 2017
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

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.

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. Mutations in genes relating to skin barrier formation produce it. [1] It is often 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 [2] and representing a major risk factor for the development of atopic dermatitis. [3] This discovery, in 2006, represented a marked a breakthrough in the understanding of these disorders. [4] Next-generation sequencing is capable of facilitating diagnosis and determining genetic causes. [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.

Other Medscape Drugs & Diseases articles on ichthyosis include the following:

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Pathophysiology

Ichthyosis vulgaris is classified as a retention hyperkeratosis. 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 water-binding compounds in the upper stratum corneum. Normal cycles of skin hydration and dehydration contribute to normal desquamation. These cycles are disrupted in ichthyosis vulgaris.

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.

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. [5, 6] 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.

An association exists between filaggrin null mutations of ichthyosis vulgaris and atopic dermatitis. [7, 8] 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. [9] 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.

Filaggrin mutations p.R501X and c.2282del4 were analyzed in patients with ichthyosis vulgaris. [10] 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. [11] Mutations R501X and 2282del4 represent the most frequent genetic cause in German ichthyosis vulgaris patients, but are probably population and family specific. [12]

Filaggrin mutations were identified in three Chinese pedigrees with ichthyosis vulgaris, two having novel FLG null mutations (c.477-478insA and c.6218-6219delAA) and a known mutation (c.3321delA). [13] The proband of one pedigree was compound heterozygous for these mutations, yet had a mild phenotype. Targeted next-generation sequencing delineated nine novel FLG variants in other Chinese study. [14]

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. [15, 16]

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. [17]

The percentage of mutations in the FLG gene was 74% with isolated ichthyosis vulgaris compared with 43% in patients with atopic dermatitis–associated ichthyosis vulgaris. [18] Thus, it appears factors other than FLG gene mutations can down-regulate profilaggrin/filaggrin expression, leading to the ichthyosiform phenotype in the context of atopic dermatitis. Interestingly, a complete filaggrin deficiency, but not a partial one, is associated with only moderate changes in transepidermal water loss and skin hydration. [19]

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Epidemiology

Frequency

United States

Hereditary ichthyosis vulgaris is a common disease in the United States, with a prevalence of approximately 1 case in 300 persons. Because symptoms improve with age, the true prevalence is probably higher. Acquired ichthyosis is extremely rare. Its prevalence in the United States is unknown.

International

Hereditary ichthyosis vulgaris is found worldwide, and the prevalence depends on the location. One study in Berkshire, England, observed a frequency of 1 case in 250 schoolchildren. Acquired ichthyosis is extremely rare. Its prevalence worldwide is unknown.

Race

Hereditary and acquired ichthyosis vulgaris have no known racial predisposition.

Sex

Hereditary and acquired ichthyosis occur equally in men and women.

Age

Hereditary ichthyosis vulgaris typically is absent at birth. It appears in most patients during the first year of life and in the vast majority by age 5 years. The extent of scaling usually intensifies up until puberty and subsequently decreases with age.

Acquired ichthyosis usually first appears in adulthood; however, age-associated systemic diseases do occur in children.

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Prognosis

The prognosis for hereditary ichthyosis vulgaris is excellent. Many patients experience improvement of symptoms with age. The prognosis for acquired ichthyosis vulgaris depends on the severity of the underlying systemic disease.

Children and adolescents with hereditary ichthyosis vulgaris may experience some morbidity in terms of cosmesis. Secondary infections may occur in fissures of the hands and feet. The morbidity and mortality of acquired ichthyosis in adults is due to associated internal disease.

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