DEFINITION
Ichthyosis is a heterogeneous family of at least 28, generalized, mostly genetic skin disorders. The word ichthyosis comes from the Ancient Greek ιχθύς (ichthys), meaning fish.
Ichthyosis Vulgaris is a skin disorder causing dry, scaly skin. It is the most common form of ichthyosis (it accounts for more than 95% of cases) and it is usually an autosomal dominant inherited disease (although a rare non-heritable version called acquired ichthyosis exists): for these reasons it is also known as "Autosomal dominant ichthyosis", "Ichthyosis simplex" and "Common ichthyosis".
(Hereditary and Acquired Ichthyosis Vulgaris, 2013 )
EPIDEMIOLOGY
Hereditary ichthyosis vulgaris is found worldwide, and the prevalence depends on the location. It is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren.
Acquired ichthyosis is extremely rare and it usually appears in adulthood.
Age
The syomptoms of hereditary ichthyosis vulgaris typically is absent at birth. They appear 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.
Sex
Hereditary and acquired ichthyosis occur equally in men and women.
Seasonality
The majority of people with ichthyosis vulgaris can sweat at least a little because of the scales, this means most would be more comfortable living in a hot and humid climate. Sweating helps to shed scales which improves the appearance of the skin and prevents "prickly itch". That's why symptoms are lighter in summer than in winter.
Strong air-conditioning and excessive consumption of alcohol can also increase the build up of scales.
Race
Mutations of the filaggrin gene, which cause ichthyosis, are observed in approximately 7.7% of Europeans and 3.0% of Asians, but appear to be infrequent in darker-skinned populations.
(Hereditary and Acquired Ichthyosis Vulgaris, 2013 )
(Ichthyosis vulgaris: the filaggrin mutation disease, 2013 )
SYMPTOMS
Although the skin in hereditary ichthyosis vulgaris looks and feels normal at birth, it gradually becomes rough and dry in early childhood.
The phenotypic characteristics of ichthyosis vulgaris include palmar hyperlinearity, keratosis pilaris, and dry, scaly skin.
Scales are small, fine, irregular, and polygonal in shape, often curling up at the edges to give the skin a rough feel. They range in size from 1–10 mm and in color from white to gray to brown, with darker-skinned people often having darker scales. The legs are usually affected more than the arms and the flexor surface of limbs is usually not involved, the forehead and cheecks may be affected in children but not in adults.
Keratosis pilaris (follicular hyperkeratosis) occurs on the side of the cheek and neck, dorsum of the upper arms, buttocks, and thighs. It consists of spiny parafollicular papules that when palpated resemble a cheese grater. Dried skin in the central portion is often white and mistaken for pus. Inflammation may or may not be present.
The pictures below show scaly skin on trunk and limbs and palmar hyperlinearity.
(Filaggrin Genotype in Ichthyosis Vulgaris Predicts Abnormalities in Epidermal Structure and Function, 2011)
(Dermacase. Ichthyosis vulgaris, 1998 )
DIAGNOSIS
HISTOLOGIC DIAGNOSIS
Skin biopsy specimens can be examined under light microscopy and electron microscopy. Take biopsy samples from regions of maximal hyperkeratosis because areas of mild scaling are less reliable for histopathologic analysis and findings may be indistinguishable from those of normal skin. The thickest scales are usually found on the anterior aspect of the lower leg.
The histological appearance of both hereditary ichthyosis and acquired ichthyosis is practically identical. The stratum corneum shows compact hyperkeratosis, although some areas can be laminated. Follicular plugging may be present and represents associated keratosis pilaris. The granular layer is usually one-layer thick or absent.
Ultrastructural studies show reduced or absent keratohyalin granules housed in the granular layer. They appear spongy or crumbly, most likely due to defective keratohyalin synthesis.
(Ichthyosis vulgaris: identification of a defect in synthesis of filaggrin correlated with an absence of keratohyaline granules, 1985 )
PATHOGENESIS
Profilaggrin is a major protein component of the keratohyalin granules of mammalian epidermis. It is initially expressed as a large polyprotein precursor which is subsequently proteolytically processed into individual functional filaggrin molecules, which aggregates keratin intermediate filaments in the lower stratum corneum, this condensed cytoskeleton is crosslinked by transglutaminases during formation of the cornified cell envelope (CCE). The CCE is the outermost barrier layer of the skin which not only prevents water loss but also impedes the entry of allergens and infectious agents. Afterward, filaggrin is proteolyzed and metabolized, producing free amino acids that play a critical role as water-binding compounds in the upper stratum corneum.
The profilaggrin molecule is composed of an N-terminal domain which has calcium-binding and nuclear localization components, followed by 10, 11 or 12 nearly identical filaggrin repeats which have keratin-binding properties, plus a C-terminal domain of unknown function.
Each of these components has a different function in the differentiating epidermis.
- the S100-like calcium binding domain: calcium is a critical factor for keratinocyte differentiation and for the expression of differentiation markers, such as loricrin and profilag-
grin, a calcium gradient has been demonstrated within the epidermis in which the calcium ion concentration in granular cells, where profilaggrin is expressed, is much higher than in undifferentiated basal cells. The specific role of this calcium binding domain is still being studied:
- calcium binding is necessary for the correct folding and subsequent packing of profilaggrin into keratohyalin granules
- calcium is involved in regulating transcription or translation itself: the accumulation of profilaggrin and binding of calcium ions might lead to the cessation of its own transcription, which requires relatively high calcium levels
- the S100-like domain may bind calcium that is required for the processing of profilaggrin to
filaggrin
- the N-terminal domain is cleaved from profilaggrin and translocates to the nucleus where it may play a role in the enucleation of keratinocytes in the outer stratum corneum.
- the precise function of the C-terminal domain is unclear but it is known to be required for the processing of profilaggrin to filaggrin.
Filaggrin is therefore a key protein in facilitating epidermal differentiation and maintaining barrier function: loss or reduction of profilaggrin leads to varying degrees of impaired keratinization.
(One remarkable molecule: Filaggrin, 2012)
(Filaggrin in the frontline: role in skin barrier function and disease)
(Characterization of the human epidermal profilaggrin gene. Genomic organization and identification of an S-100-like calcium binding domain at the amino terminus, 1992 )
PATIENT RISK FACTORS
GENETIC INHERITANCE
Ichthyosis Vulgaris is passed down through families with autosomal dominant inheritance: this means that an abnormal gene from one parent can cause disease, even though the matching gene from the other parent is normal. In this disease the altered gene is the gene encoding for filaggrin, which 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.
FLG mutations are observed in approximately 7.7% of Europeans and 3.0% of Asians, but appear to be infrequent in darker-skinned populations.
Homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) are the cause of moderate or severe ichthyosis vulgaris, mainly in European population. These mutations are semidominant and heterozygotes show a very mild phenotype with incomplete penetrance (the authors calculated a penetrance in heterozygotes of 90%).
Later, the FLG gene was sequenced in Japanese families with ichthyosis vulgaris in which the European-specific mutations R501X and 2282del4 were absent and 2 novel mutations were identified: 3321delA and S2554X.
(Ichthyosis vulgaris: the filaggrin mutation disease, 2013 )
(Physical mapping of a functional cluster of epidermal differentiation genes on chromosome 1q21, 1993 )
(Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris, 2006 )
(Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis, 2007 )
ACQUIRED ICHTHYOSIS
Acquired ichthyosis is clinically indistinguishable from hereditary ichthyosis, it is a rare nonhereditary condition associated with internal diseases, including malignancy (for example anaplastic large cell lymphoma and mycosis fungoides), sarcoidosis, leprosy, thyroid disease, hyperparathyroidism, nutritional disorders, chronic renal failure, bone marrow transplantation, and HIV infection. Autoimmune diseases, including systemic lupus erythematosus and dermatomyositis, are also linked.
(Ichthyosiform eruptions in association with primary cutaneous T-cell lymphomas, 2009 )
COMPLICATIONS and ASSOCIATED DISEASES
Ichthyosis vulgaris may cause:
- overheating: scales can reduce the capability to sweat, preventing an adequate termoregulation
- secondary infections: skin lesions favor cutaneous or more extended infections
Moreover it is often associated with atopic dermatitis and atopic asthma, in fact FLG deficiency provokes a paracellular barrier abnormality that reduces inflammatory thresholds to topical irritants, likely accounting for enhanced antigen penetration.
(FILAGGRIN DEFICIENCY CONFERS A PARACELLULAR BARRIER ABNORMALITY THAT REDUCES INFLAMMATORY THRESHOLDS TO IRRITANTS AND HAPTENS, 2009)
(The allergy gene: how a mutation in a skin protein revealed a link between eczema and asthma, 2011)
TREATMENT
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.
Because there is no cure for ichthyosis, treatment is targeted at managing the signs and symptoms. Treatment may include creams, lotions, or ointments to relieve dryness.
- topical retinoids (tretinoin or tazarotene, which is converted in tazarotenic acid) increase epidermal cell mitosis and turnover while suppressing keratin synthesis
- humectants (Ammonium Lactate 12%, cream or lotion) moisturize the skin and reduces excessive epidermal keratinization by causing loss of adhesiveness between corneocytes
- glycerol-based emollient creams
- urea-based lotions
- combined therapy with both Ammoniun Lactate and a lipid-based repair cream (containing ceramides, cholesterol, and free fatty acids) in order to care for both the corneocytes (“bricks”) and the intercellular lipid bilayer (“mortar”) of the skin.
(Efficacy of topical 10% urea-based lotion in patients with ichthyosis vulgaris: a two-center, randomized, controlled, single-blind, right-vs.-left study in comparison with standard glycerol-based emollient cream, 2011 )
(Hereditary and Acquired Ichthyosis Vulgaris, 2013 )
(Dermacase. Ichthyosis vulgaris, 1998 )
(Overcoming the Barrier Treatment of Ichthyosis: A Combination-therapy Approach, 2010 )
