Ichthyosis refers to a relatively uncommon group of skin disorders characterized by the presence of excessive amounts of dry surface scales. It is regarded as a disorder of keratinization or cornification, and it is due to abnormal epidermal differentiation or metabolism.
The ichthyosiform dermatoses may be classified according to clinical manifestations, genetic presentation, and histologic findings. Inherited and acquired forms of ichthyosis have been described, and ocular alterations may occur in specific subtypes. Five distinct types of inherited ichthyosis are noted, as follows: ichthyosis vulgaris, lamellar ichthyosis, epidermolytic hyperkeratosis, congenital ichthyosiform erythroderma, and X-linked ichthyosis.
Ichthyosis vulgaris is characterized by onset in early childhood, usually between age 3 and 12 months, with fine scales and varying degrees of dryness of the skin. Scaling is most prominent over the trunk, abdomen, buttocks, and legs. The flexural areas, such as the antecubital fossa, are spared. An association may be present between ichthyosis vulgaris and atopic diseases because one third to one half of patients show features of atopic disease and a similar proportion have relatives with atopic disease. A reported 11.5% association is noted between atopic dermatitis and primary hereditary ichthyosis. Ichthyosis vulgaris typically produces no significant ocular findings; however, scaling may be present on the eyelid skin, which could lead to punctate epithelial keratitis and recurrent corneal erosion. Linkage analysis has identified an ichthyosis vulgaris locus on band 1q22.
Two loss-of-function mutations in the coding of the filaggrin gene have been identified in both ichthyosis vulgaris and atopic dermatitis. Keratohyalin synthesis is affected because of the filaggrin mutation. Filaggrin is an epidermal protein that normally functions as a barrier molecule against environmental allergens, water loss, and infection.
In epidermolytic hyperkeratosis (bullous ichthyosiform erythroderma), a mild generalized erythroderma is present at birth. Bullae formation may occur, which may become infected and give rise to a foul skin odor.Erythrederma fades in infancy while the characteristic grey, waxy scale progresses. They are particularly prominent in the flexural creases. A mutation in the keratin genes (ie, KRT1, KRT10) is the cause of this autosomal dominant disorder.
Lamellar ichthyosis is a rare, autosomal recessive, genetically heterogeneous skin disease caused by mutations involving multiple genetic loci. Type 1 maps to band 14q11.2 and is caused by mutations in the gene for keratinocyte transglutaminase 1, an enzyme responsible for the assembly of the keratinized envelope. Type 2, which is clinically indistinguishable from type 1, maps to band 2q33-q35. In classic lamellar ichthyosis, children with the disease are referred to as collodion babies and are covered at birth by a thickened membrane that subsequently is shed. The scaling of the skin involves the whole body with no sparing of the flexural creases. Approximately one third of children affected with this disorder develop bilateral ectropion of the cicatricial type that appears to result from excessive dryness of the skin and subsequent contracture. Secondary corneal ulceration may occur secondary to long-term exposure.
In X-linked ichthyosis, generalized scaling is present at or shortly after birth. This scaling is most prominent over the extremities, neck, trunk, and buttocks. The flexural creases may be involved but palms, and soles are spared. Irregular stromal corneal opacities that are located anterior to the Descemet membrane are found in 16-50% of male patients, and this finding may be used to distinguish this form of ichthyosis from all other forms. Approximately 25% of female carriers have minor corneal opacities. The corneal opacities are not known to affect visual acuity. An example of findings in X-linked ichthyosis is shown in the image below.
This slit beam illumination photograph of the cornea localizes the corneal opacity to the posterior stroma and the pre-Descemet membrane region. This ....
Previous studies have shown a deficiency of steroid sulfatase (STS) in skin fibroblasts and a marked elevation of plasma cholesterol sulfate in patients with X-linked ichthyosis. In most cases, STS deficiency is caused by a partial or complete deletion of the STS gene mapped on band Xp22.3. Deletions of the STS gene have systemic effects, such as corneal opacities, cryptorchidism, and failed progression during labor. Deletions to flank regions of the STS gene have been linked with mental retardation. These deletions involve portions of the VCXA and VCXB1 genes.
Nonbullous congenital ichthyosiform erythroderma (NBIE) or congenital ichthyosiform erythroderma (CIE) is a milder form of the disease that is autosomal recessive in inheritance.CIE has been found to be caused by mutations in the genes coding for transglutaminase 1, 12R-lipoxygenase, and/or lipoxygenase 3. The lipoxygenase genes play a role in the epidermal permeability layer. As with lamellar ichthyosis, neonates with CIE are referred to as collodion babies, but, as children and adults, they show generalized red skin with thin, white scaling. Other manifestations include persistent ectropion and scarring alopecia.
Multiple congenital ectodermal dysplastic syndromes are associated with scaling and other system defects. The keratitis, ichthyosis, and deafness (KID) syndrome is a congenital disorder of ectoderm that affects not only the epidermis but also other ectodermal tissues, such as the corneal epithelium and the inner ear. KID syndrome may present with the Hutchinson triad (the combination of notched, widely spaced peg teeth, interstitial keratitis, and deafness). KID syndrome has been linked to mutations in the connexin 26 gene (GJB2) on band 13q11-q12.
The colobomas of the eye, heart defects, ichthyosiform dermatosis, mental retardation, and ear defects (CHIME) syndrome comprise a rare neuroectodermal disorder.
Netherton syndrome is an autosomal recessive condition that consists of an ichthyosiform dermatosis with variable erythroderma, hair shaft defects, and atopic features. Netherton syndrome has been linked to a mutation on band 5q32, specifically encoding for LEKTI (lymphoepithelial Kazal-type—related inhibitor), a serine protease inhibitor.
Sjögren-Larsson syndrome is an autosomal recessive condition that comprises ichthyosis, spastic diplegia, pigmentary retinopathy, and mental retardation.
Congenital hemidysplasia with ichthyosiform erythroderma or nevus and limb defects (CHILD) syndrome is a rare X-linked dominant malformation syndrome characterized by unilaterally distributed ichthyosiform erythroderma or nevi, often sharply delimited at the midline, and ipsilateral limb defects. This syndrome is caused by a loss-of-function mutation of nicotinamide adenine dinucleotide phosphate (NADPH) steroid dehydrogenase-like (NSDHL) protein at band Xq28.
Acquired ichthyosis usually occurs in adults and manifests as small, white, fishlike scales that frequently are concentrated on the extremities but may be seen in a generalized distribution. This form of ichthyosis may be associated with internal neoplasia (eg, Hodgkin lymphoma, leukemia), systemic illness (eg, sarcoidosis, HIV infection, hypothyroidism, chronic hepatitis, malabsorption), bone marrow transplantation, or the intake of certain medications that interfere with sterol synthesis in epidermal cells (eg, nicotinic acid).
Newborns with type 2 Gaucher disease (glucosyl cerebroside lipidosis) may present with ichthyotic skin at birth prior to neurologic manifestations, which could be mistaken for a congenital form of ichthyosis.
Ichthyosis vulgaris is the most common form and is an autosomal dominant trait with an incidence of 1 case per 300 population. Epidermolytic hyperkeratosis is an autosomal dominant disorder with an incidence of 1 case per 300,000 population. Lamellar ichthyosis, a more severe form of dermatosis, is an autosomal recessive trait with an incidence of 1 case per 300,000 population. X-linked recessive ichthyosis has an incidence of 1 case per 6000 males.
Studies show that a higher prevalence of X-linked ichthyosis as compared to ichthyosis vulgaris may be noted in Mexico, which is markedly different from the experience in the United States. In the United Kingdom, the incidence of ichthyosis vulgaris was reported to be 1 case per 250 population, in a study population of 6501 healthy school children. Similarly, in another large epidemiological study, the incidence of X-linked recessive ichthyosis was 1 case in 6190 males. In a Danish population study, the predicted incidence of X-linked recessive ichthyosis was 1 case per 2000 males. In a Danish study, Bygum et al concluded that epidermolytic ichthyosis had a prevalence of approximately 1 in 350,000, with a high percentage of de novo mutations (75%). In southern coastal Italy, the frequency of X-linked recessive ichthyosis was estimated at 1.98 in 10,000 males. In China, ichthyosis vulgaris has a prevalence of 2.29%.
An increased risk of testicular cancer in men with ichthyosis vulgaris has been suggested. In addition, an increased incidence of testicular maldescent, cryptorchidism, abnormalities of the sperm count or motility leading to infertility, and testicular cancer has been reported in patients with X-linked recessive ichthyosis.
In general, all races may be affected in the inherited and acquired forms of ichthyosis.
X-linked recessive ichthyosis is much more prevalent in males. It is caused by a deficiency of STS. Because this enzyme plays an important role in androgen metabolism, men with this ailment do not show androgenetic alopecia or develop only mild forms of this common type of hair loss.
Ocular and periocular manifestations that may be seen in the ichthyosiform syndromes include the following:
Oral retinoids display an impressive antikeratinizing action in ichthyosiform dermatoses. Acitretin (25-50 mg/d) and Isotretinoin (0.5-2 mg/kg/d) have been shown to reduce scaling, discomfort, and disfigurement. However, when these drugs are discontinued, the ichthyotic skin recurs, thereby necessitating long-term use.
Liarozole (150 mg bid), an imidazole derivative, inhibits the cytochrome P450-dependent 4-hydroxylation of retinoic acid, resulting in increased tissue levels of retinoic acid and a reduction in epidermal proliferation and scaling. It is a broad-spectrum antifungal agent; inhibits cytochrome P450 metabolic pathways, increasing levels of cytochrome P450 metabolized drugs. The US FDA has not approved this medication for use.Patients with epidermolytic hyperkeratosis may develop chronic bacterial infections of the skin necessitating long-term antibiotic therapy.
N-acetylcysteine 10% emulsion, a nontoxic and hypoallergenic amino acid derivative, can be safely and efficaciously used in the topical treatment of neonatal ichthyosis.
Clinical Context: The synthetic 13-cis isomer of the naturally occurring tretinoin (trans -retinoic acid). Both agents are structurally related to vitamin A.
Clinical Context: Metabolite of etretinate and related to retinoic acid and retinol (vitamin A). Mechanism of action unknown but thought to exert therapeutic effect by modulating keratinocyte differentiation, keratinocyte hyperproliferation, and tissue infiltration by inflammatory cells.
These agents decrease cohesiveness of abnormal hyperproliferative keratinocytes and may reduce potential for malignant degeneration. They modulate keratinocyte differentiation and have been shown to reduce risk of skin cancer formation in renal transplant patients.
Clinical Context: This is for patients with epidermolytic hyperkeratosis who develop bacterial infections of the skin .
Patients with epidermolytic hyperkeratosis may develop chronic bacterial infections of the skin necessitating long-term antibiotic therapy.
Clinical Context: Promotes hydration and removal of excess keratin in conditions of hyperkeratosis.
These agents are used to prevent cicatricial ectropion in lamellar ichthyosis, a humidified atmosphere combined with the use of topical moisturizing agents is beneficial. Petrolatum ointment and 10% urea cream applied to the eyelid skin several times daily helps to prevent skin contracture. Salicylic acid 2% and retinoic acid 0.1% ointments are also effective, but local irritation may limit their frequency of use.
Clinical Context: Lubricates and relieves dry eyes and eye irritation associated with deficient tear production.
In chronic ocular surface disorders associated with ichthyosis, nonpreserved artificial tears (carboxymethylcellulose sodium 0.5-1.0%) and ointment (white petrolatum 56.8%, mineral oil 41.5%) are preferred to prevent complications from dryness and exposure. Preservative-free lubricants may be used as often as needed while decreasing the incidence of preservative-related allergies. In cases where poor corneal epithelial adhesion is present, bandage contact lenses and temporary collagen shields may decrease symptoms and promote surface healing.
Clinical Context: N-acetylcysteine is a glutathione precursor. It may provide effective photoprotection by increasing the availability of glutathione, a potent antioxidant. A nontoxic 10% emulsion and hypoallergenic amino acid derivative can be safely and efficaciously used in the topical treatment of neonatal ichthyosis.
Agents in this category may prove effective in the topical treatment of neonatal ichthyosis.