Ichthyosis

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Background

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,[1] 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.

Pathophysiology

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 (filament aggregating protein) 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. Erythroderma 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.[2] 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.



View Image

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.[3, 4] 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 (gap junction protein) 26 gene (GJB2) on band 13q11-q12.

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.

Epidemiology

Frequency

United States

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.

International

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%).[5] 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%.

Mortality/Morbidity

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.

Race

In general, all races may be affected in the inherited and acquired forms of ichthyosis.

Sex

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.

History

See Pathophysiology.

Physical

Ocular and periocular manifestations that may be seen in the ichthyosiform syndromes include the following:

Causes

See Pathophysiology.

Laboratory Studies

In some congenital ichthyosiform disorders, routine histopathology, electron microscopy, and frozen sections of skin biopsy specimens may be required to determine the specific classification of disease. Tests that may be required to diagnose the type of ichthyosis may include the following:

Acquired ichthyosis may be a marker of various autoimmune disorders or malignancy. Acquired ichthyosis may also be a marker of concomitant infection with HIV in intravenous drug users and occurs after profound helper T-cell depletion. Important laboratory tests to consider in addition to HIV testing are as follows:

Imaging Studies

In congenital ichthyosis syndromes, excessive intra-amniotic debris and polyhydramnios on ultrasonography scanning in utero may be the first indication of disease.

Using ultrasonography scanning in utero, fetal foot length may be an important and probably the first marker, seen in the second trimester, for the diagnosis of harlequin ichthyosis.

Other echographic findings may include a persistently open mouth, dense amniotic fluid, and fixed flexion of the extremities.

Other Tests

Studies have shown that a low maternal serum unconjugated estriol during pregnancy screening may be a good indication of placental STS deficiency and X-linked recessive ichthyosis.

Microdeletion of the STS gene can be confirmed by fluorescence in situ hybridization (FISH) analysis of cultured amniotic fluid in X-linked ichthyosis.

Prenatal diagnosis of lamellar ichthyosis can be made by direct mutational analysis of the keratinocyte transglutaminase gene.

Procedures

Fetal skin biopsy that examines keratinized hair canals and amniotic fluid at approximately 19 weeks estimated gestation age may provide an early diagnosis of certain forms of ichthyosis (ie, Harlequin type, which is extremely severe and usually fatal).[6]

Histologic Findings

In ichthyosis vulgaris, the affected skin displays mild hyperkeratosis and a diminished granular layer in the epidermis, while the dermis has normal features.

Affected skin in X-linked ichthyosis shows an expanded stratum corneum without parakeratosis or acanthosis. In contrast to ichthyosis vulgaris, the granular cell layer may be normal. However, in some cases, it may be absent, which makes histologic differentiation from ichthyosis vulgaris very difficult.

Lamellar ichthyosis displays massive, compact orthohyperkeratosis with variable degrees of parakeratosis and a markedly thick stratum corneum. The granular layer is either normal or increased.

In epidermolytic hyperkeratosis, the skin biopsy specimen shows epidermal acanthosis and hyperkeratosis. Bullous formation may be manifested by intercellular and intracellular spaces as a result of suprabasal cytolysis within the granular layer.

The skin biopsy specimen from patients with congenital ichthyosiform erythroderma (CIE) shows compact hyperkeratosis and moderate increase in stratum corneum thickness. There is variable mild parakeratosis and acanthosis and a normal or prominent granular layer. A mild upper dermal lymphocytic infiltrate and prominent dermal blood vessels may be present.

Medical Care

Systemic therapy

Oral retinoids display an impressive antikeratinizing action in ichthyosiform dermatoses. Etretinate (1 mg/kg/d) and isotretinoin (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. Similarly, 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.

Patients with epidermolytic hyperkeratosis may develop chronic bacterial infections of the skin necessitating long-term antibiotic therapy.

Patients with Sjögren-Larsson syndrome have a deficiency of fatty aldehyde dehydrogenase (FALDH). Data suggest that bezafibrate, a hypolipidemic drug, induces the activity of FALDH in patients with some residual enzyme activity.

Ocular therapy

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.

Topical therapy

Topical cyclosporine A 2% given 3 times daily has been shown to be beneficial in the treatment of deep stromal keratitis associated with KID syndrome.

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 also are effective, but local irritation may limit their frequency of use. In the hyperproliferative variants of ichthyosis, calcipotriene ointment has been shown to be beneficial. However, the use of calcipotriene in treating congenital hyperproliferative disorders is limited by the theoretical risk of hypercalcemia from absorption of the drug from the skin.

Pimecrolimus 1% (Elidel) an immunomodulating agent used in the treatment of atopic dermatitis, has been shown to be effective in patients with Netherton syndrome. The immunomodulating effects are similar to tacrolimus but without evidence of lipophilic adverse effects.

Surgical Care

When cicatricial ectropion develops in patients with lamellar ichthyosis despite room humidification and vigorous skin lubrication, the danger of corneal breakdown and perforation is noted. Full-thickness skin grafts from the forearm, postauricular, and groin areas may be used to successfully repair the abnormalities.[7] In addition, Apligraf (Organogenesis Inc, Canton, Mass), a human skin equivalent, may facilitate the repair of cicatricial ectropion in severe cases when autologous donor graft tissue is not available. A concomitant medial and/or lateral lid tarsorrhaphy is recommended in severe cases. The incidence of ectropion recurrence may be decreased if surgery can be postponed until suitable nonscaly patches of skin can be clearly identified to serve as graft donor sites.

For a persistent corneal epithelial defect, an amniotic membrane transplantation may be necessary to promote epithelial wound healing.

For diffuse limbal stem cell deficiency, keratolimbal allografting with chronic systemic immunosuppression may be necessary, although the success rate has been poor.

Consultations

Because ichthyosis is primarily a skin disorder, periodic evaluation by a dermatologist is recommended.

The ophthalmologist may be helpful in the treatment of ocular manifestations and in the identification of the specific type of ichthyosis, particularly, lamellar and X-linked forms.

Diet

In patients with Refsum disease (ichthyosis and pigmentary retinopathy), chlorophyll in the diet should be excluded (ie, green vegetables [phytanic acid], animal fat [phytol]). Because rapid weight loss mobilizes tissue phytanic acid, this should be avoided.

Medication Summary

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.

Isotretinoin (Amnesteem, Claravis, Sotret)

Clinical Context:  The synthetic 13-cis isomer of the naturally occurring tretinoin (trans -retinoic acid). Both agents are structurally related to vitamin A.

Acitretin (Soriatane)

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.

Class Summary

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.

Erythromycin (EES, Ery-Tab, Erythrocin)

Clinical Context:  This is for patients with epidermolytic hyperkeratosis who develop bacterial infections of the skin.

Class Summary

Patients with epidermolytic hyperkeratosis may develop chronic bacterial infections of the skin necessitating long-term antibiotic therapy.

Urea (Ureacin, Carmol, Keralac)

Clinical Context:  Promotes hydration and removal of excess keratin in conditions of hyperkeratosis.

Class Summary

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.

Carboxymethylcellulose 0.5 to 1% (Optive, Refresh Plus)

Clinical Context:  Lubricates and relieves dry eyes and eye irritation associated with deficient tear production.

Class Summary

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.

N-acetylcysteine (Acetadote)

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.

Class Summary

Agents in this category may prove effective in the topical treatment of neonatal ichthyosis.

Further Outpatient Care

The mainstay of ichthyosis therapy includes removal of surface scales, and application of a water barrier.

In disabling cases, oral retinoids may reduce cosmetic disfigurement, depression, and social isolation.

Complications

Because skeletal hyperostosis and arthralgia may occur with long-term oral etretinate and isotretinoin use, this form of treatment is reserved only for those patients with very severe scaling and cosmetic deformity. The clinical adverse effects of oral liarozole are reminiscent of those with oral retinoids; therefore, precaution is warranted with long-term use. Topical dermatologic retinoid preparations are irritating to the conjunctival fornices; therefore, it should not be applied directly to the eye. Topical tazarotene 0.1% gel may be an effective alternative to oral retinoids, with a decreased risk of systemic complications.

In the hyperproliferative variants of ichthyosis, topical calcipotriene ointment has been shown to be beneficial. However, the use of calcipotriene in treating congenital hyperproliferative disorders is limited by the theoretical risk of hypercalcemia from absorption of the drug from the skin.

Prognosis

The dryness of the eyes can be treated with artificial tears, ointments, bandage contact lenses, punctal occlusion, and possibly surgery, depending on the presence of abnormal lid closure or limbal stem cell deficiency.

Patient Education

Patients must realize that this condition is chronic, and they will need long-term therapy. Without long-term therapy, the defective permeability barrier associated with ichthyosis can result in a chronic loss of water and calories, which may impair growth in children.

Author

Andrew A Dahl, MD, FACS, Assistant Professor of Surgery (Ophthalmology), New York College of Medicine (NYCOM); Director of Residency Ophthalmology Training, The Institute for Family Health and Mid-Hudson Family Practice Residency Program; Staff Ophthalmologist, Telluride Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Steven R Feldman, MD, PhD, Professor, Departments of Dermatology, Pathology and Public Health Sciences, and Molecular Medicine and Translational Science, Wake Forest Baptist Health; Director, Center for Dermatology Research, Director of Industry Relations, Department of Dermatology, Wake Forest University School of Medicine

Disclosure: Received honoraria from Amgen for consulting; Received honoraria from Abbvie for consulting; Received honoraria from Galderma for speaking and teaching; Received consulting fee from Lilly for consulting; Received ownership interest from www.DrScore.com for management position; Received ownership interest from Causa Reseasrch for management position; Received grant/research funds from Janssen for consulting; Received honoraria from Pfizer for speaking and teaching; Received consulting fee from No.

Chief Editor

Hampton Roy, Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Arash Taheri, MD, Research Fellow, Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine

Disclosure: Nothing to disclose.

Kenneth M Goins, MD, Professor of Clinical Ophthalmology, Director of Cornea and External Diseases and Refractive Surgery, Department of Ophthalmology, University of Iowa Hospitals and Clinics; Medical Director of Iowa Lions Eye Bank

Disclosure: Nothing to disclose.

Matthew Rauen, MD, Fellow in Corneal, External Diseases and Refractive Surgery, Department of Ophthalmology and Visual Sciences, University of Iowa Health Care

Disclosure: Nothing to disclose.

Seth Adam Anderson, Des Moines University College of Osteopathic Medicine

Disclosure: Nothing to disclose.

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This slit beam illumination photograph of the cornea localizes the corneal opacity to the posterior stroma and the pre-Descemet membrane region. This type of corneal opacity is commonly present in X-linked recessive ichthyosis.

This direct illumination slit lamp photograph discloses a reticular central corneal haze that is seen bilaterally. Visual acuity is 20/20 in both eyes. The patient's chief complaint is photophobia and dry scaly skin.

This slit beam illumination photograph of the cornea localizes the corneal opacity to the posterior stroma and the pre-Descemet membrane region. This type of corneal opacity is commonly present in X-linked recessive ichthyosis.

An orbital mass is shown on CT scan in a 38-year-old male with human immunodeficiency virus (HIV) who presented with a late onset generalized ichthyotic rash and proptosis.