¹Department of Dermatology, McGovern Medical School at The University of Texas Health Sciences Center at Houston, Houston, TX, USA
²Center for Clinical Studies, Houston, TX, USA

Conflict of interest:
The authors have no conflicts to declare for this work.

Abstract:
The ichthyoses, also termed the disorders of keratinization, are a heterogenous group of skin diseases in which a distinctive horny layer arises secondary to excessive transepidermal water loss. Although occasionally acquired, the majority of ichthyoses are inherited and can be pinpointed to characteristic genetic mutations. Management depends on disease severity and includes topical agents and lifestyle modifications with or without oral retinoids. Genetic counseling is also an important consideration. This review aims to highlight advances in our understanding of disease pathogenesis as well as the holistic approach necessary to adequately manage ichthyosis patients.

Key Words:
ichthyosis, keratinization, lifestyle, management, pathogenesis, treatment

Introduction

Ichthyoses are an inherited group of skin disorders in which cornified layer accumulation leads to characteristic phenotypic features including xerosis, hyperkeratosis, excessive scaling, keratosis pilaris, and palmar and plantar hyperlinearity.¹ The common manifestations of this heterogeneous group of diseases arise due to abnormal skin barrier function that causes increased transepidermal water loss and a resultant compensatory hyperproliferation.² The clinical symptoms of ichthyosis typically present at birth or within the first few years of life.² With limited treatment regimens and no current cure, it is important to acknowledge the associated impaired quality of life that patients with lifelong ichthyosis experience.³ A recent study demonstrated that adults affected with this disorder report diminished quality of life regarding their physical health (impaired appearance of skin and mobility), daily life (cost of disease), and relationships with others and oneself (negative reaction of others to disease).³ In the following brief review, we aim to update advances in understanding the pathophysiology and management of ichthyosis.

Pathogenesis

As previously mentioned, the ichthyoses, or disorders of keratinization, are characterized by hyperproliferation triggered by increased transepidermal water loss.² The distinctive horny layer can be localized or diffuse and may be complicated by hypohidrosis, erythema, and infection. Although occasionally acquired, ichthyosis is largely an inherited condition with over 50 genes implicated in its pathogenesis. These genes influence a variety of cellular functions from DNA repair to adhesion, with the end result being a dysfunctional epidermal barrier.² The common ichthyoses are ichthyosis vulgaris and X-linked recessive ichthyosis, both of which are caused by well-characterized genetic mutations.^2,4 Ichthyosis vulgaris occurs due to autosomal dominant mutations in the filaggrin gene (FLG), and X-linked recessive ichthyosis results from alterations in the STS gene, which encodes steroid sulfatase.^2,4 Harlequin ichthyosis, lamellar ichthyosis, and congenital ichthyosiform erythroderma all result from autosomal recessive mutations.² Harlequin ichthyosis is associated with homozygous loss of function mutations in ABCA12, which encodes an ATP-binding cassette transporter.² Lamellar ichthyosis, congenital ichthyosiform erythroderma, and others exist on a spectrum of autosomal recessive congenital ichthyoses characterized by mutations in TGM1, NIPAL4/ ICHTHYIN, ALOX12B, ALOXE3, CYP4F22, ABCA12, PNPLA1, CERS3, LIPN, SDR9C7, and SULT2B1.^2,5-7 Understanding the impact of genetics in the pathogenesis of the ichthyoses gives perspective as to why these diseases often present in infancy or childhood, why they are lifelong burdens to those affected, and why finding a cure presents a challenge.

Management

Topical Agents

Ichthyosis management should incorporate hydration and lubrication with the addition of keratolytics and modulators of keratinocyte differentiation depending on scale severity.⁸ Hydration can be accomplished with creams and ointments containing low concentrations of salt, urea, or glycerol. Such topical therapies are employed to increase the water-binding capacity of the stratum corneum. Hydrophobic ointments such as petroleum jelly are effective for adequate lubrication. Of note, evidence does not support the use of skin-lipid-containing creams over the aforementioned plain creams and ointments in ichthyosis. When disease is characterized by markedly thickened stratum corneum, topical keratolytics such as alpha-hydroxy acids (lactic acid, glycolic acid), salicylic acid, N-acetylcysteine, propylene glycol, and high-dose urea allow for desquamation while keratinocyte differentiation modulators such as the retinoids (tretinoin, adapalene, tazarotene) and calcipotriol limit epidermal proliferation.⁸

Oral Medications

Although generally not necessary in the management of the common ichthyoses (ichthyosis vulgaris and X-linked recessive ichthyosis), oral retinoids are a mainstay in the systemic management of severe disease.⁸ Patients suffering from lamellar ichthyosis, epidermolytic hyperkeratosis, or congenital ichthyosiform erythroderma can benefit from retinoids as the drug’s keratolytic effects allow shedding and prevent further hyperproliferation. It is recommended that these agents be administered in low, effective doses as their use could be lifelong in ichthyosis patients.⁸ Additionally, retinoids are well-known teratogens.⁹ Retinoic acid plays a significant role in transcription regulation by binding retinoic acid response elements (RAREs) that are located proximally to numerous genes. RAREs have been found to inhibit Fgf8, homeobox genes, and other genes integral to neuron and organ development, thereby causing major craniofacial, thymic, cardiac, and central nervous system malformations in addition to spontaneous abortion.^9,10 In an effort to increase awareness and reduce birth defects associated with isotretinoin use, US-based physicians prescribing isotretinoin should be certified in and patients taking the medication should be registered with the iPLEDGE Program.¹¹ For female patients of child-bearing potential, this program mandates regular pregnancy tests and requires two forms of contraception.¹¹ Providers and patients in other countries should adhere strictly to local pregnancy avoidance programs and policies. In a patient considering pregnancy, isotretinoin may actually be preferred to acitretin due to its shorter half-life and resultant shorter washout period.⁸ At this time, data suggest oral retinoids are safe to use in reproductively active men.¹²

While retinoids share many features, some agents may be more effective than others situationally.⁸ For example, isotretinoin and aromatic retinoids (such as etretinate, acitretin) appear equally efficacious in the treatment of lamellar ichthyosis, whereas the propensity of acitretin to act on volar skin makes it the preferred therapy in palmoplantar hyperkeratosis.⁸

Lifestyle Considerations

The majority of ichthyosis therapies aim to improve the barrier function of the skin. Important aspects of an ichthyosis patient’s daily routine include bathing and proper application of the bland creams and ointments discussed previously.¹³ Daily bathing with water or mild cleanser and the application of plain emollients directly after bathing, as well as frequently throughout the day, help to seal in moisture.¹⁴ It is thought that bathing aids to hydrate and promote shedding of the stratum corneum, therefore reducing the thickness of scaling and improving overall skin appearance.¹³ Many emollients are not covered by insurance; in addition, patients self-report applying topical agents as time-consuming.³ Thus, it is important to be aware of the possible financial and lifestyle stresses with which these therapies may burden the ichthyosis patient population.

In addition, patients diagnosed with ichthyosis should be aware of the lifelong course of this group of disorders, as there is currently no cure. Patients who are carriers of the FLG gene mutation may be at increased risk of developing atopic disorders, such as atopic dermatitis and asthma.¹ To decrease potential risks for the development of atopic disorders, individuals diagnosed with ichthyosis vulgaris should be advised to avoid certain environmental risk factors including professions involving wet work or excessive metal and contact irritant exposure.¹ Smoking tobacco should also be discouraged as an interaction between FLG mutations and tobacco smoking has been shown to favor the development of asthma in patients with ichthyosis vulgaris.^1,15

Finally, it is important to acknowledge lifestyle factors that commonly influence the quality of life in ichthyoses patients. Patients self-report suffering from altered skin and eye appearance, including pain, pruritus, and “smelly” skin, that worsen in relation to environmental and psychological changes.³ To accommodate these changes, most patients refrain from activities that risk exacerbating their condition by avoiding hot atmospheres and activities in which they cannot hide their skin.³ As affected patients consistently express dissatisfaction with their medical care, it is prudent for physicians to advocate for the development of strategies and therapeutic programs targeted at improving the care and quality of life of these individuals.³

Genetic Counseling

Gene therapy is not yet a reality in ichthyosis therapy; however, genetic counseling remains an integral aspect of disease management. As mentioned previously, the most common forms of ichthyosis are ichthyosis vulgaris and X-linked recessive ichthyosis, which are inherited in autosomal (pseudo-) dominant and X-linked recessive patterns, respectively, via well-characterized genetic mutations. Although the diagnosis of ichthyosis vulgaris in particular may be evident from biopsy alone, the diagnosis of X-linked recessive ichthyosis requires polymerase chain reaction analysis, Southern blot, or fluorescent in situ hybridization analysis.^4,8 A positive male-only family history of scaly skin, the detection of low estriol on the prenatal triple screen, and/or low estrogen and nonhydrolyzed sulfated steroids in maternal urine can point toward a diagnosis of X-linked recessive ichthyosis, thus prompting analysis of chorionic villi or amniotic fluid using the aforementioned techniques.⁴ Additionally, a recent case report suggests that a rare and extreme form of fetal ichthyosis, harlequin ichthyosis, can be detected on ultrasonography as early as the second trimester with subsequent genetic screening to elucidate mutations in ABCA12.^2,16 A referral to a genetic counselor can serve to answer questions and alleviate anxiety regarding the diagnosis of a congenital ichthyosis as well as assist parents in consideration of future pregnancies.

Future Considerations

Topical therapy is necessary in the management of ichthyosis; thus, consideration should be given to the cosmetic appeal and fragrance of treatment creams and ointments. A recent case report found preliminary success utilizing carbocysteine cream in the treatment of ichthyosis.¹⁷ Carbocysteine is a molecule similar to N-acetylcysteine except that it contains a bound sulfhydryl group rather than a free one.¹⁷ As the sulfhydryl group cannot be liberated, this cream lacks the rancid egg smell of N-acetylcysteine cream, a major barrier to treatment compliance.¹⁷ Further research dedicated to such creams, ointments, and even cosmetic products has the potential to improve the quality of life in patients suffering physical discomfort and social stigmata due to their condition. In addition, development of gene therapy has tremendous potential in treating patients with these disorders and should be explored further.

Conclusion

The ichthyoses are typically inherited conditions exhibiting disordered keratinization secondary to excessive transepidermal water loss, with the most common variants being ichthyosis vulgaris and X-linked recessive ichthyosis. Ichthyosis management requires a multimodal approach, including topical and oral agents in addition to lifestyle modifications. Topical creams and ointments are the mainstays of treatment utilized to achieve adequate hydration and, when applicable, keratolysis, while more severe phenotypes benefit from the use of oral retinoids. Patients should also be educated regarding bathing practices and avoidance of topical irritants and tobacco, as well as be actively supported by their clinician, as ichthyosis patients often report decreased quality of life.

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Department of Medicine (Dermatology), University of Washington, Seattle, WA

ABSTRACT

The ichthyoses are a heterogeneous group of inherited scaling skin disorders that can also affect other organs. Management should be directed at both the skin and other sites. Skin therapy is not specific at this time, although new products may offer more directed therapy in the future. Moisturizers and keratolytics are the mainstay of topical therapy. Calcipotriene, retinoids, and for select types, anti inflammatories such as topical steroids and calcineurin inhibitors have also been used. Systemic therapy is limited to the retinoids. Superinfection of the skin should be anticipated and treated. Pruritus can be disabling. Failure to sweat normally may result in heat intolerance. Eye care should seek to prevent corneal changes resulting from ectropion and more specific changes associated with specific disorders. Hearing can be impaired by the accumulation of material in the external auditory canal. Severely affected children may require caloric supplementation to avoid growth retardation. Affected individuals and their family should be counseled about the long term outlook and the genetic nature of their disorder, and informed of FIRST, the Foundation for Ichthyosis and Related Skin Types, the lay foundation that offers support and information.
Key Words: ichthyoses

The ichthyoses are a heterogeneous group of inherited scaling skin diseases (this article excludes acquired ichthyosis, although treatment is much the same with the exception that an underlying cause should be sought). In some cases, other organs are also involved.¹ Although recent studies have revealed that mutations underlie many of the ichthyoses,² specific treatments have yet to follow. Current therapy should be aimed at the skin, other organ involvement, and secondary conditions related to the underlying disorder. Perhaps equally important is to acknowledge the unrelenting nature of the ichthyoses and to direct affected individuals and their families to groups who offer support.

Past and Current Therapies

“The treatment of ichthyosis is essentially external… removal of the scaliness and the maintenance of a soft and pliable condition of the skin.”³ Unfortunately, efficacy of treatment has paralleled neither the understanding of the molecular basis of the disorders nor the expansion of topical treatments seen since this time (Table 1). Moisturizers are the mainstay of therapy of the ichthyoses. They work by increasing the flexibility of the epidermis, hydrating and restoring epidermal barrier function, and by covering and removing scale.⁴ Moisturizers are complex. They have been reviewed recently in this forum.5 If one talks with a group of individuals affected with different ichthyoses, it becomes clear that everyone has his/her “best” moisturizer. My interpretation is that these differences reflect not only the way different disorders affect the skin, but also differences between individuals. One approach is to offer general dry skin care along with a list of moisturizers and suggest that affected individuals compare several until the “best” product for that person is identified (see Table 2). Keratolytics and humectants are worth singling out from the moisturizers because published, double-blind controlled clinical trials of topical therapy demonstrate efficacy.^6,7 However, the trials are short, the numbers of treated individuals are small, irritation is common, and high plasma urea levels have been reported.^8,9

The retinoids and calcipotriene have been used as topical therapy for ichthyosis in a small number of trials.^10-12 Their use has been, for the most part, anecdotal.

Elias and coworkers recently espoused topical therapy based on the underlying defect of specific ichthyoses.13 Anecdotal reports support successful use of “a patented ceramide dominant ratio of epidermal lipids [ceramides, fatty acids, and cholesterol]” in some disorders (Elias PM, personal communication, 10.8.2002).

Topical steroids have not been effective in the treatment of the ichthyoses, with the exception of eczema in ichthyosis vulgaris and Netherton syndrome. The inflammation that is present likely results from the underlying barrier defect. Topical tacrolimus is contraindicated in Netherton disease because of the risk of systemic absorption.¹⁴ We have had anecdotal success using topical tacrolimus in Hailey-Hailey and Darier disease, however systemic levels have not been measured.

Systemic therapy with oral retinoids is the most effective therapy available for most of the ichthyoses.¹⁵ It is said that the aromatic retinoids are more effective than 13-cis retinoic acid, but convincing support for this statement is lacking. Although the retinoids have profound effects on epidermal differentiation, the most likely mechanism of action is thinning of the stratum corneum and accelerated loss of scale. The retinoids have significant guaranteed and potential sideeffects.¹⁶ Many severely affected individuals use the retinoids chronically, but this should occur only after thoughtful discussion with a physician about the risks and benefits.

Table 1: Treatment Options – Skin

Cost based on average wholesale price, 2001 Drug Topics Redbook₁

Consideration of the management of the ichthyoses is incomplete without a review of aspects beyond primary skin involvement. Specifics of individual disorders (e.g., the corneal changes in KID syndrome, etc.) are beyond the scope of this discussion. Barrier function in ichthyotic skin is impaired, which often leads to secondary infection. In addition to bacterial infection, viral and fungal (especially dermatophyte) infections are common but can easily be missed in the setting of an underlying blistering or scaling dermatosis if a high index of suspicion is not present.¹⁵ Pruritus can be incapacitating. Sweating is often impaired, perhaps due to eccrine duct occlusion, and precautions against overheating should be advised. The eye is commonly affected in the setting of ectropion; a corneal ophthalmologist should be involved in care. Ears often plug with cellular debris and require periodic cleaning. Hair and scalp care should address scaling, scaring alopecia, and hair shaft abnormalities leading to fragility. Children with severe erythroderma may display severe growth retardation. This may be the result of increased energy loss caused by evaporative water loss,¹⁷ and may respond to topical treatments and to addressing the nutritional needs of the child. See Table 3. FIRST offers “Fact Sheets” on overheating, retinoids, scalp scaling, ear wax & scale, and itching.

Table 2: Suggestions For Treatment Of Dry Skin

Table 3: Treatment considerations beyond primary skin involvement.

Conclusion

Time and thought should be given to affected individuals and their families in order to inform them accurately of the diagnosis and prognosis of their disorder. If the diagnosis is in question, referral to a dermatologist with particular interest in these disorders may be helpful. Work with the individual and family to identify the most effective therapy. FIRST, the Foundation for Ichthyosis and Related Skin Types, is a lay foundation that supports affected individuals and their family members (650 N. Cannon Avenue, Lansdale, PA 19446, 800 545-3286, 215 631-1411, 215 631-1413 [FAX], info@scalyskin.org, www.scalyskin.org). The National Registry for Ichthyosis and Related Disorders, 1-800-595- 1265, ichreg@u.washington.edu, www.skinregistry.org/, offers one means of “empowerment” and may be able to help with the diagnosis.

Conflict of interest: the author participated in the clinical trial of Lac-Hydrin® cream (Westwood).

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