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.
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.
ichthyosis, keratinization, lifestyle, management, pathogenesis, treatment
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.
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.
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
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
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
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.
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.
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.
- Thyssen JP, Godoy-Gijon E, Elias PM. Ichthyosis vulgaris: the filaggrin mutation disease. Br J Dermatol. 2013 Jun;168(6):1155-66.
- Marukian NV, Choate KA. Recent advances in understanding ichthyosis pathogenesis. F1000Res. 2016 5.
- Mazereeuw-Hautier J, Dreyfus I, Barbarot S, et al. Factors influencing quality of life in patients with inherited ichthyosis: a qualitative study in adults using focus groups. Br J Dermatol. 2012 Mar;166(3):646-8.
- Fernandes NF, Janniger CK, Schwartz RA. X-linked ichthyosis: an oculocutaneous genodermatosis. J Am Acad Dermatol. 2010 Mar;62(3):480-5.
- Sathishkumar D, Peter D, Pulimood S, et al. Bathing suit variant of autosomal recessive congenital ichthyosis (ARCI) in two Indian patients. Case Rep Dermatol Med. 2018 2018:3140473.
- Lima Cunha D, Alakloby OM, Gruber R, et al. Unknown mutations and genotype/ phenotype correlations of autosomal recessive congenital ichthyosis in patients from Saudi Arabia and Pakistan. Mol Genet Genomic Med. 2019 Mar;7(3):e539.
- Youssefian L, Vahidnezhad H, Saeidian AH, et al. Autosomal recessive congenital ichthyosis: genomic landscape and phenotypic spectrum in a cohort of 125 consanguineous families. Hum Mutat. 2019 Mar;40(3):288-98.
- Vahlquist A, Ganemo A, Virtanen M. Congenital ichthyosis: an overview of current and emerging therapies. Acta Derm Venereol. 2008 88(1):4-14.
- Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med. 1985 Oct 3;313(14):837-41.
- Cunningham TJ, Duester G. Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nat Rev Mol Cell Biol. 2015 Feb;16(2):110-23.
- iPLEDGE: Committed to Pregnancy Prevention. 2016. Available at: https://www. ipledgeprogram.com/iPledgeUI/home.u. Accessed November 25, 2019.
- Kumar P, Das A, Lal NR, et al. Safety of important dermatological drugs (retinoids, immune suppressants, anti androgens and thalidomide) in reproductively active males with respect to pregnancy outcome: A brief review of literature. Indian J Dermatol Venereol Leprol. 2018 Sep-Oct;84(5):539-46.
- Glick JB, Craiglow BG, Choate KA, et al. Improved management of harlequin ichthyosis with advances in neonatal intensive care. Pediatrics. 2017 Jan;139(1).
- Craiglow BG. Ichthyosis in the newborn. Semin Perinatol. 2013 Feb;37(1):26-31.
- Berg ND, Husemoen LL, Thuesen BH, et al. Interaction between filaggrin null mutations and tobacco smoking in relation to asthma. J Allergy Clin Immunol. 2012 Feb;129(2):374-80, 80 e1-2.
- Liang Q, Xiong F, Liang X, et al. Two successive cases of fetal harlequin ichthyosis: a case report. Exp Ther Med. 2019 Jan;17(1):449-52.
- Batalla A, Davila-Pousa C, Feal C, et al. Topical carbocysteine: a new option for the treatment of ichthyosis. Pediatr Dermatol. 2018 Nov;35(6):e357-e9.