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تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک

Inherited ichthyosis: Overview of management

Inherited ichthyosis: Overview of management
Literature review current through: May 2024.
This topic last updated: Nov 15, 2023.

INTRODUCTION — The ichthyoses are a heterogeneous group of hereditary disorders of keratinization of varying severity characterized by hyperkeratosis and scaling, often associated with underlying inflammation. They are caused by pathogenic variants in genes encoding epidermal structural proteins and enzymes that affect synthesis or metabolism of proteins and lipids involved in maintaining and regulating the stratum corneum and the epidermal barrier function. The defective skin barrier results in increased transepidermal water loss, compensatory epidermal hyperplasia and/or epidermal retention hyperkeratosis, and, in most patients, some degree of inflammation.

There are no specific therapies for ichthyosis known to be useful in all patients. Treatment is individualized according to ichthyosis type and personal preference. Skin care measures and use of topical or systemic medications aimed at reducing hyperkeratosis and scaling and hydrating and softening the skin can provide symptomatic relief in most patients. However, more recent understanding of the pathogenesis of ichthyosis subtypes is leading to more targeted treatment with anti-inflammatory biologics, small molecule inhibitors, and gene replacement therapy.

This topic will discuss the approach to the management of patients with ichthyosis. The pathogenesis, clinical presentation, and diagnosis of specific types of ichthyosis are discussed separately.

(See "Overview and classification of the inherited ichthyoses".)

(See "Ichthyosis vulgaris".)

(See "X-linked ichthyosis".)

(See "Autosomal recessive congenital ichthyoses".)

(See "Keratinopathic ichthyoses".)

(See "Palmoplantar keratoderma".)

(See "Netherton syndrome".)

GENERAL CONSIDERATIONS — There are no curative therapies for ichthyosis. Treatment is largely symptomatic, aimed at reducing skin dryness and scaling, limiting excess transepidermal water loss, hydrating and softening the stratum corneum, promoting desquamation of scales, and controlling inflammation and pruritus [1]. (See 'General measures' below.)

Decision making about the choice and aggressiveness of therapy depends on the age of the patient, morphology, distribution, severity of disease, whether the disorder is limited to the skin (nonsyndromic ichthyosis) or involves internal organs and systems as well (syndromic ichthyosis), and safety of long-term therapy (table 1A-B). (See "Overview and classification of the inherited ichthyoses", section on 'Nonsyndromic inherited ichthyoses' and "Overview and classification of the inherited ichthyoses", section on 'Syndromic ichthyoses'.)

Because ichthyoses and other disorders of differentiation are chronic, patients require long-term, comprehensive care. For patients with severe or syndromic forms of ichthyosis, early consultation with a multidisciplinary team of specialists (including dermatology, genetics, neonatology, ophthalmology, otolaryngology, orthopedic and plastic surgery, occupational and physical therapy, nutrition, and social services) is essential. Psychiatric and mental health support for patients and their families/caregivers is also of utmost importance and should address issues affecting coping strategies and quality of life [2].

GENERAL MEASURES — General skin care measures, including frequent tub soaks or showers, environment humidification, exfoliation, and liberal use of emollients, are the foundation of ichthyosis management [1,3]. Patients and families/caregivers can be referred to the Foundation for Ichthyosis and Related Skin Types (FIRST) website for guidance and tips from experts, including information about skin care products [4].

Bathing — The majority of patients with congenital forms of ichthyosis find prolonged, daily or twice-daily baths (at least 30 minutes of soaking) to be extremely valuable for softening scales before exfoliation. Bath additives (sodium chloride, sodium bicarbonate, sodium hypochlorite, acetic acid/vinegar) are helpful to reduce odor (thought to result from bacterial overgrowth in the excessive scale), pruritus, and to help with exfoliation (table 2) [4-8]. Patients are encouraged to try different additives, as benefit and tolerance of products varies on an individual basis. Superfatted soap or soapless "synthetic detergents" may be better tolerated than regular soaps or body washes. Oils can also be added to baths, but they make bathtubs slippery, and care must be taken to avoid falls.

Anecdotal patient experiences support the use of bathtubs producing microbubbles and portable devices using micro/nanobubble technology to improve skin hydration and exfoliation, as well as to decrease irritation, bacterial load, and odor. However, no studies have tested their benefit for ichthyoses.

Exfoliating — Removal of scales while bathing, particularly in patients with lamellar ichthyosis, recessive X-linked ichthyosis, and epidermolytic ichthyosis, can be accomplished by gently rubbing on the affected areas with a loofah sponge, bathing glove or mitt, or pumice bars or stones. Pumice stones with smaller pores are gentler and may be best for sensitive areas, whereas those with larger pores are suitable for the hyperkeratotic skin of the hands and feet. Stones should be cleaned well after use using a bristled brush and can be boiled in hot water for five minutes to reduce the bacterial load on the surface. Drills and mechanical paring instruments can be helpful for exfoliating thicker scales on the hands and feet.

Moisturizing — After bathing and exfoliating, a thick layer of moisturizer should immediately be applied to retain hydration and soften the skin. Adding a few ounces of a humectant, such as glycerin, can prolong moisturization [9,10]. Moisturizers may also reduce inflammation and improve the barrier function. Application of petroleum jelly has been shown to increase expression of antimicrobial peptides and upregulate innate immunity genes through selective modulation of the proinflammatory T helper type 17 (Th17) and T helper type 22 (Th22) pathways [11].

For most patients with ichthyosis, ointments, which have the highest oil-to-water ratio, are preferred. However, during hot, humid weather, occlusive moisturizers may worsen heat intolerance and favor the development of folliculitis or miliaria. If needed, less occlusive products (eg, creams or lotions) may be used. Because of the recognized increased risk of cutaneous infection with Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus [MRSA]) and fungi and demonstration of dysbiosis on ichthyotic skin [12], patients should be reminded not to "double dip" into their moisturizer jars and potentially transfer bacteria into them. Items such as disposable spoons or popsicle sticks can be used to scoop out moisturizer from the containers [7].

Thick emollients (eg, petrolatum) can stain clothes and other fabrics. Either presoaking clothing with hydrogen peroxide-based stain removers or vinegar or adding one-fourth cup of vinegar to a standard laundry load can help remove stains and reduce odor.

Scalp care — As with skin, scalp scale and dryness are best managed by scale moisturization and removal. Scale can be softened with a variety of oils, ranging from mineral oil to coconut oil and other vegetable oils, prior to shampooing. Virgin coconut oil has been shown to be effective in reducing inflammation and transepidermal water loss in patients with atopic dermatitis and seems to have antibacterial properties against S. aureus [13,14]. In contrast, olive oil has been associated with increased inflammation, and tea tree oil is a recognized sensitizer [15-17].

Wetting the scalp before application of oil can improve its effect. Use of a shower cap or plastic wrap both decreases mess and may increase penetration through its occlusion. Fluocinolone 0.01% oil (table 3) can be substituted for unmedicated oil intermittently for patients who also experience scalp pruritus. The oil can be left on for an hour to overnight before shampooing. A shampoo containing a keratolytic agent (eg, alpha-hydroxy acids, beta-hydroxy acids, propylene glycol) can further help to loosen scales. After shampooing and use of conditioner if desired, scales can be further removed with a brush or comb.

Control of pruritus — Pruritus is a major issue for patients with ichthyosis. Scratching, sleep disturbance, and loss of concentration result in poor quality of life [18]. Measures that help reduce pruritus in patients with ichthyosis include:

Keeping the skin moist with regular, frequent use of emollients. Moisturizers containing oat milk or colloidal oatmeal may also be beneficial due to the anti-inflammatory properties of colloidal oatmeal extracts [19].

Wearing looser clothing.

Minimizing exposure to heat and humidity and applying cooling compresses to itchy areas.

First-generation, sedating oral antihistamines (ie, hydroxyzine, diphenhydramine) may be helpful for nighttime itching that disrupts sleep. Nonsedating antihistamines are generally ineffective. (See "Pruritus: Therapies for generalized pruritus" and "Pruritus: Therapies for localized pruritus".)

Prevention of overheating — Ineffective sweating and resultant heat intolerance with hyperthermia is an issue for many individuals with congenital ichthyosis. Thickened skin, keratin plugging of sweat glands, and abnormalities in eccrine system development may contribute to ineffective sweating.

Measures to avoid overheating and reduce body temperature include:

Avoiding exposure to high environmental temperatures

Using caution in direct sunlight

Staying hydrated with fluids

Recognizing signs of overheating (eg, facial flushing and reddened skin)

Being cognizant of when body temperature rises (eg, knowing when to stop during sports or exercise)

Dousing the face or body with water or wearing a wet T-shirt

Using cooling bandanas, cool packs, or cooling vests

Considering providing an education plan (eg, a 504 plan or Individualized Educational Plan [IEP] in the United States) for students to have access to a cool environment and water during physical education if needed

Additional information on overheating and suggestions for keeping cool can be found online at the National Foundation for Ectodermal Dysplasias and the Foundation for Ichthyosis and Related Skin Types (FIRST) [20,21]. FIRST also includes a list of cooling products with company contact information. Many individuals have experienced increased ability to sweat after puberty, perhaps related to increased eccrine and apocrine gland function. Some patients have reported improvement in sweating with the use of systemic retinoids [22,23].

TOPICAL KERATOLYTIC AGENTS — Topical keratolytic agents are first-line treatment for reducing scale in children and adults with ichthyosis. The Foundation for Ichthyosis and Related Skin Types (FIRST) provides a product listing to patients with ichthyosis and their families/caregivers upon request. Alpha-hydroxy acids, beta-hydroxy acids, urea preparations, and propylene glycol are most commonly used. The response of different types of ichthyosis to topical keratolytic agents is summarized in the table (table 4).

Alpha-hydroxy and beta-hydroxy acids

Glycolic acid and lactic acid are the most commonly used alpha-hydroxy acids [7]. Glycolic acid at 5 to 10% concentrations is included in over-the-counter creams and lotions at a relatively low cost. Higher concentrations used in chemical peels for cosmetic purposes are not recommended for ichthyoses treatment [7]. Lactic acid preparations have the added benefit of increasing ceramide production, which may improve the skin barrier [24-26]. Concentrations ranging from 5 to 12% have been beneficial in treating ichthyosis [27,28]. Stronger preparations can be found over the counter, but irritation limits use. Examples of lactic acid preparations include over-the-counter AmLactin 12% cream/lotion and U-Lactin lotion (2% lactic acid plus 10% urea) as well as prescription ammonium lactate 12% lotion (Lac-Hydrin).

Salicylic acid is a beta-hydroxy acid that has the added benefit of softening and moisturizing the skin, in addition to desquamating the stratum corneum [27,29]. Salicylic acid in concentrations up to 20% can be found over the counter [7]. Compounded preparations with higher concentrations (up to 50%) are available by prescription and can be used for difficult-to-treat, limited body areas and for the palms and soles [7]. Several 2% salicylic acid preparations are available over the counter. Examples of higher concentrations available by prescription are Keralyt (6%) gel and Salex (6%) lotion/cream. Salicylic acid is also easily compounded alone or with urea (eg, salicylic acid 5 to 10% plus urea 5 to 10% in cream/ointment or, for plantar keratoderma, salicylic acid 50% plus urea 20% in petroleum).

Neutrogena T/Sal or DHS Sal Shampoo Maximum Strength (3% salicylic acid) are keratolytic shampoos.

Urea – Low-dose (10 to 20%) topical urea preparations can be found over the counter. Compounded preparations with higher concentrations (up to 40% [eg, Carmol 40]) are available by prescription and can be used for difficult-to-treat, limited skin areas. In a small, randomized, right-left comparison trial that included 32 patients with ichthyosis vulgaris, a 10% urea lotion applied daily for four weeks was more effective than an emollient cream in reducing scaling, roughness, and fissures [30].

Propylene glycol – The use of aqueous propylene glycol 40 to 60% applied under occlusion was first described in patients with X-linked ichthyosis and ichthyosis vulgaris [31]. Propylene glycol is a common ingredient in topical products but has been reported to cause allergic and irritant contact dermatitis.

Combined preparations – Application of compounded 5% lactic acid with 20% propylene glycol or 6% salicylic acid with 60% propylene glycol in a fatty base can significantly decrease scaling in patients with autosomal recessive congenital ichthyosis, especially lamellar ichthyosis. The combination of salicylic acid and propylene glycol is also particularly helpful for the treatment of palmoplantar keratoderma [32,33].

Administration – Topical keratolytics are applied once or twice daily. Higher concentrations are typically needed for areas of severe involvement or thickening, such as the palms and soles.

Adverse effects and precautions

Infants <6 months should not be exposed to keratolytic agents because of the risk of systemic absorption. Use in infants and young children should also be limited in extent, due to the high risk of systemic absorption relative to their body surface area. For this same reason, pediatric patients of all ages should be monitored when keratolytic agents are used to cover large surface areas for prolonged periods [34].

Special attention should be paid to patients using salicylic acid. Although rare, there have been documented cases of salicylism and even death from systemic absorption of topically applied salicylic acid [35,36].

Propylene glycol is a weak sensitizer and potential irritant [37]. Toxicity from extensive application and transdermal absorption can induce agitation, cardiac arrhythmia or arrest, central nervous system toxicity, hyperosmolarity, hemolysis, lactic acidosis, and seizures [38].

In infants, topical urea-based preparations can elevate blood urea nitrogen levels when applied to larger surface areas [7,39,40].

RETINOIDS — Retinoids are analogues of vitamin A (all-trans retinol) that selectively bind to specific subunits of nuclear retinoic acid receptors (RARs) and modulate epidermal maturation, keratinocyte differentiation, apoptosis, immune function, and carcinogenesis. In ichthyosis, retinoids act principally as antikeratinizing agents, thus reducing hyperkeratosis and scaling. Retinoids are typically used in conjunction with the general measures outlined above and with copious use of emollients. (See 'General measures' above.)

Because of the rarity of the congenital ichthyosis subtypes that benefit from treatment with retinoids, there is a lack of high-quality, large studies evaluating their efficacy and long-term adverse effects. Evidence supporting their use is mainly derived from small, observational studies and clinical experience. Expert consensus guidelines addressing the use of retinoids for the management of ichthyosis in children and adolescents have been published in Europe and the United States [3,41].

Topical retinoids — Topical retinoids, including adapalene, topical isotretinoin, tretinoin, tazarotene, and trifarotene, have a limited role in the management of ichthyosis [3,41]. Tazarotene is used more frequently than lower-potency agents, such as tretinoin and adapalene (table 5). Trifarotene is a newer topical retinoid that specifically targets RAR-gamma. It is expressed more abundantly in the skin than RAR-alpha and RAR-beta and expressed less in other organs, potentially resulting in increased effectiveness and the reduced potential for systemic side effects [42].

Trifarotene is being evaluated in a phase 2, randomized, multicenter trial of adults and adolescents with lamellar ichthyosis (NCT03738800). Topical isotretinoin is also being studied in a phase 2 clinical trial for patients nine years of age and older with recessive X-linked ichthyosis and lamellar ichthyosis subtypes (NCT04154293).

Indications Tazarotene has been successfully used to loosen areas of contracture in neonates and infants with harlequin ichthyosis [43-46] and for the treatment of ectropion in children and adults with lamellar ichthyosis [47,48] (see 'Special sites' below and 'Harlequin ichthyosis' below). Tazarotene has also been used in patients with recessive X-linked ichthyosis, lamellar ichthyosis, erythrokeratoderma variabilis, and neutral lipid storage disease with ichthyosis [44,45,49-51].

Administration – Treatment with tazarotene should be initiated at the lowest therapeutic dose possible and titrated up, as tolerated, to achieve the desired effect. For example, some individuals with ichthyosis do well with topical retinoid application only once per week and become irritated with higher frequency use. Available in 0.05 and 0.1% creams and gels, tazarotene can also be mixed 1:3 to 1:1 with petrolatum at home to reduce the initial dose, allowing up-titration to full strength and promoting better tolerance. Areas of the body differ in their responsiveness. Dilution is useful for delicate areas (eg, the periorbital region), whereas higher concentrations may be needed for palmoplantar keratoderma.

Adverse effects and precautions – Worsening erythema, irritation, and xerosis are common adverse reactions to topical retinoid treatment. Increased risk of sunburn has also been described with topical retinoid use. Due to their dose-dependent response, increasing potency may also increase associated adverse effects [7]. However, tolerance is generally improved by slowly increasing the concentration and/or frequency of application. Concurrent use of emollients may mitigate xerosis [52]. Temporary discontinuation of the retinoid and application of a topical corticosteroid may be needed for severe skin inflammation and discomfort.

There are limited data regarding the safety of the use of topical retinoids in pregnancy and lactation. A meta-analysis of four observational studies comparing the outcome of 654 pregnancies exposed to topical retinoids with those of 1375 control (unexposed) pregnancies did not find an increased rate of major congenital malformations, spontaneous abortion, stillbirth, low birth weight, or prematurity associated with exposure to topical retinoids during the first trimester of pregnancy [53]. Although pregnancy testing is unnecessary with use of topical retinoids, safety findings have not been confirmed in larger studies, and it is prudent to avoid using tazarotene during pregnancy.

Systemic retinoids — Acitretin and isotretinoin are the two oral retinoids available in the United States for the off-label treatment of ichthyosis. Oral alitretinoin is available in Europe and Canada but not in the United States [54].

Indications – Systemic retinoids are indicated for patients with forms of ichthyosis who have severe and extensive scaling and hyperkeratosis that are insufficiently improved with topical therapies alone, in particular for patients with autosomal recessive congenital ichthyosis [1,3]. Other rare subtypes of ichthyosis that can benefit from systemic retinoid therapy include recessive X-linked ichthyosis [55], ichthyosis with confetti [56], erythrokeratodermia variabilis [57], KID (keratitis-ichthyosis-deafness) syndrome [58,59], KLICK (keratosis linearis with ichthyosis congenita and sclerosing keratoderma) syndrome [60], and Sjögren-Larsson syndrome [61]. The response of different subtypes of ichthyosis to systemic retinoids is summarized in the table (table 4).

Choice of systemic retinoid Isotretinoin, alitretinoin, and acitretin are all effective in removing scale and reducing hyperkeratosis, although response may vary in different types of ichthyosis (table 4) and in individual patients. Acitretin also improves hypohidrosis and ectropion in patients with lamellar ichthyosis and is beneficial for patients with epidermolytic ichthyosis with KRT10 variants [62].

The choice of one agent over the other is influenced by several factors, including type and severity of ichthyosis, age and sex of the patient, pharmacokinetic properties, safety profile, and consideration of pregnancy planning in female patients. Isotretinoin has a much shorter half-life than acitretin and is cleared from the body within days to a few weeks of treatment discontinuation [3]. Thus, for female patients of reproductive potential, isotretinoin remains the treatment of choice, and consideration should be given to switching young female patients being treated with acitretin to isotretinoin as they become closer to childbearing potential and sexually active [3].

Pregnancy can occur safely one month after the last dose of isotretinoin. In contrast, patients on acitretin therapy must avoid pregnancy for a minimum of three years due to metabolic conversion of acitretin to etretinate as an effect of alcohol ingestion, long-term storage of etretinate in fat, and chronic release into the circulation [63].

Administration – The optimal dose for systemic retinoids is the lowest dose required for obtaining the desired therapeutic effect with tolerable adverse effects.

Acitretin is formulated in capsule doses of 10 and 25 mg. The usual dose for acitretin is 0.5 to 1 mg/kg/day in both children and adults, with a maximum of 75 mg/day. Upon achieving a satisfactory response, the dose can be tapered to the lowest dose necessary to maintain improvement.

Isotretinoin is formulated in capsule doses of 10, 20, 30, and 40 mg. Guidelines recommend initiation at 1 mg/kg/day and reduction to maintenance dosing of 0.5 to 1 mg/kg/day. Intermittent dosing or "retinoid holidays" do not result in rebound flares. Thus, temporary discontinuation and cyclic use may mitigate adverse effects and increase adherence to treatment in many patients.

Tips for administering retinoid capsules to children [3]:

-Capsules should be used immediately upon removal from their package, kept out of direct sunlight, and administered with high-fat foods (eg, whole milk, ice cream, or peanut or other nut butter) for best absorption.

-Capsules can be swallowed whole or chewed. They can be frozen within bite-sized, soft-centered chocolate for tastier chewing in children.

-For infants or younger children, a hole can be poked in the capsule with a sharp knife or nail clippers and the powder added directly to food or a small amount of breast milk or formula (15 to 30 mL).

Adverse effects and precautions – Much of our understanding about the potential risks associated with systemic retinoid treatment is based on studies of isotretinoin for acne and acitretin for psoriasis. The toxicity of long-term systemic use in children with disorders of cornification has not been well studied. In a cohort of 174 children (94 with congenital ichthyosis) treated with acitretin for an average of 3.5 years, clinical and laboratory adverse events, all reversible, occurred in 24 percent of patients and led to permanent cessation of treatment in 10 percent of patients [64].

Common adverse effects – The most common side effects of systemic retinoids are cheilitis (virtually 100 percent), increased skin dryness and irritation, skin fragility, and xerosis of mucous membranes. Elevation of fasting levels of lipids, especially triglycerides, is the most common metabolic adverse event [3,65,66], but in most cases, lipid-lowering treatment is not required. However, in patients on long-term retinoid treatment who persistently have elevated lipid levels of clinical importance, retinoid treatment can be continued in combination with lipid-lowering agents [3]. (See "Dyslipidemia in children and adolescents: Management" and "Hypertriglyceridemia in adults: Management".)

Headaches, vision changes, hepatotoxicity, arthralgias, and bone changes are uncommon but should be monitored (table 5) [3,65]. Pseudotumor cerebri (idiopathic intercranial hypertension) is a rare adverse event [67].

Psychiatric issues – Psychiatric issues are a recognized comorbidity of ichthyosis, with 34 percent of adults and 30 percent of children screening positive for depression and 27 percent of adults and 37 percent of children screening positive for anxiety [68]. Although depression has been mentioned as a potential adverse effect of the use of isotretinoin, depression and suicidal ideation associated with isotretinoin use for acne in teenagers and young adults is thought to be primarily related to the age of the patients and the psychologic impact of acne [66,69] (see "Oral isotretinoin therapy for acne vulgaris", section on 'Psychiatric effects'). In patients with ichthyosis, the potential benefit of effective disease management with retinoids on psychosocial functioning and quality of life is important. That said, psychiatric monitoring for the development of psychiatric symptoms is recommended in patients on systemic retinoids [3]. If there is any concern, partnership with a behavioral health provider to formulate a treatment plan that addresses mental health concerns as well as ichthyosis treatment is recommended.

Pregnancy – Pregnancy is contraindicated with the use of systemic retinoids because they are known teratogens. Boxed warnings for systemic retinoids indicate extreme risk of severe, congenital anomalies in exposed fetuses. With the use of systemic retinoids, patients must use two forms of contraceptives simultaneously if they are sexually active (abstinence is acceptable), one of which should be considered highly effective (eg, an intrauterine device). In addition, in the United States, all patients on isotretinoin must commit to the iPLEDGE program designed to prevent pregnancy and eliminate fetal exposure to isotretinoin. (See "Oral isotretinoin therapy for acne vulgaris", section on 'iPLEDGE program'.)

OTHER THERAPIES — Other therapies that have been tried in a limited number of patients include:

Topical N-acetylcysteine – Treatment with N-acetylcysteine (NAC) was first reported to improve lamellar ichthyosis when used twice daily and, since then, has also been found to be helpful for patients with other forms of ichthyosis [70-72]. Although its advantage is minimal systemic absorption (3 percent systemic bioavailability), NAC may cause irritation and/or increased scaling and has a foul, sulfuric odor that is difficult to mask [71,72]. It also needs compounding (typically as 5 to 10% NAC in 5% urea), is costly, and is often not covered by insurance [72].

Topical carbocysteine – A formulation combining 10% carbocysteine and 5% urea was used to treat three children (ages five to nine years) with autosomal recessive congenital ichthyosis and one adult with ichthyosis vulgaris, with clinical effectiveness in three out of the four patients [73]. Since the carbocysteine molecule is like NAC but has a bound sulfhydryl group rather than a free one, it lacks the foul smell that NAC-compounded formulations emit. This is especially advantageous for treatment compliance and may help improve quality of life from a social perspective. No adverse effects were reported.

Vitamin D – Ichthyoses, especially epidermolytic ichthyosis and autosomal recessive congenital ichthyosis, have been associated with an increased risk of vitamin D deficiency and rickets [74,75]. Proposed mechanisms include decreased ultraviolet (UV) light exposure, inability of ultraviolet B (UVB) radiation to penetrate thick scale, or a keratinocyte abnormality in processing vitamin D3 in response to UVB radiation [76]. Vitamin D levels should be monitored, and adjunct therapy with vitamin D3 should be implemented for anyone with a deficiency. (See "Vitamin D insufficiency and deficiency in children and adolescents".)

In a small case series, seven children with congenital ichthyosis and severe vitamin D deficiency (serum 25(OH)D <4 ng/mL), of whom six had clinical and radiologic evidence of rickets, were treated with a 10-day course of high-dose vitamin D3 (60,000 international units daily) plus 40 mg/kg/day of elemental calcium, followed by daily supplementation of 400 to 600 international units of cholecalciferol (recommended daily allowance) [77]. Six of seven children experienced improvement in scaling and skin stiffness after five days of beginning treatment. Hypercalcemia developed in one patient. Whether vitamin D oral supplementation at the recommended doses for the treatment of nutritional rickets [78] is beneficial for children with congenital ichthyosis has not been determined. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Vitamin D replacement'.)

Topical vitamin D analogues – Data are limited on the use and effectiveness of topical synthetic vitamin D analogs (calcipotriol and calcipotriene) for treating disorders of cornification, but case reports suggest some response in patients with lamellar ichthyosis, epidermolytic ichthyosis, recessive X-linked ichthyosis, and Netherton syndrome [7,79-81].


Harlequin ichthyosis — As is the standard of care for collodion babies, neonates with harlequin ichthyosis should be treated in neonatal intensive care units and placed in an isolette with 50 to 70 percent humidification to allow for proper temperature regulation and prevention of excess transepidermal water loss. (See "Autosomal recessive congenital ichthyoses", section on 'Neonates with harlequin ichthyosis'.)

Careful and close monitoring of body weight, hydration status, and electrolyte balance is important. Prophylactic initiation of systematic antibiotics is not recommended, but careful observation for signs and symptoms of sepsis is required. Given the poor cutaneous barrier and potential toxicity, use of keratolytic agents should be avoided during infancy in all neonates and younger infants with ichthyosis [34,35].

In harlequin ichthyosis specifically, early initiation of systemic retinoids should be considered, particularly if there are digital and/or thoracic contractures [82]. Acitretin is the oral retinoid of choice. It can be compounded by breaking the capsule and mixing the powder with a small amount of formula or breast milk [83]. The suggested dosing is 0.5 to 1 mg/kg once daily. Topical application of tazarotene, or surgical lysis if indicated, can also quickly reduce the digital encasing bands (pseudoainhum), which can otherwise lead to digital and limb constriction [46,83]. Retinoids may be tapered and discontinued by six months of age in many affected babies, with continued use of topical retinoids as needed [83,84]. Pain control with acetaminophen or opioids may be necessary [83].

Fungal infection of the skin and hair — Individuals with ichthyosis are prone to develop dermatophyte infection, which may not be recognized during routine care. In the presence of suddenly worsening alopecia or localized scaling and erythema, the presence of intercurrent fungus infection should be considered.

Special sites

Eyes — Special attention should be given to eye care for patients with ectropion [85]. Preservative-free eye lubricant ointments, and potentially eye shield use at night, are critical for those who cannot fully close the eyes to avoid keratitis [1,5]. Early and routine ophthalmology evaluation is recommended. A small case series and a case report showed improvement and, in some cases, complete reversal of ectropion with daily or twice-daily application of tazarotene 0.05 to 0.1% cream [47,48].

Surgical correction for contracture release and grafting with autologous skin or engineered human skin is generally reserved for severe cases [86-88]. Although good results have been reported after surgery, patients may still have difficulty in fully closing the eye, and cosmetic results may not be perfect. Systemic retinoids may be an alternative to surgery or may be given following surgery to prevent recurrence [85].

Ears — Accumulation of debris can lead to conductive hearing loss [5]. Early evaluation and removal of debris by a professional every 3 to 12 months, as needed, is important, particularly in infants and young children who are developing speech skills [89]. Acetic acid 0.25%, aluminum acetate 2%, or over-the-counter ear wax removal drops can help soften keratin plugs [83]. External otitis occurs more often in individuals with ichthyosis. Treatment with a 7- to 10-day course of topical antibiotics with or without a steroid component is usually effective. (See "External otitis in adults: Treatment", section on 'Topical otic preparations: General principles'.)

Extremity contractures — Regular physical therapy should be prescribed in conjunction with topical or systemic retinoid treatment [5,46,83].

TARGETED AND INVESTIGATIONAL THERAPIES — The discovery of the genetic alterations underlying the inherited disorders of keratinization and an evolving understanding of the implicated pathogenetic mechanisms promoted efforts to develop pathogenesis-based therapies for this group of genodermatoses.

Compounded topical statin-cholesterol – There are a few case reports of successful use of compounded topical statin-cholesterol for the treatment of the skin manifestations of CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome [90-92] and porokeratosis [93,94].

CHILD syndrome is a rare, X-linked dominant disorder caused by a variant in NSDHL, encoding NAD(P) sterol dehydrogenase-like, a key enzyme in the cholesterol biosynthesis pathway [95]. The accumulation of toxic sterol precursors is primarily responsible for the abnormal cornification and skin barrier function, likely exacerbated by reduction of cholesterol in the barrier. Targeted treatment for cutaneous manifestations using compounded 2% lovastatin/2% cholesterol ointment prevents toxic metabolite formation and replenishes cholesterol, leading to rapid improvement in skin erythema and scaling [90]. The use of alternative statins (eg, topical simvastatin) compounded with cholesterol and the combination with topical glycolic acid have also been reported as beneficial [91,92,96]. (See "Overview and classification of the inherited ichthyoses", section on 'X-linked dominant disorders'.)

Porokeratosis includes a group of disorders of cornification characterized by the cornoid lamella histologically and leading to a specific pattern of scaling. Gene variants all involve the mevalonate components of the cholesterol biosynthesis pathway, upstream of the NSDHL product. Similar to CHILD syndrome, targeted treatment with 2% statin/2% cholesterol can improve disseminated superficial actinic porokeratosis, porokeratosis palmaris et plantaris disseminate, and linear porokeratosis [93,94]. (See "Porokeratosis".)

Biologics – Studies have shown strong interleukin (IL) 17/tumor necrosis factor (TNF)-alpha cytokine activation in the skin and blood of patients with severe types of congenital ichthyosis (eg, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis, and Netherton syndrome) similar to that seen in psoriasis [97-100]. These findings have led to a proposal for repurposing targeted therapies used for psoriasis and atopic dermatitis for the treatment of rare, severe forms of ichthyosis [101].

Secukinumab and ustekinumabSecukinumab and ustekinumab are inhibitors of IL-17 and IL-12/IL-23 pathways, respectively. Both agents induced remarkable improvement in some, but not all, treated patients with Netherton syndrome [102,103] and congenita ichthyosiform erythroderma [104].

Ustekinumab was also successfully used in two patients with erythrokeratodermia-cardiomyopathy (EKC) syndrome, an autosomal dominant, ichthyotic disorder presenting in infancy with failure to thrive, dental and nail anomalies, woolly hair with alopecia, and the development of life-threatening cardiomyopathy [105,106]. Secukinumab improved skin manifestations, growth, and quality of life in two patients with SAM (severe dermatitis, multiple allergies, and metabolic wasting) syndrome, a rare genodermatosis characterized by congenital erythroderma and striate palmoplantar keratoderma and associated with a dysregulation of the IL-17 pathway [107,108]. (See "Peeling skin syndromes", section on 'SAM syndrome'.)

A clinical trial of ustekinumab in children and adults with ichthyosis is ongoing (NCT04549792).

DupilumabDupilumab, an anti-IL-4 receptor-alpha antibody approved for treating atopic dermatitis, has been shown to reduce erythema and scaling in a few patients with Netherton syndrome [109-113]. Clinical trials of dupilumab for Netherton syndrome and other congenital ichthyoses are underway (NCT04244006 and NCT04996485).

Infliximab – Based on the demonstration of increased TNF-alpha expression in Netherton syndrome skin, infliximab therapy led to reduced erythema in one patient, but the xerosis, scaling, and high serum immunoglobulin E (IgE) levels did not improve [114].

Omalizumab – In one patient with Netherton syndrome, a four-month course of omalizumab therapy in conjunction with pulse prednisone and antihistamines led to decreased pruritus, erythema, desquamation, and mucosal symptoms within four weeks [115].

IxekizumabIxekizumab, a humanized anti-IL-17A/F antibody, induced substantial improvement of the inflammatory skin lesions in two of three patients with Netherton syndrome after six months of treatment [116].

Gene therapy – Gene therapy trials with grafts of autologous keratinocytes transduced with the normal SPINK5 gene using a lentivirus vector are ongoing in patients with Netherton syndrome (NCT01545323) [117,118].

A trial of topical application of TGM1 (the gene encoding transglutaminase 1) inserted as multiple copies into an inactivated herpes simplex virus in adult patients with lamellar ichthyosis who carry a null TGM1 variant is also underway (NCT04047732).

PATIENT SUPPORT — Disorders of cornification have a negative impact on the quality of life and psychosocial well-being for patients and their families/caregivers [119]. The Foundation for Ichthyosis and Related Skin Types (FIRST) hosts meetings for patient interactions and provides educational materials and information on available treatment options. A listing of over-the-counter products, created by FIRST in collaboration with patients and families/caregivers, can be provided to clinicians and members of the organization upon request.

Other foundations that support the families/caregivers of patients with ichthyosis include the European Network for Ichthyosis, the Ichthyosis Support Group (United Kingdom), and the Asociación Española de Ictiosis (Spain).

Camp Discovery is a week-long opportunity for children and adolescents with hair and skin disorders, including disorders of cornification, sponsored by the American Academy of Dermatology.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ichthyosis".)


Goals of treatment – There are no curative therapies for ichthyosis. Treatment is largely symptomatic, aimed at reducing skin dryness and scaling, limiting excess transepidermal water loss, hydrating and softening the stratum corneum, and controlling skin inflammation and pruritus. Because of the chronic nature of these disorders, patients require long-term, comprehensive care. For patients with severe disease, early consultation with a multidisciplinary team (including dermatology, genetics, neonatology, ophthalmology, otolaryngology, orthopedic and plastic surgery, occupational and physical therapy, and nutrition) is essential. (See 'General considerations' above and 'General measures' above.)

General measures – General skin care measures, including bathing, exfoliation, and liberal use of emollients, are the mainstay of ichthyosis management. Long, daily baths with additives (eg, sodium bicarbonate, bleach, acetic acid) facilitate scale removal, reduce bacterial colonization and odor, and hydrate the skin. (See 'General measures' above.)

Topical therapies

Topical keratolytics – Topical keratolytic agents are first-line treatment for children and adults with ichthyosis. Creams and ointments containing alpha-hydroxy acids, beta-hydroxy acids, urea, and propylene glycol, in various concentrations and combinations, are commonly used with good response in most types of ichthyosis (table 4). Topical keratolytics are contraindicated in infants younger than six months and should be used with caution in older infants and children due to the risk of adverse effects from systemic absorption. (See 'Topical keratolytic agents' above.)

Topical retinoidsTazarotene, the most potent topical retinoid, is the preferred topical retinoid for the scaling of ichthyosis and is the preferred first-line agent for treating ectropion in lamellar ichthyosis. Tazarotene can also be used to loosen areas of contracture in neonates and infants with harlequin ichthyosis. (See 'Topical retinoids' above.)

Systemic retinoids – Systemic retinoids (acitretin and isotretinoin) are indicated for patients with severe and extensive scaling and hyperkeratosis that are insufficiently improved with topical therapies alone (table 4). Both acitretin and isotretinoin are initiated at a dose of 0.5 to 1 mg/kg/day, with subsequent adjustments to the lowest dose required for obtaining the desired therapeutic effect with tolerable adverse effects. Systemic retinoids are teratogenic. Because of its shorter half-life and more rapid clearance, isotretinoin is preferred to acitretin for the treatment of female patients of childbearing potential. (See 'Systemic retinoids' above.)

Targeted therapies – Improved understanding of the underlying pathogenesis of ichthyoses, beyond the gene variants, has led to the emergence of pharmacologic, pathogenesis-based approaches. Targeted treatment with topical statin-cholesterol greatly improves the skin manifestations of CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome and porokeratosis. Repurposing of biologic agents, such as interleukin (IL) 23/T helper type 17 (Th17) pathway inhibitors secukinumab and ustekinumab, has improved inflammation and scale in a subset of patients with erythrodermic forms (eg, congenital ichthyosiform erythroderma, Netherton syndrome, erythrokeratodermia-cardiomyopathy [EKC] syndrome, and SAM [severe dermatitis, multiple allergies, and metabolic wasting] syndrome). (See 'Targeted and investigational therapies' above.)

Online resources for patients with ichthyosis and their families/caregivers include the Foundation for Ichthyosis and Related Skin Types (FIRST), the European Network for Ichthyosis, the Ichthyosis Support Group, and the Asociación Española de Ictiosis. (See 'Patient support' above.)

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