Formal diagnostic guidelines for the DOC have not yet been established. Questions about history should ascertain prematurity and perinatal complications, presentation during the neonatal period (e.g., as a collodion baby, with erythroderma but not collodion membrane, blistering), course of the disorder, and experience with interventions. A pedigree should be obtained to suggest pattern of inheritance. Review of systems may reveal involvement of other organs (eyes, neurologic, etc.). Physical examination is crucial to define the cutaneous manifestations (character, severity and distribution of scaling, thickening and inflammation; presence of blisters or erosions; ectropion, eclabium, alopecia, and other hair changes) and observe any extracutaneous manifestations (see Table 5.1).

In some cases, diagnosis can be made prenatally. For example, pregnant mothers who carry a fetus with X-linked ichthyosis often have low serum unconjugated estriol levels during the second trimester, and FISH analyses can show the deletion in the fetal X-chromosome. Ultrasonographic findings may also suggest a diagnosis of ichthyosis, such as in Conradi syndrome (limb anomalies) or harlequin ichthyosis [3, 4]. If families have a risk of an affected fetus and the DNA mutation has been detected, prenatal diagnosis can be performed by amniocentesis or chorionic villus sampling to determine if the fetus is affected. Amniotic fluid itself may have a turbid appearance because of the large amount of desquamated skin floating in the amniotic cavity (the “snowflake sign”) [5]. Preimplantation diagnosis is a technique using in vitro fertilization that enables only unaffected blastomeres to be implanted; preimplantation has been performed for an at-risk family for Netherton syndrome [6].

In addition to DNA analysis for a specific genotype, laboratory testing can aid in the clinical diagnosis of several forms of DOC. Routine assessment of skin sections is often nonspecific, but may show specific histological features, such as the orthokeratosis and epidermolysis of epidermolytic ichthyosis and the suprabasal acantholysis, corps rond, and grains of Darier disease. Biochemical testing may also be helpful, such as in detecting high serum cholesterol sulfate levels in recessive X-linked ichthyosis and increased levels of phytanic acid in the cerebrospinal fluid of individuals with Refsum disease [7]. Simply observing blood smears will demonstrate the lipid-containing vacuoles in circulating white blood cells of neutral lipid storage disease [8]. Another relatively simple diagnostic tool is a hair mount; observation of broken hairs may demonstrate the characteristic trichorrhexis invaginata (“bamboo hair”) of Netherton syndrome, trichorrhexis nodosa (nodes along the hair shaft) or, under polarized light, the “tiger tail” patterning of trichothiodystrophy.

Genetic testing for mutation analysis is becoming more accessible as technology progresses, and can be a useful diagnostic tool for patients and families [9]. The more recent availability of amplicon-based tools for genotyping major forms of ichthyoses and of whole exome sequencing to find rare mutations in known genes and discover new genes that underlie DOC (for example, GJA1 mutations in a form of erythrokeratodermia variabilis) [10] have increased our understanding of these disorders and will drive pathogenesis-based personalized therapy.

Emollients (also called moisturizers) are considered a critical component of care for individuals with DOC. Emollients fill the empty spaces between the cells of the stratum corneum, resulting in a smoother and shinier skin surface [13]. There are two types of emollients: occlusives and humectants. Occlusives prevent transepidermal water loss (TEWL) and trap moisture derived from the deeper dermis and epidermis in the stratum corneum. Examples of occlusives include mineral oil, lanolin, and silicones. Petroleum jelly is by far the most effective occlusive, decreasing TEWL by 98 % when applied properly [13]. Humectants attract moisture from the environment when humidity is greater than 70 %. In less humid environments, humectants attract water molecules from the deeper layers of the skin. Examples of humectants include glycerin, propylene glycol, and alpha-hydroxy acids [14]. When humectants are used in isolation, they can actually increase TEWL, emphasizing the importance of use of humectants in conjunction with an occlusive moisturizer to retain skin hydration [15]. Hydration of the skin affects its barrier function, thus playing a role in both the integrity of the stratum corneum and influencing penetration through the upper layers of the epidermis [14]. Emollients are thought to decrease TEWL, creating an optimal environment for repair of the stratum corneum and its associated lipids. Emollients also play a role in lipid regeneration and maintenance, can decrease inflammation, and help to rebuild a defective barrier. However, a recent study showed that emollients (with both occlusive and humectants) improved skin dryness in individuals with RXLI, but had no impact on TEWL, pH, or gene expression [16], suggesting that more study is needed to understand the role of emollients in the ichthyoses.

DOC are often associated with hyperkeratosis, which is an increase in the thickness of the stratum corneum. Substances used to treat hyperkeratosis are termed keratolytics. Several types of keratolytics are used to decrease the scaling of these disorders:

Bacterial colonization and infection, especially with S. aureus, and dermatophyte infection is not uncommon in the retained scale and fissured skin of individuals with DOC. In particular, overgrowth of bacterial organisms contribute to the skin odor and discomfort of children, such as with EI, the lamellar phenotype of ARCI, Netherton syndrome and keratitis-ichthyosis-deafness (KID) syndrome. Prophylactic use of antibiotics should be avoided, especially in neonates, in order to prevent the development of resistance and creation of a growth environment favoring Pseudomonas aeruginosa. Although chronic or repeated administration of antibiotics should be avoided, systemic intervention is necessary for infection. Cephalexin (10–15 mg/kg/dose given three times daily for 10 days) is most commonly administered for staphylococcal infection, although intervention should be based on resistance patterns if MRSA infection. Very localized bacterial infection can be managed by topical antibiotics. Bacterial infection tends to be characterized by pustules, abscesses, crusting, or increased erythema and swelling, and can be associated with discomfort. Maintenance intervention with antiseptics in the bath and antibacterial soaps (see section on “Baths”, below) are beneficial for colonization that leads to odor in the absence of infection [21].

Individuals with ichthyosis are also predisposed to the development of secondary fungal infections. Diagnosis of dermatophyte infection can be particularly tricky, given the generalized scaling (including of the scalp) and often associated inflammation of the ichthyosis. An annular patterning of the scaling and recalcitrance to therapy may be clues, but fungal infection may present only as worsening of itch and desquamation. The threshold for performing potassium hydroxide mount evaluation and fungal culture should be low in patients. Standard doses of griseofulvin (20 mg/kg/day divided into two doses; requires 2–4 weeks longer than terbinafine and other interventions), terbinafine (62.5 mg/day for 10–20 kg, 125 mg/day for 20–40 kg and 250 mg/day for more than 40 kg; given daily for 2–4 weeks for tinea corporis and 4–6 weeks for tinea capitis), itraconazole (5 mg/kg/day), or fluconazole (6 mg/kg/day). The dermatophyte infection in ichthyosis may be more persistent than in normal skin and require prolonged systemic antifungals courses [22].

Bathing should be encouraged to be a part of every ichthyosis patient’s daily regimen. Many patients with ichthyosis find that soaking for long periods (even an hour) hydrates the skin and facilitates scale removal. Bath additives can be soothing, antiseptics, and may promote desquamation. Use of oils or lanolin in the bathtub [23] should be avoided with young children, because of the risk of increased slipperiness. Addition of two cups of baking soda to a full standard tub [24] has been suggested. Baking soda increases the pH of tap water to an alkaline range, which may increase protease activity and promote scale desquamation. Adding salt to bath water may also be soothing and lead to decreased pruritus [25]. Adding bleach (sodium hypochlorite) at a concentration of 0.005 % (one half-cup to a full standard bath; 1 cc per L) to the bath water can be a convenient and affordable measure to minimize bacterial overgrowth. Although no studies of its effect in ichthyosis have been performed, in individuals with atopic dermatitis, at least twice-weekly dilute bleach baths have been shown to decrease disease activity, including inflammation and scaling [26]. Recently, sodium hypochlorite has been shown to inhibit NF-kB signaling and reduce radiation dermatitis in a murine model [27], suggesting a direct anti-inflammatory effect. Hydrotherapy treatments showed to have short- and medium-term efficacy, but are only available in specific centers [28]. Application of emollient immediately after bathing and while the skin is well hydrated is essential (see section on “Emollients”).

Patients with ichthyosis are more susceptible to overheating from hypohidrosis. Although occlusion of eccrine ducts by scaling has been blamed, many affected individuals continue to have issues with heat intolerance and inadequate sweating after therapeutic response to intervention, suggesting a developmental abnormality. Keeping a temperature-controlled environment throughout the year, wetting the skin with spray bottles of water or wet towels, and wetting clothing during outdoor activities in warm weather, or even using cooling suits, are highly recommended.

Soaking in water for prolonged periods softens the stratum corneum and allows for removal of the thickened skin with rough-textured sponges or abrasives [7]. The repetitive mechanical procedure may be physically and emotionally exhausting, but rewarding both cosmetically and symptomatically. Earwax from excessive desquamation in the ear canal can lead to conductive hearing loss. Earwax softeners (e.g., carbamide peroxide drops) can facilitate scale removal, which should be performed up to quarterly, as needed, by a trained professional. Although in general home earwax removal is discouraged, a flexible plastic loop with a safety stop (Ear-Wiz®) allows removal of excess wax without touching the eardrum. For patients with palmoplantar keratoderma, focal soaks and paring excess skin with a sharp hand tool is the most effective way to decrease thickening that interferes with performance of daily activities [29]. Surgical approaches, including CO₂ laser treatments and full thickness excision and grafting, have anecdotally been described for adult patients [30, 31]. Constrictive skin bands in neonates with harlequin ichthyosis may lead to contractures, compartment syndrome, circulatory compromise, and autoamputation; releasing the skin bands with a 2 mm curette [9], an 11 blade [32], or with a linear band incision technique [33] should be done by a skilled dermatologist, plastic surgeon, or orthopedist. Patients with localized problematic ichthyotic areas of CHILD syndrome may benefit from excision and grafting from the contralateral, unaffected donor region [34].

Both topical and oral retinoids are used to treat various DOC [35]. Their primary effect is to normalize epidermal differentiation, which improves epidermal thickness and hyperkeratosis. In general, topical retinoids are used for milder localized disease and oral retinoids are used for more severe, widespread disease.

Liarozole, an imidazole derivative, is a RAMBA that has orphan drug status for topical and oral use for congenital ichthyosis in Europe, but is not available in the United States. Liarozole inhibits the oxidative metabolism of retinoic acid, leading to higher levels of retinoic acid in the plasma and skin, which then normalizes keratinocyte differentiation and proliferation. Via CYP inhibition, liarozole can affect synthesis of estrogen, androgens, and cortisone, but these effects do not appear to be clinically significant. Liarozole appears to have similar clinical efficacy to retinoids, with fewer retinoid side effects. Topical use did lead to systemic absorption of varying degrees, which led to a decrease in estradiol concentrations, but not to any significant systemic side effects [44, 45].

The progress of understanding the genetic basis and the pathogenesis of many of the ichthyoses has enabled more targeted therapy. Approaches may be gene-based or pathway-based pharmacologic. Gene-based therapy requires knowing the specific gene and/or mutation of the patient to replace, correct, or modulate the expression of the mutant gene. At this time, gene-based therapy has yet to be performed for the ichthyoses, but transduction of the normal SPINK5 gene using a viral vector normalized LEKTI expression in Netherton syndrome keratinocytes and restored normal skin architecture after transplantation; [46] phase I clinical trials are beginning using transplantation. Gene insertion also corrected the TGM1 mutation in a mouse model of lamellar ichthyosis [47, 48] and the restored lipid secretion in lamellar granules of ABCA12-mutated harlequin ichthyosis keratinocytes [49].

An example of pathway-based pharmacologic therapy is correction of a deficient end product (cholesterol) and blockade of accumulation of toxic metabolites (by a statin) in CHILD syndrome. The clinical and histological cutaneous abnormalities are reversed after application of 2 % cholesterol and 2 % lovastatin [50]. Systemic administration of orlistat, an intestinal lipase inhibitor, has led to significant reduction of phytanic acid levels and improved the neurological and dermatological symptoms of two siblings with Refsum’s disease [51].

A 14-year-old boy, treated with topical adapalene gel 0.1 % for his facial lesions, sustained good results during 2 years of usage [36].

ARCI is a group of disorders that most commonly presents at birth as a collodion baby. It encompasses a spectrum of ichthyosis phenotypes, ranging from mild to severe and from congenital ichthyosiform erythroderma (CIE) to lamellar ichthyosis (LI) (Fig. 5.2). All forms are autosomal recessive, although rare autosomal dominant cases of ARCI have been described. Mutations in at least nine genes have been found to underlie ARCI (Table 5.1).

The collodion baby shared phenotype (Fig. 5.3) presents at birth as encasement in shiny thickened skin, often with associated ectropion (eversion of the upper and lower eyelids) and eclabium (lip eversion), exposing the ocular and oral mucosae, respectively. Despite the thickening, the skin barrier of collodion babies is impaired. Transepidermal loss of water and electrolytes is increased, the skin is more permeable to topically applied agents, and there is a heightened risk of temperature instability and bacterial and fungal infection. The collodion membrane tends to be shed during the first month of life and the phenotype is revealed in the subsequent months.

As discussed under interventions above, individuals with ARCI often have severe pruritus and, especially with the thick scaling of lamellar ichthyosis, an odor in association with overgrowth of skin bacteria (see increased risk of bacterial and fungal infections, above). Ectropion and extensive scaling of the ear canals lead to issues that may require special expertise. The defect in sweating can manifest in overheating.