Ichthyosis Vulgaris (Ichthyosis Congenita)

Are You Confident of the Diagnosis?

The diagnosis of ichthyosis vulgaris (IV) is difficult to make because there are no clinical findings that are entirely specific for this condition. Rather, it is based on a combination of features that, when put together, increase the likelihood of this diagnosis.

What you should be alert for in the history

IV is generally not present at birth but will start to appear months later. Patients and families will report dry, scaly skin that is worsened by dry and cold weather. The condition will tend to improve in the summer months and in a humid environment. Patients will also complain of dryness on the extensor surfaces and pruritus.

It is unusual for IV to involve the intertriginous areas of the body which are generally moist, alleviating the dryness. For instance, in infants, the diaper area is rarely affected. In severe cases, patients may complain of scaling that can affect the trunk, face, and scalp. IV is also frequently associated with keratosis pilaris, recently reported as high as 52.9%.

Patients will often worsen through childhood but then improve into adulthood, usually following puberty. On occasion, patients living in humid environments may not even be aware that they have IV until moving to a dryer, cooler climate unmasks their symptoms.

Asking about a family history of dry, scaly skin will aid in the diagnosis, as IV is a genetic disorder that is inherited in an autosomal semi-dominant manner (exhibiting an interemediate phenotype between normal hosts and those homozygous for the gene defect), and therefore will often cluster within families. Patients may also present with atopic dermatitis or asthma, as people with IV are at increased risk for both of these conditions.

Characteristic findings on physical examination

On physical examination, fine, white, flaky, scale is often present on the lower abdomen, arms, and legs (Figure 1). Subtle hyperkeratosis of the palms and soles will give rise to palmar and plantar hyperlinearity (Figure 2). Evidence of keratosis pilaris can be found on the lateral upper arms, thighs, and back most typically, but also on other parts of the body, such as the face in children. These appear as monomorphic perifollicular papules with surrounding erythema and a central keratotic core.

Figure 1.

Fine white flaky scale in an adult patient with icthyosis vulgaris (Courtesy of Bryan Anderson, MD)

Figure 2.

Palmar hyperlinearity.

Expected results of diagnostic studies

There are no recommended laboratory studies that will confirm the diagnosis of IV. Commercially available methods for genotyping mutations in the gene encoding the epidermal barrier protein profilaggrin can identify mutations (R501X and c.2282del4) that cause IV in 80-90% of people of North- or Western-European decent. However, these tests would result be limited in identifying mutations in patients of non-European descent.

Overall, due to the high frequency of mutations in the general population and high cost of this test, its utility remains undefined in the clinical setting. The presence of the mutation would not rule out other ichthyoses (eg, acquired ichthyosis which can be associated with malignancy).

A skin biopsy is usually not necessary as the diagnosis of IV may be made on clinical grounds. In rare cases where a biopsy is deemed appropriate, one would expect to find mild orthokeratotic hyperkeratosis and an attenuated granular cell layer on hematoxylin and eosin staining. Electron microscopy can demonstrate structurally abnormal or absent keratohyaline granules as well. However, these findings are inconsistent and therefore biopsy remains unreliable. There is no value in imaging studies.

Diagnosis confirmation

The differential diagnosis of IV includes the following entities (1) xerosis; (2) X-linked ichthyosis which occurs in male patients. These patients present with larger brown scale, can have cryptorchidism, and often have a history of prolonged maternal labor; (3) acquired ichthyosis which presents later in life and can be associated with malignancy, malnutrition, infection, or inflammatory conditions; and (4) asteototic dermatitis which would present much later in life.

Who is at Risk for Developing this Disease?

IV is very common with an overall incidence of 1 in 250 people. Ask the patient about a family history of dry, scaly skin as this is inherited in an autosomal semi-dominant manner. Furthermore, ask about both personal and family history of atopic dermatitis, asthma, and hay fever as 37-50% of people with IV will suffer from atopic disease. Among patients with atopic dermatitis, 2.5-37% will have clinical evidence of IV.

What is the Cause of the Disease?

Mutations in the gene encoding profilaggrin have been shown to cause ichthyosis vulgaris. Profilaggrin is a large, complex polypeptide stored within the keratohyaline granules of the epidermis. An inactive precursor, it is cleaved by proteases in the skin into the active filaggrin polypeptide, which helps to mediate proper differentiation of the epidermis but is also broken down into components that comprise natural moisturizing factor (NMF). These components include hygroscopic amino acids, urocanic acid, and pyrolidone carboxylic acid.

By these various mechanisms, filaggrin is thought to ensure epidermal barrier integrity. If filaggrin is dysfunctional or absent, the epidermal barrier is disrupted, leading to the clinical findings seen in IV. Previous studies suggest that mutations leading to the absence of two copies of filaggrin lead to more severe IV than mutations in only one copy.

Systemic Implications and Complications

The importance of recognizing IV was demonstrated by studies showing an increased risk of atopic dermatitis in patients with ichthyosis vulgaris. Given that atopic dermatitis is the first allergic disease to present in a series of allergic diseases such as food allergies, asthma, and hay fever, it is important to recognize IV as these patients may be at increased for these conditions. The ‘atopic march’ theory argues that early cutaneous sensitization leads to the development of allergies at other epithelial barrier surfaces, such as the gastrointestinal tract and upper and lower airways.

A recent study has shown that severity of IV, independent of filaggrin genotype, is associated with earlier onset and more severe atopic dermatitis as well as hay fever. Furthermore, another study has shown that filaggrin mutations confer an increased risk for hay fever, independent of the presence of atopic dermatitis. Taken together, these studies suggest that proper treatment of barrier dysfunction in patients with IV may be important for decreasing one’s risk for allergic disease later in life. Further studies are required to definitively prove this concept.

Treatment Options

Treatment options for IV are sumarized in Table I.

Table I.
Medical Treatment Surgical Procedures Physical Modalities
Topical occlusive emollients (eg, white petrolatum)Topical emollients containing propylene glycol, ceramides, and ureaTopical salicylic acid, alpha-hydroxy acids None Soak and smear techniqueWet wrap technique

Optimal Therapeutic Approach for this Disease

Topical white petrolatum or emollients containing propylene glycol, ceramide, or urea are the cornerstones of treating IV. White petrolatum acts as an occlusive emollient that traps in moisture. Propylene glycol draws water into the stratum corneum by creating a gradient, ceramide replaces the natural moisturizing factor that is deficient as a result of the loss of filaggrin, and urea helps works as a humectant. These are all excellent first-line therapies as they are effective and safe.

Examples of propylene glycol-containing products include Cetaphil Moisturizing Cream and Vanicream Moisturizing Skin Cream, which both contain petrolatum as well. Ceramide-containing products include Cerave Moisturizing Cream, Cetaphil Restoraderm, and EpiCeram Skin Barrier Emulsion. Examples of urea-containing products include Carmol 20 Cream and Eucerin Plus Intensive Repair Creme. In general, all of these products should be used twice daily on all affected areas.

Topical keratolytics such as salicylic acid and alpha-hydroxy acids (eg, lactic acid) are also very effective therapies that work by removing scale from the stratum corneum. Salicylic acid should be used with some caution, as salicylate poisoning has been reported as a result of systemic absorption. Nonetheless, keratolytics remain excellent and safe second-line agents in the treatment of IV.

Keralyt 6% Gel can be used on particularly scaly and hyperkeratotic areas at bedtime. It should not be used in children under 2 years of age and should used with caution in children under 12 years of age. Amlactin or Lac-Hydrin 12% should be used twice daily and, unlike salicylic acid, has been shown to safe in infants and children.

For severe and recalcitrant disease, all of the above emollients can be used in conjunction with a modified soak and smear technique whereby patients soak in plain lukewarm water for 20 minutes and then apply the emollient to wet skin. This can be followed by occlusion with long-sleeved cotton pajamas. Additionally, this can be modified into a wet wrap technique whereby damp cotton pajamas are placed following soak and smear with an outer layer of dry cotton pajamas for a couple hours at room termperature.

Topical steroids are not effective for IV in the absence of atopic dermatitis. Though topical and oral retinoids have been reported to be effective in other forms of ichthyoses, particularly congenital forms, their efficacy in classic IV remains unclear and are not typically recommended.

Improvement is gradual and can be expected over the course of 2 weeks of aggressive treatment with the above modalities

Given that the genetic and molecular mechanisms of IV are becoming clearer, we are likely to see newer therapies to specifically target pathways that are perturbed by loss of filaggrin expression and its active components that lead to disease.

Patient Management

Explain the natural history of IV to the patient before beginning treatment. This is a chronic condition, which will likely improve from childhood into adulthood without any treatment over the course of many years. Accordingly, treatments may help, but progress may be very slow.

Encourage patients to persist with treatment; they will improve over time. Advise the use of combinations of therapeutic modalities for potential synergistic effects (eg, NMF-replenishing ceramides in addition to occlusive petrolatum-based emollients). Furthermore, emollient under occlusion may also be beneficial.

Another potential useful strategy is a mild soak and smear technique whereby patients soak in plain, lukewarm water for 20 minutes and then apply emollients immediately after onto wet skin. This technique can be used in conjunction with occlusion or a wet wrap technique to potentiate the trapping of moisture and penetration of moisturizing factors into the skin. Finally, patients should use gentle soaps such as Dove for Sensitive Skin Beauty Bar (Fragrance Free) or Cetaphil Gentle Cleanser to prevent further damage to the stratum corneum.

Tell the patient that IV is not dangerous, so that the risks of any potential treatments must be carefully weighed against potential benefit. For mild disease requiring only topical treatment, patients need to be seen only periodically (every 3 to 6 months); for pediatric patients or those requiring aggressive treatments such as keratolytics, patients should be seen more frequently to monitor for proper use and the potential development of atopic dermatitis. An endpoint to treatment is based on what the patient hopes to have accomplished, but also the potential prevention of the development of atopic dermatitis, a major risk factor in IV.

Unusual Clinical Scenarios to Consider in Patient Management

Remember that despite the fact that IV is hereditary, due to variable penetrance, the family history may be difficult to accurately obtain. Classic IV should develop early in childhood and improve into adulthood. However, the disease may worsen if a patient moves from a humid climate to a colder, dryer climate and appear to worsen over time.

Though difficult to clinically distinguish, acquired ichthyosis that develops in adulthood should prompt the concern for underlying malignancy (lymphoma, mycosis fungoides, multiple myeloma), thyroid disease, sarcoidosis, leprosy, nutritional deficiency, HIV, and autoimmune diseases. A skin biopsy can demonstrate changes that would be more consistent with ichthyosis vulgaris by the absence of keratohyaline granules on a hemotoxylin and eosin stained section. However, due to the high frequency of ichthyosis vulgaris in the general population, one must still be concerned for acquired ichthyosis that develops later in life that cannot be attributed to a change in the environment.

What is the Evidence?

Smith, FJ, Irvine, AD, Terron-Kwiatkowski, A, Sandilands, A, Campbell, LE, Zhao, Y. “Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris”. Nat Genet. vol. 38. 2006. pp. 337-42. (The original article establishing filaggrin null mutations as the causative factor in ichthyosis vulgaris.)

Palmer, CN, Irvine, AD, Terron-Kwiatkowski, A, Zhao, Y, Liao, H, Lee, SP. “Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis”. Nat Genet. vol. 38. 2006. pp. 441-6. (The original article establishing filaggrin null mutation as a clear presdisposing factor for the development of atopic dermatitis.)

Osawa, R, Akiyama, M, Shimizu, H. “Filaggrin Gene defects and the risk of developing allergic disorders”. Allergol. vol. 60. 2011. pp. 1-9. (A review of the risks of developing various allergic diseases as a result of filaggrin mutations known to date.)

Bremmer, SF, Hanifin, JM, Simpson, EL. “Clinical detection of ichthyosis vulgaris in an atopic dermatitis clinic: implications for allergic respiratory disease and prognosis”. J Am Acad Dermatol. vol. 59. 2008. pp. 72-78. (This article demonstrates that the clinical presence of ichthyosis vulgaris is predictive of the development of allergic airway disease independent of filaggrin genotype.)

Simpson, EL, Berry, TM, Brown, PA, Hanifin, JM. “A pilot study of emollient therapy for the primary prevention of atopic dermatitis”. J Am Acad Dermatol. vol. 63. 2010. pp. 587-93. (This pilot study suggests that therapy with topical emollient in ichthyosis vulgaris may prevent the development of atopic dermatitis.)

Lebwohl, MG, Heymann, WR, Berth-Jones, J, Coulson, I. “Treatment of skin disease: comprehensive therapeutic strategies”. 2006. pp. 1-723. (An outstanding overview of therapeutic approaches appropriate for various forms of ichthyoses.)