Bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis, keratinopathic ichthyosis)

Are You Confident of the Diagnosis?

What you should be alert for in the history

The newborn period is characterized by widespread blistering, denudation, and erythroderma that may lead to secondary infection and sepsis. Only focal hyperkeratosis is present at this age and misdiagnosis as epidermolysis bullosa is common. With age, blistering and denudation are replaced by variable degrees of diffuse, thick, hyperkeratotic scaling. Itch is common. Health is generally good otherwise. A parent may be affected.

Characteristic findings on physical examination

By 3 to 4 months of age, infants have generalized hyperkeratosis and only focal areas of denudation (Figure 1). The ichthyosis is more prominent in the flexures and over joints. The scales are dark, spiny (hystrix) and warty with a tendency to form ridges that are likened to corrugated cardboard (Figure 2, Figure 3). The face may be strikingly spared. Palmoplantar keratoderma is variable and may result in digit contractures and some nail dystrophy but, overall, hair, teeth, and nails are normal. Bacterial overgrowth leads to an odor that is characteristic and immediately recognizable. An abnormal, lumbering gait may be seen.

Figure 1.

Figure 2.

Figure 3.

Expected results of diagnostic studies

Bullous congenital ichthyosiform erythroderma (CIE) is one of the few ichthyoses where plain H&E pathology is diagnostically helpful, demonstrating hyperkeratosis, a thickened granular layer, and vacuolar degeneration of the upper epidermis (epidermolytic hyperkeratosis; Figure 4). These findings together with the clinical presentation are diagnostic and no other testing is needed. Genetic testing will confirm the specific keratin 1, 2 or 10 abnormality but is expensive and unnecessary in most cases.

Figure 4.

Diagnosis confirmation

The main differential diagnosis in the newborn period is epidermolysis bullosa. Pathology and, if needed, electron microscopy or immunophenotype mapping will differentiate the two. With time, the clinical distinction becomes very clear as the ichthyotic component of bullous CIE dominates the picture.

Staphylococcal scalded skin syndrome, diffuse candidiasis, and neonatal herpes may be entertained, but scrapings, culture, and pathology will rule out these entities.

With age, bullous CIE might be confused with ichthyosis vulgaris (autosomal dominant, flexural sparing, hyperlinear palms, decreased or absent granular layer), X-linked ichthyosis (only males, prolonged labor, sparing of palms, soles and flexures, comma-shaped corneal opacities, steroid sulfatase deficiency), autosomal recessive congenital ichthyosis (generalized scaling, erythroderma, ectropion, severe heat intolerance), Sjögren-Larsson syndrome (mental retardation, spastic di-tetraplegia, atypical retinal pigmentation degeneration), and Netherton syndrome (severe eczema-like symptoms, abnormal hair showing trichorrhexis nodosa, high IgE level).

Who is at Risk for Developing this Disease?

The incidence is about 1 in 200,000-300,000 births. Incidence is not affected by race, nationality or sex. Since the inheritance is autosomal dominant, there will be a 50% chance of a newborn having bullous CIE if a parent is affected.

What is the Cause of the Disease?

Etiology

Bullous CIE is the result of an autosomal dominant mutation in keratins 1, 2 (milder ichthyosis bullosa of Siemens variety), or 10. About 50% of cases are new, spontaneous mutations. There are rare reports documenting autosomal recessive inheritance resulting from null mutations in keratin 10 from each parent, so it is important to question about parental consanguinity.

Pathophysiology

Abnormal keratin scaffolding within the epidermal cells of the upper, nucleated cell layers results in a cell that is poorly resistant to mechanical trauma. The abnormal keratins also interfere with the movement of lamellar bodies toward the cell periphery, leaving them trapped within the corneocytes in the stratum corneum.

Systemic Implications and Complications

There are no systemic disorders directly associated with bullous CIE. Newborns are at great risk of developing fluid and electrolyte abnormalities, temperature instability, secondary infections, and sepsis. They should be monitored closely during this period, probably in a neonatal intensive care unit.

Older children and adults may suffer from variable degrees of hypohidrosis and are at some risk of overheating, albeit not to the degree of the autosomal recessive congenital ichthyoses. Avoiding the heat and having a spray bottle on hand are important interventions.

Secondary infection with Staphylococcus aureus and herpes simplex is a lifelong potential problem. Culture and/or DFA testing is important monitoring for this possibility, although patients will frequently recognize a secondary infection when it occurs. Systemic antibiotics and antiviral agents are needed to treat documented infections.

Treatment Options

NON-MEDICAL OPTIONS

Education and psychological support

TOPICAL MEDICAL OPTIONS

–Tubbing and very gentle exfoliation, bath oils or sodium bicarbonate

–Bland emollients

–Topical antibiotics for infection

–Topical retinoids

SYSTEMIC MEDICAL OPTIONS

–Oral retinoids

–Oral antibiotics for documented infection

SURGICAL/PHYSICAL OPTIONS

–Orthopedic or physical therapy consultation for digit contractures

Optimal Therapeutic Approach for this Disease

Avoid friction. Tape should not be placed on the skin.

Hydration and soothing of the skin through bathing helps soften the stratum corneum and allows for GENTLE debridement of loose skin. A soft face cloth or an abrasive sponge (eg, loofah sponge) can facilitate this process. Scale removal may be aided with the addition of 1 to 2 handfuls of sodium bicarbonate in the bath tub although some patients complain of stinging when this is done. Bath oils (eg, RoBathol) provide some comfort and emolliency but care must be taken to avoid slipping. Bacterial overgrowth on dead skin and resultant odor can be ameliorated with antibacterial soaps or by adding a cup of bleach to a full adult-sized tub.

Lubricating creams and ointments should be applied immediately after the tub while still moist or after quickly dabbing dry. The choice of product depends on personal taste (a view of internet chat boards shows recommendations covering a wide spectrum) and preference but is preferably thick, fragrance and chemical-free, and inexpensive. As such, plain petrolatum is a very nice choice. Less greasy creams may be preferred by the patient, and some trial and error may be needed until a particular product is chosen. Some initial recommendations might be Cetaphil, CeraVe, Eucerin, or PDS creams, but patients and families quickly connect with other bullous CIE families and share ideas. Browsing www.ichthyosis.com is a good start.

Additional applications through the course of the day are optimal but not always practical, and patients may concentrate on exposed, visible areas of skin. The scalp may need special care in loosening scale and providing lubrication. Overnight application of bland emollients or oils, preferably occluded by a shower cap or saran wrap, facilitates scale removal the following morning. P&S liquid is particularly helpful at loosening scale. Salicylic acid shampoos are helpful.

Localized areas of superficial bacterial infection should be treated with mupirocin ointment. The routine daily use of topical antibiotics is not warranted. Cellulitis or widespread infection requires oral or intravenous antibiotics, most often against Staphylococcus aureus. Culture should be done. It is important to consider infection with herpes simplex and treat with acyclovir, valacyclovir, or famciclovir when documented.

Keratolytic agents such as ammonium lactate, salicylic acid , and glycolic acid are poorly tolerated in bullous CIE and should not be used or used with caution.

Response to topical retinoids is variable and irritation may result from their use. Tretinoin, Adapalene, and tazarotene have been tried with good results in some patients. Cost, irritancy, and potential systemic absorption limit the surface that can be treated so that use on just the face or other exposed areas is most practical. Adding an emollient over the top may help the irritancy. Tazarotene is a pregnancy category X medication.

The oral retinoids, isotretinoin and acitretin, have been used with some success in various ichthyotic conditions, and seems to be especially helpful in bullous CIE caused by keratin 10 mutations (usually lacking palmoplantar keratoderma). Long-term doses of .5 to 1mg/kg/day of isotretinoin or .25 to .5mg/kg/day of acitretin are needed, but the effects are life altering for some patients who will wear shorts or a bathing suit for the first time in their life.

Treatment should be started at a low dose and slowly increased because high doses can induce blistering. An enhanced tendency toward Staphylococcus aureus infections must be monitored. Both medications are teratogenic, and isotretinoin is a better choice for females of child bearing potential due to its shorter half-life. Mucous membrane dryness, joint aches, hair thinning, headaches, pseudotumor cerebri, lipid elevations, mood alterations, and bone changes are some other side effects. Laboratory monitoring of liver enzymes, lipids and pregnancy test for women is necessary.

Periodic skeletal surveys consisting of a lateral view of the cervical and thoracic spine, a lateral view of the heel and a posteroanterior view of the pelvis should be done.

Patient Management

Most patients will not need regular monitoring, and families will rapidly become more knowledgeable regarding the plethora of treatment options than their practitioners.

Yearly or every other year visits are advised to monitor for any problems with growth and development, secondary infections, or digital contractures. Referral to orthopedics or physical therapy may be needed.

Genetic counseling should be offered to all patients and families. The risks associated with future pregnancies and the availability of genetic testing should be clearly and expertly explained and must consider the nuance of rare autosomal recessive inheritance and dominant inheritance from a parent with an epidermal nevus demonstrating epidermolytic hyperkeratosis. Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies can be performed but require prior identification of the disease-causing mutations in the family.

Special attention should be paid to the emotional well-being of the patient and family. Counseling should be offered as needed or appropriate. Support groups such as the Foundation for Ichthyosis and Related Skin Types (FIRST) offer patient/family conferences and multiple sources of information. Children may enjoy one of the several camps for children with chronic skin diseases offered by the American Academy of Dermatology.

Patients on systemic retinoids need regular laboratory and skeletal monitoring as above.

Unusual Clinical Scenarios to Consider in Patient Management

Epidermal nevus with epidermolytic hyperkeratosis represents a mosaic, postzygotic mutation for keratin 1 or 10. It is important to recognize that an individual with this form of epidermal nevus might have gonadal involvement and can parent a child with full blown bullous CIE. Examination of parents is necessary before assuming that a child with bullous CIE born to normal appearing parents is a spontaneous mutation. Parents may consequently have future children without realizing that they have a 50% chance of conceiving another child with bullous CIE.

Ichthyosis Curth-Macklin results from a keratin 1 mutation but lacks blistering and epidermolytic hyperkeratosis. It is characterized as palmoplantar keratoderma and warty hyperkeratosis over joints and flexures.

Ichthyosis bullosa of Siemens has the phenotype of mild bullous CIE and is caused by a mutation in keratin 2. There is no erythroderma and it has the distinct feature of molting of the skin in upper epidermal layers; hyperkeratosis develops on flexures, over joints, and on the dorsal hands and feet.

Cyclic ichthyosis with epidermolytic hyperkeratosis is a rare form of bullous CIE consisting of flares of polycyclic psoriasiform plaques that may last for weeks to months and normal skin with palmoplantar hyperkeratosis between flares. Mutations in keratin 1 and 10 have been found.

Thickened palms and soles will sometimes become secondarily infected with dermatophytes. A trial on an oral antifungal agent such as griseofulvin or terbinafine may result in some improvement.

What is the Evidence?

DiGiovanna, JJ, Robinson-Bostom, L. “Ichthyosis. Etiology, diagnosis, and management”. Am J Clin Dermatol. vol. 4. 2003. pp. 81-95. (Overview of all ichthyoses with a good discussion of treatment options.)

Oji, V, Traupe, H. “Ichthyosis. Clinical manifestations and practical treatment options”. Am J Clin Dermatol. vol. 10. 2009. pp. 351-64. (Overview of all ichthyoses with a good discussion of treatment options.)

Oji, V, Traupe, H. “Ichthysosis: differential diagnosis and molecular genetics”. Eur J Dermatol. vol. 16. 2006. pp. 349-59. (Review of the ichthyoses concentrating on diagnosis and the latest genetic findings.)

Oji, V, Tadini, G, Akiyama, M, Blanchet Bardon, C, Bodemer, C, Bourrat, E. “Revised nomenclature and classification of inherited ichthyoses: results of the first ichthyosis consensus conference in Soreze 2009.”. J Am Acad Dermatol. vol. 63. 2010. pp. 607-41. (New classification scheme for the ichthyoses emphasizing the use of keratinopathic ichthyosis as the most appropriate term for bullous congenital ichthyosiform erythroderma.)

Terheyden, P, Grimberg, G, Hausser, I, Rose, C, Korge, BP, Krieg, T. “Recessive epidermolytic hyperkeratosis caused by a previously unreported termination codon mutation in teh keratin 10 gene”. J Invest Dermatol. vol. 129. 2009. pp. 2721-3. (One of very few reports documenting autosomal recessive inheritance, null mutations from each parent, important to question about parental consanguinity.)

Vahlquist, A, Ganemo, A, Virtanen, M. “Congenital ichthyosis: an overview of current and emerging therapies”. Acta Derm Venereol. vol. 88. 2008. pp. 4-14. (Review of therapy for ichthyosis including state of the art therapies that are not yet available.)

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