Epidermolytic Ichthyosis (Epidermolytic Hyperkeratosis or Bullous Congenital Ichthyosiform Erythroderma)

Epidermolytic ichthyosis (EI), formerly known as epidermolytic hyperkeratosis (EHK) or bullous congenital ichthyosiform erythroderma (bullous CIE),[1] is a form of congenital ichthyosis. It is inherited in an autosomal dominant fashion, with about 50% of cases representing spontaneous mutations. Epidermolytic ichthyosis presents at birth with erythroderma, blisters, and erosions and evolves over time into varying degrees of hyperkeratosis.

Epidermolytic ichthyosis results from heterozygous mutations in the genes encoding keratin 1 (KRT1) and keratin 10 (KRT10).[2] Mutations cause defects that compromise keratin alignment and assembly of intermediate filaments, leading to cellular collapse, blistering, and impaired barrier function. Compensatory hyperproliferation leads to hyperkeratosis.

Defects in genes for keratin 1 (KRT1) and 10 (KRT10) are the cause of epidermolytic ichthyosis.[3, 4, 5, 6, 7] Usually, these mutations are missense substitutions into the highly conserved alpha-helical rod and the nonhelical H1 domains of the keratin proteins.[8]

Palmoplantar keratoderma is usually associated with KRT1 mutations; however, in rare cases, palmoplantar keratoderma may be observed in patients with KRT10 mutations.[9] Novel mutations in both genes continue to be reported.

Patients with generalized epidermolytic ichthyosis may be born to parents with epidermolytic epidermal nevi (mosaic epidermolytic ichthyosis).[10, 11] Epidermal nevi with histologic changes of epidermolytic hyperkeratosis are caused by postzygotic mutations in keratin 1 or keratin 10. If the mutation also involves gonadal cells, which is thought to be more likely in patients with more extensive cutaneous involvement, affected individuals can have offspring with generalized epidermolytic ichthyosis.

Frequency

The incidence of epidermolytic hyperkeratosis is estimated to be 1 in 200,000-300,000.

Race

No racial predilection is apparent for epidermolytic ichthyosis.

Sex

No sex predilection is recognized for epidermolytic ichthyosis.

Age

Epidermolytic ichthyosis is a lifelong condition with an onset at birth or in the neonatal period.

Epidermolytic ichthyosis is a lifelong condition. Some patients may experience amelioration of symptoms as they age. Risk for morbidity and mortality is highest in the neonatal period, where infants are at increased risk for complications such as sepsis and dehydration because of impaired barrier function. Later in life, affected patients may experience recurrent skin infections.

Educate patients with epidermolytic ichthyosis about the potential of passing the genetic defect on to offspring.

Epidermolytic ichthyosis (EI) presents at birth or shortly thereafter with erythema, blistering, and/or erosions. Phenotype evolves in early infancy to varying degrees of generalized hyperkeratosis.

Epidermolytic ichthyosis is inherited in an autosomal dominant fashion, so patients may have an affected family member; however, as many as half of reported cases arise as a result of sporadic mutations. Rare autosomal recessive cases have also been reported.[12, 13]

Epidermolytic ichthyosis presents in neonates as widespread superficial blisters, which, when ruptured, leave raw, denuded areas. Within the first few months of life, hyperkeratosis begins to predominate, and while skin fragility persists over time, it becomes far less severe, with most patients experiencing infrequent blisters and erosions. Hyperkeratosis can vary from mild to severe and is typically more prominent over joints and in flexural sites. The scale is classically described as corrugated or cardboardlike. Palmoplantar keratoderma is seen primarily in patients with KRT1 mutations and can be severe and disabling at times. Some patients also experience joint contractures. Hair, nails, and teeth are normal and ectropion is generally absent. Superficial bacterial infections are common and are often associated with a characteristic odor of the skin.

See the images below.

The scale in epidermolytic ichthyosis is classically described as "corrugated". Patients often experience erosions as a result of skin fragility.

The scale in epidermolytic ichthyosis is classically described as "corrugated". Patients often experience erosions as a result of skin fragility.

Palms and soles may have varying degrees of hyperkeratosis.

Epidermolytic ichthyosis has been infrequently found to be associated with other clinical findings. Rare cases of patients with epidermolytic ichthyosis and hypocalcemic rickets, with or without vitamin D resistance, have been reported.[14, 15] A report also describes epidermolytic ichthyosis and congenital platelike osteoma cutis in a child,[16] as well as epidermolytic ichthyosis localized to the vulva.[17]

Additional clinical images of epidermolytic ichthyosis are below.

Hyperkeratosis involving the abdomen.

Hyperkeratosis involving the knee.

Patients with epidermolytic ichthyosis are at an increased risk for recurrent infections.

No general laboratory studies are needed for epidermolytic ichthyosis (EI), except if necessary to follow chosen therapy or bacterial culture for suspected infection.

Genetic studies can be performed on buccal swabs or blood. Once a mutation is identified in an affected individual, mutation-specific testing for relatives and prenatal diagnosis is available.

Along with clinical presentation and history, skin biopsy can be helpful, with the histologic findings confirming a diagnosis of epidermolytic ichthyosis.

Prenatal diagnosis can be made through chorionic villus sampling, analysis of amniotic cells, or fetal skin biopsies.

In epidermolytic ichthyosis, hematoxylin and eosin findings are distinctive but not unique to epidermolytic ichthyosis. Typical findings include marked hyperkeratosis, a thick granular layer, coarse keratohyaline granules, and vacuolar degeneration of the upper epidermis. Occasionally, deeper granular cells become dense, enlarged, and irregular, and the shaped masses appear to be keratohyaline granules. In addition, dyskeratosis is frequently present to varying degrees.[18] Patients whose pathologic slides demonstrate continuous involvement of the entire horizontal epidermis with these distinctive findings are more likely to have generalized disease; those with focal involvement revealing skip areas of normal epidermis are more likely to have a mosaic form of epidermolytic ichthyosis.[19]

On electron microscopy, large, round-to-oval, dense clumps of keratin tonofilaments can be seen in the lower epidermal layers.

Hematoxylin and eosin staining of epidermolytic ichthyosis is shown in the images below.

Pathology of epidermolytic ichthyosis (hematoxylin and eosin stain).

Pathology of epidermolytic ichthyosis (hematoxylin and eosin stain).

Accurate diagnosis of epidermolytic ichthyosis (EI) is important in order to properly inform and counsel parents. Genetic counseling and prenatal diagnosis also can be offered.[20]

Newborns with epidermolytic ichthyosis who have denuded skin are at increased risk for infection, secondary sepsis, and electrolyte imbalance. These newborns should be transferred to the neonatal ICU to monitored and treated as needed. They should be handled gently to avoid further trauma to the skin.

Wound care for blistering and moisturization/emollients are important in the newborn period. In older children, topical emollients and topical keratolytics are generally the mainstays of treatment. The accumulation of scale predisposes to overgrowth of bacteria, in particular with Staphylococcus aureus, which is often associated with odor. Patients may benefit from the use of mild antibacterial soaps or dilute bleach baths. Some patients may also benefit from therapy with oral or topical retinoids.[21, 22]

No surgical care is needed or recommended for epidermolytic ichthyosis.

Refer patients who are considering conceiving children to a geneticist for reproductive concerns and assistance. Prenatal diagnosis can be made by ultrastructural analysis and by direct gene sequencing.

Prenatal diagnosis of epidermolytic ichthyosis can be performed by ultrastructural analysis of fetal skin biopsy specimens and amniotic fluid cells. Keratin 1 and keratin 10 are expressed suprabasally as early as week 14 of gestation; normal fetal keratinization does not begin until the 24th week. To date, keratin filament aggregates have been detected for diagnostic purposes in the 19th week of gestation.

Chorionic villus sampling can diagnose epidermolytic ichthyosis earlier by direct gene sequencing if the familial mutation is known. The earliest documented diagnosis by this method is at the 15th week of gestation, but the chorionic villus sampling theoretically can be tested as early as the eighth week of gestation.

No special diet is needed for patients with epidermolytic ichthyosis.

Activity restrictions are not necessary for patients with epidermolytic ichthyosis.

Schedule routine follow-up visits as needed for symptomatic relief or to follow laboratory studies during systemic therapies for epidermolytic ichthyosis.

There is no cure for epidermolytic ichthyosis (EI). The primary goal of therapy is to reduce hyperkeratosis. This can be achieved with topical keratolytics such as lactic acid, alpha-hydroxy acid, or urea. Topical emollients such as those containing glycerin are also often useful. Topical and oral retinoids can lead to significant improvement; however, care must be taken to avoid causing an increase in skin fragility.