Epidermolytic Hyperkeratosis (Bullous Congenital Ichthyosiform Erythroderma) Clinical Presentation

Epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) presents at birth or shortly thereafter with erythema, blistering, and/or peeling. Symptoms in some patients may ameliorate over time.

EHK is inherited in an autosomal dominant fashion, so patients may have a family history of a similar condition. However, as many as half the cases are a result of sporadic mutations. Moreover, rare autosomal recessive cases have also been reported.^{[1, 2]}

Epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) presents in neonates as widespread superficial blisters, which, when ruptured, leave raw denuded areas. Hyperkeratosis appears from the third month on, but subtle skin thickening or scaling may be apparent during the first month of life. As patients age, the scaling becomes thicker and the propensity to blister decreases. The ichthyosis is typically generalized and is often more prominent at flexures and overlying joints. The scale is classically described as “corrugated cardboard”–like. Palms and soles have varying degrees of hyperkeratosis. Note the images below. Ectropion does not occur, and the hair, nails, and teeth are normal. Pungent body odor may often be associated.

In 1994, DiGiovanna and Bale separated the various clinical presentations of epidermolytic hyperkeratosis into 2 primary types, including NPS (without severe palm/sole hyperkeratosis) and PS (with severe palm/sole hyperkeratosis) based on the presence or absence of severe palmoplantar hyperkeratosis.^[3] The 2 primary types were subdivided further into 3 subtypes each depending on the clinical presentations. Some of the subtypes have general involvement, while others are localized only.

• NPS epidermolytic hyperkeratosis subtypes do not have severe palmoplantar involvement. Distinctions between the 3 NPS epidermolytic hyperkeratosis subtypes are based on different clinical presentations.

  • NPS-1 epidermolytic hyperkeratosis has normal palmoplantar surfaces, no digital contractures, a hystrix scale, a generalized skin distribution, no history of erythroderma, a positive history of blistering, and patients may have abnormal gait.
  • NPS-2 epidermolytic hyperkeratosis is similar to NPS-1 epidermolytic hyperkeratosis. The only differences are a brown scale instead of a hystrix scale and a lack of gait abnormalities.
  • NPS-3 epidermolytic hyperkeratosis has no palmoplantar hyperkeratosis, no digital contractures, and is generalized in skin distribution, similar to NPS-1 epidermolytic hyperkeratosis and NPS-2 epidermolytic hyperkeratosis. In contrast, the palmoplantar surface in NPS-3 epidermolytic hyperkeratosis is hyperlinear, has minimal scale, and a thin white scale is most prominent on the trunk. Erythroderma is mild to moderate. NPS-3 epidermolytic hyperkeratosis may have associated gait abnormalities similar to NPS-1 epidermolytic hyperkeratosis.
• PS epidermolytic hyperkeratosis subtypes have severe palmoplantar involvement. The 3 subtypes are differentiated based on clinical presentations.

  • PS-1 epidermolytic hyperkeratosis has smooth palmoplantar hyperkeratotic surfaces, no digital contractures, a localized distribution of skin involvement (limited flexural involvement, truncal sparing), no erythroderma, a localized blistering, and no gait abnormalities.
  • PS-2 epidermolytic hyperkeratosis has smooth palmoplantar hyperkeratotic surfaces but has digital contractures, generalized skin involvement with hyperkeratosis most severe over the joints at both flexor and extensor surfaces, mild-to-moderate erythroderma, positive blistering, and may have gait abnormalities.
  • PS-3 epidermolytic hyperkeratosis has cerebriform palmoplantar surfaces, no digital contractures, a tan scale, generalized skin involvement, no erythroderma, neonatal blistering, and no gait abnormalities.

Epidermolytic hyperkeratosis has been infrequently found to be associated with other clinical findings. Rare cases of patients with epidermolytic hyperkeratosis and hypocalcemic rickets, with or without vitamin D resistance, have been reported.^{[4, 5]} A case of epidermolytic hyperkeratosis with no facial involvement has also been reported.^[6] More recently, there has been a report of epidermolytic hyperkeratosis and congenital platelike osteoma cutis in a child,^[7] as well as epidermolytic hyperkeratosis localized to the vulva.^[8]

The following are clinical images of epidermolytic hyperkeratosis lesions of the ankles:

Defects in genes for keratin 1 (KRT1) and 10 (KRT10) are the cause of epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]).^{[9, 10, 11, 12, 13]} Usually, these mutations are missense substitutions into the highly conserved alpha-helical rod and the nonhelical H1 domains of the keratin proteins.^[14] Defects in keratin 1 are associated with the PS epidermolytic hyperkeratosis variants; defects in keratin 10 are associated with the NPS epidermolytic hyperkeratosis variants.

Palmoplantar keratoderma is usually associated with KRT1 mutations; however, a girl with epidermolytic hyperkeratosis and palmoplantar keratoderma with the KRT10 mutation has been reported.^[15] In the medical literature, new mutations in both genes continue to be reported.

Patients with generalized EHK may be born to parents with epidermolytic epidermal nevi^[16] or linear epidermolytic hyperkeratosis.^[17] An epidermal nevus with histologic changes of epidermolytic hyperkeratosis is a mosaic condition in which the affected skin carries a mutation in keratin 1 or keratin 10. Individuals with more extensive forms can have offspring with generalized epidermolytic hyperkeratosis, due to germline mutations in keratin 1 or keratin 10.