Epidermolytic hyperkeratosis (Epidermolytic ichthyosis)
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A neonate is born with widespread blistering and superficial denudation of the skin, initially raising concern for epidermolysis bullosa. Over the following months, blistering subsides and is replaced by thick, dark, ridged ("corrugated") hyperkeratosis at flexures and over joints, with a foul odor. Skin biopsy shows the diagnostic pattern of epidermolytic hyperkeratosis with vacuolar degeneration of suprabasal keratinocytes and clumped keratin filaments.
Usually AD; KRT1 or KRT10, the suprabasal keratin pair that polymerizes to form the intermediate filament cytoskeleton of differentiating keratinocytes. About 50% of cases are de novo. Rare AR forms (typically KRT10) occur in consanguineous families.
| Gene | Common features |
|---|---|
| KRT1 | Often palmoplantar hyperkeratosis prominent; palms and soles affected |
| KRT10 | Palms and soles typically spared (KRT10 not expressed in palmoplantar epidermis, where KRT9 is) |
Mosaicism, the key counseling pearl:
A parent with a post-zygotic mosaic KRT1 or KRT10 pathogenic variant can present as an epidermal nevus (linear or Blaschko-distributed area of hyperkeratosis). If the mosaic variant is also present in the gonads, that parent has a substantial risk (theoretically up to 50% per offspring) of transmitting the variant in the germline, producing a fully generalized epidermolytic ichthyosis in the child.
Whenever an apparently de novo case is born, examine both parents' skin carefully for a Blaschko-distributed epidermal nevus; it changes recurrence counseling dramatically.
- Neonatal: widespread blistering, skin fragility, denudation, often confused with EB
- Infantile transition: blistering decreases; thick, ridged ("corrugated") hyperkeratosis develops at flexures, over joints, and (in KRT1) on palms/soles
- Persistent skin fragility: superficial blistering with friction continues throughout life
- Recurrent secondary bacterial infection with foul odor (cutaneous flora colonization)
- Heat intolerance (impaired sweating from hyperkeratotic skin)
- Histology: epidermolytic hyperkeratosis, vacuolar degeneration of suprabasal cells with perinuclear clumped keratin tonofilaments; pathognomonic on H&E
- Skin biopsy with the histologic pattern of epidermolytic hyperkeratosis is highly suggestive
- KRT1/KRT10 sequencing confirms; expanded keratin gene panels capture related disorders (superficial epidermolytic ichthyosis = KRT2; ichthyosis hystrix = certain KRT1/KRT10 variants)
- Epidermolysis bullosa (esp. EB simplex): primary blistering without the later hyperkeratosis
- Lamellar ichthyosis (TGM1, ABCA12 missense, NIPAL4, others): thick scale at birth without blistering; histology shows orthohyperkeratosis without the epidermolytic pattern
- Harlequin ichthyosis: see harlequin-ichthyosis; much more severe at birth, ABCA12 LOF
- Bullous congenital ichthyosiform erythroderma: older name for the same entity
- Superficial epidermolytic ichthyosis (Siemens): KRT2; milder, more superficial blistering
- Emollients with keratolytics (urea, lactic acid)
- Topical retinoids (variable tolerance)
- Systemic retinoids (acitretin, isotretinoin): improve hyperkeratosis but can worsen blistering; titrate carefully
- Aggressive treatment of skin infections; bleach baths
- Avoid friction; cotton clothing; address heat intolerance
- Genetic counseling including parental skin exam for occult mosaic epidermal nevus