Background: The clinical condition generalized epidermolytic hyperkeratosis, also known as bullous congenital ichthyosiform erythroderma, is an autosomal dominant disorder and presents as a bullous disease of the newborn followed by an ichthyotic skin disorder throughout life. Clinical epidermolytic hyperkeratosis (cEHK) has characteristic histopathologic findings. Mosaic cEHK, which occurs without a family history, is a sporadic condition that clinically resembles epidermal nevi but demonstrates histopathologic findings similar to the generalized disorder; when a postzygotic mutation involves the germ line, the disease can occur in subsequent generations as generalized cEHK. Ichthyosis bullosa of Siemens (IBS) is similar histopathogically, but is clinically distinct from generalized cEHK, presenting with more superficial bullae.
Objectives: It is well established that the clinical diagnoses generalized cEHK, mosaic cEHK, and IBS have similar histopathologic findings of epidermolysis with hyperkeratosis. We sought (1) to characterize the spectrum of histopathologic features and (2) to assess whether there were histopathologic differences between these clinically distinct disorders.
Methods: One hundred seventeen skin biopsy slides from the National Registry for Ichthyosis and Related Skin Disorders were reviewed, with those reviewers blinded to clinical information. All slides were systematically evaluated for a variety of features, including differences in the pattern of the epidermolysis and hyperkeratosis. Clinical predictions of whether the biopsy specimen was obtained from patients with generalized cEHK, mosaic cEHK, or IBS were made on the basis of histologic pattern of the epidermolysis and hyperkeratosis.
Results: Eighteen of the 117 slides revealed features sufficient to make a histologic diagnosis of epidermolytic hyperkeratosis (hEHK). One additional slide, for which a definitive histologic diagnosis was not possible, had features of both hEHK and acantholytic dyskeratosis. Two distinct patterns of the histopathologic changes were observed within the 18 slides diagnostic of hEHK: (1) continuous involvement of the entire horizontal epidermis and (2) focal involvement revealing skip areas of normal-appearing epidermis along the horizontal epidermis. Upon clinical correlation, all 12 of the slides with continuous involvement were from patients with generalized cEHK. One slide was from acral skin and had continuous involvement; this was from a patient with Vorner's palmoplantar keratoderma. Of the remaining 5 slides with focal involvement, two patterns were observed: focal involvement of both granular and spinous layers and focal involvement of only the granular layer. The 3 slides with focal involvement of the granular and spinous layers were from patients with mosaic cEHK. Of the two slides with focal involvement confined to the granular layer, one was from a patient with IBS and the other from a patient with generalized cEHK.
Limitation: The sample pool is biased by who was enrolled in the Registry and therefore may not represent the full spectrum of the disease.
Conclusion: The pattern of histologic involvement may be a useful predictor of the clinical phenotype of cEHK.