Phenotypic/genotypic correlations in patients with epidermolytic hyperkeratosis and the effects of retinoid therapy on keratin expression

Dominant-negative mutations in the KRT1 and KRT10 genes cause epidermolytic hyperkeratosis, a rare form of ichthyosis sometimes associated with palmop lantar keratoderma. Although there is no permanent cure, some patients impr ove on retinoid therapy. More knowledge is needed, however, about the mecha nism of action of retinoids and the genotypic/phenotypic correlations in th is disease. Thirteen patients from 10 families with generalized disease and 2 sporadic patients with nevoid lesions were studied, probably representin g most of the patients in Sweden and Norway. All patients, except one nevoi d case, were known to have KRT1 or KRT10 mutations. Those with mutated kera tin 1 (KI) invariably had associated keratoderma (n=6). In contrast, only 1 of 7 patients with K10 mutations had this problem (p=0.0047). Five out of 6 patients with KRT10 mutations benefited from treatment with oral acitreti n (5-25 mg/day) or topical tretinoin/tazarotene, but none of the patients w ith KRT1 mutations derived any benefit. Quantitative analysis of K1 and K10 mRNA in skin biopsies obtained before and after retinoid therapy (n=8) sho wed no consistent downregulation of mutated keratin that would explain the therapeutic outcome. Instead, the mRNA expression of K2e (a normal constitu ent of the upper epidermis) diminished especially in nonresponders. In cont rast, K4 mRNA and protein (marker of retinoid bioactivity in normal epiderm is) increased in almost all retinoid-treated patients. In conclusion, our s tudy confirms a strong association between KRT1 mutations and palmoplantar keratoderma. Retinoid therapy is particularly effective in patients with KR T10 mutations possibly because they are less vulnerable to a down-regulatio n of K2e, potentially functioning as a substitute for the mutated protein i n patients with KRT1 mutations.