darier disease ( dd ) is a rare , autosomal dominant , inherited acantholytic dermatosis caused by a mutation in the atp2a2 gene on chromosome 12 .
the diagnosis of dd is suggested by the clinical findings of a persistent eruption of greasy hyperkeratotic papules and plaques usually occurring over seborrheic areas as well as distinctive nail abnormalities .
numerous treatments such as topical corticosteroids , topical retinoids , topical 5-fluorouracil , diclofenac sodium 3% gel , dermabrasion and laser therapy have reportedly been used for the treatment of dd , with limited success .
systemic retinoids , including acitretin , isotretinoin and alitretinoin , are the most effective treatment for dd .
however , their use is limited by potential deleterious side effects . considering the recently reported efficacy of doxycycline for hailey - hailey disease , an inherited acantholytic skin disorder pathogenetically similar to dd , we report the case of a patient with extensive dd who showed a dramatic response to oral doxycycline monotherapy .
a 77-year - old patient with a 57-year history of dd was referred to our department for a severe exacerbation of dd that was recalcitrant to conventional topical treatments , including emollients , topical corticosteroids and topical mupirocin ointment .
physical examination revealed malodorous eroded hyperkeratotic papules and plaques on the axillae , groin , perineum and lower back ( fig .
classical nail changes , which included white and red longitudinal bands , were present . the mucosa was not affected .
a skin biopsy specimen from a lower back lesion showed characteristic histopathological findings consistent with a diagnosis of dd ( fig .
2 ) . a therapeutic regimen of oral doxycycline ( 100 mg / day ) was started .
the skin lesions showed marked improvement and were in complete remission after 1 month ( fig .
3 ) . the patient was maintained on a half - dose therapy ( 50 mg / day ) and did not experience any relapse within 3 months of follow - up .
dd is caused by mutations in the atp2a2 gene that encodes the sarcoplasmic / endoplasmic reticulum calcium atpase 2 ( serca2 ) , which is a calcium pump .
serca2 plays a central role in cellular calcium homeostasis and actively transports calcium ions from the cytosol into the lumen of the endoplasmic reticulum in order to maintain a low cytoplasmic calcium level .
the molecular mechanisms by which specific atp2a2 mutations alter the function of the serca2 protein and cause acantholysis ( loss of cell - to - cell adhesion ) and dyskeratosis ( premature and abnormal keratinization ) , the histological hallmarks of dd , remain unclear . as a consequence of the loss of serca2 calcium transport , darier keratinocytes display depleted endoplasmic reticulum calcium stores .
in addition to their antibiotic potential , tetracyclines and their analogues exhibit anti - inflammatory properties by inhibiting granulocyte chemotaxis and secretion .
interestingly , matrix metalloproteinase 9 and its inhibitor , tissue inhibitor of metalloproteinase 1 , have been shown to be involved in dd and hailey - hailey disease .
tetracyclines bind divalent metal cations and circulate in blood plasma primarily as calcium and magnesium chelators .
furthermore , once chelated , tetracyclines can act as ionophores that are capable of transporting bound calcium and magnesium through lipophilic phases , such as cellular membranes , and delivering ions into intracellular compartments .
after intracellular incorporation , calcium can act as a secondary messenger and affect pathways , such as those involved in secretory processes , receptor activation or inhibition , cell division and metabolic reactions .
it can be hypothesized that these chelation properties can affect the release of calcium from storage organelles such as sarcoplasmic / endoplasmic reticulum and act on the molecular mechanisms involved in the disruption of calcium homeostasis in darier keratinocytes , leading to the clinical symptoms of the disease . due to its non - antibiotic properties and favorable safety profile compared to oral retinoids
further studies are warranted to confirm these findings and to assess the efficacy of oral doxycycline in the treatment of dd .
 darier disease ( dd ) is a rare dominantly inherited genodermatosis characterized by loss of intercellular adhesion ( acantholysis ) and abnormal keratinization . 
 dd is often difficult to manage . 
 numerous treatments have reportedly been used for the treatment of dd , with limited success . 
 systemic retinoids are considered the drug of choice for treating dd . 
 however , their use is limited by potential deleterious side effects . considering the recently reported efficacy of doxycycline for hailey - hailey disease , an inherited acantholytic skin disorder pathogenetically similar to dd , we report the case of a patient with extensive dd who showed a dramatic response to oral doxycycline monotherapy . 
Introduction
Case Report
Discussion
Statement of Ethics
Disclosure Statement