Darier's Disease: Current Understanding of Pathogenesis and Future Role of Genetig Studies

Abstract

Darier's disease is an uncommon skin disorder with autosomal dominant transmission. During the course of the investigation of a large family in which several members are affected with schizophrenia, it was found that many family members also suffer from Darier's disease. Recent advances in molecular genetic techniques have made the identification of such families important for an understanding of the causes of inherited diseases. The role of genetic linkage analysis of Darier's disease is discussed following a review of the current state of knowledge of its pathogenesis and genetics. CLINICAL BACKGROUNDDarier's disease is a potentially disfiguring disease characterized by the presence of warty, brown papules and plaques primarily affecting the so-called seborrheic areas of the skin on the face, scalp, trunk, and groin (Fig. 1).1 In addition, involvement of nails and mucous membranes is common.2 In more severe cases, the lesions may become extensive, vegetative, and malodorous leading to major adverse social consequences for the sufferer. Affected persons are at risk for widespread cutaneous viral and bacterial superinfection, which can lead to further disability and hospitalization.The disease typically has its onset in the second decade of life and tends to persist lifelong with periods of exacerbation related to sweating, minor cutaneous trauma, and ultraviolet light exposure. Complete remissions are rare.Routine histopathology of Darier's disease shows characteristic abnormalities with evidence of abnormal keratinization and acantholysis (loss of cohesion) of epidermal cells.4Treatment remains unsatisfactory although the use of oral aromatic retinoids (isotretinoin and etretinate) has benefitted some patients with more severe disease.5 More definitive therapy awaits better understanding of the pathogenesis of the disease.

Novel mutations in Darier disease and association to self-reported disease severity

“…Whether these variants have an effect on SERCA2 protein function is unknown, as none have been characterised. It is also possible that these patients could be DD phenocopies (non-genetic forms of the disease); however, Berg and Basset (1993) suggest the likelihood of this is rare [ 40 ]. This is because DD is a rare disease that is clearly inherited in an autosomal dominant manner [ 40 ].…”

“…It is also possible that these patients could be DD phenocopies (non-genetic forms of the disease); however, Berg and Basset (1993) suggest the likelihood of this is rare [ 40 ]. This is because DD is a rare disease that is clearly inherited in an autosomal dominant manner [ 40 ]. There is also the possibility that the patients could harbour a second undetected ATP2A2 variant (i.e.…”

Darier's (Darier–White) disease/keratosis follicularis

“…The exact pathogenesis of Darier's disease is an enigma despite the conclusive evidence that it results from mutations in SERCA‐2 13,24,26–30 . Studies have been conducted in the past to delineate its pathogenesis, using various immunocytochemical and explant tissue culture techniques 48–58 . Setoyama et al 59 .…”

“…13,24,[26][27][28][29][30] Studies have been conducted in the past to delineate its pathogenesis, using various immunocytochemical and explant tissue culture techniques. [48][49][50][51][52][53][54][55][56][57][58] Setoyama et al . 59 studied desmoplakin I and II in various acantholytic dermatoses, and concluded that these important components are preserved in pemphigus, but are dissolved in Darier's disease.…”

Recurrent presumed herpes simplex keratitis and episcleritis in keratosis follicularis (Darier's disease)

“…Characteristic histological findings include focal clefting of dyskeratotic round epidermal cells on light microscopy, known as ‘corps ronds’ 2. Darier's disease is rare (prevalence 2.7 in 100 000)3 and ocular sequelae have been reported in a few cases. This is the first report, to the best of our knowledge, to describe a case of recurrent herpes simplex virus (HSV) keratitis and episcleritis in Darier's disease.…”