Therapeutic Options for the Treatment of Darier’s Disease: A Comprehensive Review of the Literature

Darier’s disease (also known as keratosis follicularis or dyskeratosis follicularis) is an autosomal dominant inherited disorder which manifests as hyperkeratotic greasy papules in the first or second decade of life. Aside from symptom management and behavioral modifications to avoid triggers, there are currently no validated treatments for Darier’s disease (DD). However, a variety of treatments have been proposed in the literature including retinoids, steroids, vitamin D analogs, photodynamic therapy, and surgical excision. The purpose of this review article is to identify therapeutic options for treating DD and to outline the evidence underlying these interventions. A search was conducted in Medline for English language articles from inception to July 4, 2020. Our search identified a total of 474 nonduplicate studies, which were screened by title and abstract. Of these, 155 full text articles were screened against inclusion/exclusion criteria, and 113 studies were included in our review. We identified Grade B evidence for the following treatments of DD: oral acitretin, oral isotretinoin, systemic Vitamin A, topical tretinoin, topical isotretinoin, topical adapalene gel, topical 5-flououracil, topical calciptriol and tacalcitol (with sunscreen), grenz ray radiation, and x-ray radiation. All other evidence for treatments of DD consisted of case reports or case series, which is considered grade C evidence. Considering the quality and quantity of evidence, clinicians may consider initiating a trial of select topical or oral retinoids first in patients with localized or generalized DD, respectively.

Cystatin M/E Variant Causes Autosomal Dominant Keratosis Follicularis Spinulosa Decalvans by Dysregulating Cathepsins L and V

Keratosis follicularis spinulosa decalvans (KFSD) is a rare cornification disorder with an X-linked recessive inheritance in most cases. Pathogenic variants causing X-linked KFSD have been described in MBTPS2, the gene for a membrane-bound zinc metalloprotease that is involved in the cleavage of sterol regulatory element binding proteins important for the control of transcription. Few families have been identified with an autosomal dominant inheritance of KFSD. We present two members of an Austrian family with a phenotype of KFSD, a mother and her son. The disease was not observed in her parents, pointing to a dominant inheritance with a de novo mutation in the index patient. Using whole-exome sequencing, we identified a heterozygous missense variant in CST6 in DNA samples from the index patient and her affected son. In line with family history, the variant was not present in samples from her parents. CST6 codes for cystatin M/E, a cysteine protease inhibitor. Patient keratinocytes showed increased expression of cathepsin genes CTSL and CTSV and reduced expression of transglutaminase genes TGM1 and TGM3. A relative gain of active, cleaved transglutaminases was found in patient keratinocytes compared to control cells. The variant found in CST6 is expected to affect protein targeting and results in marked disruption of the balance between cystatin M/E activity and its target proteases and eventually transglutaminases 1 and 3. This disturbance leads to an impairment of terminal epidermal differentiation and proper hair shaft formation seen in KFSD.

Molecular Pathogenesis and Complications Associated with Keratosis Follicularis: A Clinical Review

Keratosis follicularis or Darier's disease (DD) is a rare autosomal dominant disorder characterized by the appearance of multiple scaly papules affecting seborrheic areas. It is a multisystem disorder that occurs in the first or second decade of life, and extends beyond cutaneous involvement. It has been reported to be associated with various basal cell carcinoma (BCC) and other skin cancers, nail changes, ocular/mucosal manifestations and neuropsychiatric disorders. Additionally, individuals with DD have a greater risk of being diagnosed with Type 1 Diabetes Mellitus as well as disease-specific risk of heart failure. The goal of this review is to explore the molecular pathogenesis of keratosis follicularis, and to investigate the extent and severity of various complications associated with this condition. Furthermore, dermatologic practice recommendations will be reviewed for the management of DD.

MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders

The MBTPS2 gene on the X-chromosome encodes the membrane-bound transcription factor protease, site-2 (MBTPS2) or site-2 protease (S2P) which cleaves and activates several signaling and regulatory proteins from the membrane. The MBTPS2 is critical for a myriad of cellular processes, ranging from the regulation of cholesterol homeostasis to unfolded protein responses. While its functional role has become much clearer in the recent years, how mutations in the MBTPS2 gene lead to several human disorders with different phenotypes including Ichthyosis Follicularis, Atrichia and Photophobia syndrome (IFAP) with or without BRESHECK syndrome, Keratosis Follicularis Spinulosa Decalvans (KFSD), Olmsted syndrome, and Osteogenesis Imperfecta type XIX remains obscure. This review presents the biological role of MBTPS2 in development, summarizes its mutations and implicated disorders, and discusses outstanding unanswered questions.

The Role of Trichoscopy in Keratosis Follicularis Spinulosa Decalvans: Case Report and Review of the Literature

<b><i>Introduction:</i></b> Keratosis follicularis spinulosa decalvans (KFSD) is a rare, X-linked, hereditary disorder of keratinization, characterized by skin involvement and progressive scarring alopecia of scalp, eyebrows, and eyelashes. The diagnosis is helped by the particular clinical features, but pathology is mandatory. <b><i>Case Presentation:</i></b> We described a case of a female patient referred to the outpatient’s hair consultation of our department, in which we performed trichoscopy as a very useful tool for the diagnosis, followed by pathology that confirmed KFSD. <b><i>Conclusion:</i></b> In our article, we underlined the importance of trichoscopy for the diagnosis of this hair disease, with also a review of the literature on diagnosis and treatment.

Familial case of Darier’s disease: A rare genodermatosis

Darier’s disease, also known as keratosis follicularis is a rare autosomal dominant inherited genodermatosis characterized by abnormal keratinization . A 39-year old non-diabetic, normotensive man presented to dermatology OPD with discretely distributed dark brown greasy, warty, malodorous, hyperkeratotic papules over his whole body for last 15 years. He has two young daughters and both has started initial stage of similar lesions for last 6 months. Characteristic v-shaped nicking at the tip of the nails with longitudinal red & white ridges were seen. Nails at the distal ends were broken. Biopsy of skin for histopathological examination showed more specific and confirmatory ‘corps ronds and grains’. This article reports a case of familial darier’s disease. Good improvement was noticed after acitretin therapy. Bangladesh Crit Care J March 2020; 8(1): 55-57