title: Targeting epidermal lipids for treatment of Mendelian disorders of cornification.
abstract: BACKGROUND
  Inherited ichthyoses or Mendelian disorders of cornification (MeDOC) are clinically heterogeneous disorders with high unmet therapeutic needs, which are characterized by skin hyperkeratosis and scaling. Some MeDOC types are associated with defects of the epidermal lipid metabolism, resulting in perturbed barrier permeability and subsequent epidermal hyperplasia, hyperkeratosis and inflammation. An example is the CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked dominant multisystem MeDOC caused by mutations in the NSDHL (NAD(P)H steroid dehydrogenase-like protein) gene, which is involved in the distal cholesterol biosynthetic pathway. The skin manifestations of the CHILD syndrome have been attributed to two major mechanisms: deficiency of cholesterol, probably influencing the proper corneocyte membrane formation, and toxic accumulation of aberrant steroid precursors.
  
  
  METHODS
  Here we addressed the efficacy of an ointment containing cholesterol and simvastatin, an agent inhibiting endogenous cholesterol synthesis in a compassionate-use treatment of three patients with CHILD syndrome. To test the specificity of this therapeutic approach, we applied the same topical treatment to two patients with other types of MeDOC with disturbed skin lipid metabolism.
  
  
  RESULTS
  The therapy with simvastatin and cholesterol was highly effective and well-tolerated by the CHILD syndrome patients; only lesions in the body folds represented a therapeutic challenge. No improvement was noted in the patients with other types of MeDOC.
  
  
  CONCLUSIONS
  This therapy is inexpensive and accessible to every patient with CHILD syndrome, because both simvastatin and cholesterol are available worldwide. Our data provide initial evidence of the specificity of the therapeutic effect of the simvastatin-cholesterol ointment in CHILD syndrome in comparison to other types of MeDOC.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Kiritsi
authors.forename: Franziska
authors.initials: F
authors.lastname: Schauer
authors.forename: Ute
authors.initials: U
authors.lastname: Wölfle
authors.forename: Manthoula
authors.initials: M
authors.lastname: Valari
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.affiliation: Department of Dermatology, Medical Center-University of Freiburg, 79104 Freiburg, Germany. cristina.has@uniklinik-freiburg.de.
authors.forename: Cristina
authors.initials: C
authors.lastname: Has
authors.forename: Rudolf
authors.initials: R
authors.lastname: Happle
mesh_terms: D000293:Adolescent; D000328:Adult; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D006801:Humans; D007057:Ichthyosis / Q000235:genetics / Q000628:therapy*; D050356:Lipid Metabolism