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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Orphanet Journal of Rare Diseases 1/2014

Targeting epidermal lipids for treatment of Mendelian disorders of cornification

Zeitschrift:
Orphanet Journal of Rare Diseases > Ausgabe 1/2014
Autoren:
Dimitra Kiritsi, Franziska Schauer, Ute Wölfle, Manthoula Valari, Leena Bruckner-Tuderman, Cristina Has, Rudolf Happle
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1750-1172-9-33) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

DK performed the necessary invasive diagnostic procedures and the experiments. DK, FS, RH and CH are responsible for the follow up of the patients. DK, FS, UW, LBT, CH and RH participated in the interpretation of data. DK and RH designed the study and drafted the manuscript. CH participated in the design and coordination of the study and helped to draft the manuscript. All authors have read and approved the final manuscript.

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.
Zusatzmaterial
Authors’ original file for figure 1
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Authors’ original file for figure 2
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Authors’ original file for figure 3
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Literatur
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