Targeting Epidermal Lipids for Treatment of Mendelian Disorders of Cornification

Overview

Journal Orphanet J Rare Dis

Publisher Biomed Central

Specialty General Medicine

Date 2014 Mar 11

PMID 24607067

Citations 7

Authors

Dimitra Kiritsi

Franziska Schauer

Ute Wolfle

Manthoula Valari

Leena Bruckner-Tuderman

Cristina Has

Rudolf Happle

Affiliations

Soon will be listed here.

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.

Citing Articles

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Luo L, Guo Y, Chen L, Zhu J, Li C Front Immunol. 2023; 14:1124786.

PMID: 37234169 PMC: 10206135. DOI: 10.3389/fimmu.2023.1124786.

Not lost to follow-up: A rare case of CHILD syndrome in a boy reappears.

Fackler N, Zachary C, Kim D, Smith J, Sarpa H JAAD Case Rep. 2018; 4(10):1010-1013.

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Use of Topical Glycolic Acid Plus a Lovastatin-Cholesterol Combination Cream for the Treatment of Autosomal Recessive Congenital Ichthyoses.

Khalil S, Bardawil T, Saade S, Chedraoui A, Ramadan N, Hasbani D JAMA Dermatol. 2018; 154(11):1320-1323.

PMID: 30208477 PMC: 6248126. DOI: 10.1001/jamadermatol.2018.2904.

Update on Genetic Conditions Affecting the Skin and the Kidneys.

Reimer A, He Y, Has C Front Pediatr. 2018; 6:43.

PMID: 29552546 PMC: 5840143. DOI: 10.3389/fped.2018.00043.

Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.

Heinz L, Kim G, Marrakchi S, Christiansen J, Turki H, Rauschendorf M Am J Hum Genet. 2017; 100(6):926-939.

PMID: 28575648 PMC: 5473727. DOI: 10.1016/j.ajhg.2017.05.007.

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