Novel EBP gene mutations in Conradi–Hünermann–Happle syndrome

Steijlen, P.M.; Geel, Michel van; Vreeburg, Maaike; Marcus-Soekarman, D.; Spaapen, L. J. M.; Castelijns, F.C.; Willemsen, M.A.A.P.; Steensel, M.A.M. van

doi:10.1111/j.1365-2133.2007.08254.x

Cited by 27 publications

(23 citation statements)

References 20 publications

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“…The cholesterol/statin combination would likely be useful for another, closely-related disorder in this pathway (Fig. 1), Conradi-Hünermann-Happle syndrome (CDPX2), which similarly presents with bone malformations and patterned ichthyotic skin lesions, but without lateralization (Akiyama et al , 2009; Steijlen et al , 2007). In fact, topical application of an end-product plus an upstream pathway inhibitor could well be useful for the many syndromic and non-syndromic disorders of fatty acid and ceramide metabolism.…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis-Based Therapy Reverses Cutaneous Abnormalities in an Inherited Disorder of Distal Cholesterol Metabolism

Paller

Steensel

Rodríguez-Martín

et al. 2011

Journal of Investigative Dermatology

101

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Identification of the underlying genetic, cellular, and biochemical basis of lipid metabolic disorders provides an opportunity to deploy corrective, mechanism-targeted, topical therapy. We assessed this therapeutic approach in two patients with Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD) syndrome, an X-linked dominant disorder of distal cholesterol metabolism. Based upon the putative pathogenic role of both pathway-product deficiency of cholesterol and accumulation of toxic metabolic intermediates, we assessed the efficacy of combined therapy with lovastatin and cholesterol. We also evaluated the basis for the poorly understood, unique lateralization of the cutaneous and bone malformations of CHILD syndrome by analyzing gene activation in abnormal and unaffected skin. Ultrastructural analysis of affected skin showed evidence of both cholesterol depletion and toxic metabolic accumulation. Topical treatment with lovastatin/cholesterol (but not cholesterol alone) virtually cleared skin lesions by 3 months, accompanied by histologic and ultrastructural normalization of epidermal structure and lipid secretion. The unusual lateralization of abnormalities in CHILD syndrome reflects selective clearance of keratinocytes and fibroblasts that express the mutant allele from the unaffected side. These findings validate pathogenesis-based therapy that provides the deficient end-product and prevents accumulation of toxic metabolites, an approach of potential utility for other syndromic lipid metabolic disorders.

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Section: Discussionmentioning

confidence: 99%

Pathogenesis-Based Therapy Reverses Cutaneous Abnormalities in an Inherited Disorder of Distal Cholesterol Metabolism

Paller

Steensel

Rodríguez-Martín

et al. 2011

Journal of Investigative Dermatology

101

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“…Mutation to LSS has been associated with autosomal‐recessive hypotrichosis simplex presenting with sparse scalp hair . Mutations to EBP in Conradi–Hünermann syndrome are associated with Follicular atrophoderma and patchy scarring alopecia . DHCR24 knockout mouse present with fewer hair follicles and thickening of the epidermis .…”

Section: Cholesterol Homeostasis: a Cellular Overviewmentioning

confidence: 99%

“…Mutations in EBP, which functions in the cholesterol biosynthesis pathway (see Figure A) and is suppressed in cases of PCA, causes Conradi‐Hünermann syndrome . Phenotypically, Conradi‐Hünermann syndrome presents with chondrodysplasia punctata (premature calcification of the long bones) in the surviving patients (the dominant X‐linked disease is lethal in the majority of males).…”

Section: Associations Between Cholesterol and Hair Pathologiesmentioning

confidence: 99%

Cholesterol homeostasis: Links to hair follicle biology and hair disorders

Palmer

Blakeborough

Harries

et al. 2019

Experimental Dermatology

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Lipids and lipid metabolism are critical factors in hair follicle (HF) biology, and cholesterol has long been suspected of influencing hair growth. Altered cholesterol homeostasis is involved in the pathogenesis of primary cicatricial alopecia, mutations in a cholesterol transporter are associated with congenital hypertrichosis, and dyslipidaemia has been linked to androgenic alopecia. The underlying molecular mechanisms by which cholesterol influences pathways involved in proliferation and differentiation within HF cell populations remain largely unknown. As such, expanding our knowledge of the role for cholesterol in regulating these processes is likely to provide new leads in the development of treatments for disorders of hair growth and cycling. This review describes the current state of knowledge with respect to cholesterol homeostasis in the HF along with known and putative links to hair pathologies.

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“…The cutaneous features resolve after infancy, leaving atrophy (follicular atrophoderma and alopecia) and, in some instances, a mild ichthyosis on the extremities (108). Disease severity is dependent on both the specific mutations and the extent to which the mutant X chromosome is active in affected tissues (109)(110)(111)(112). The resolution of the cutaneous phenotype presumably reflects the dilution of effects as a consequence of the diminished viability of keratinocytes bearing the mutant X (113).…”

Section: Disorders Of Distal Sterologenesis With Ichthyosiform Phenotmentioning

confidence: 99%

Thematic review series: Skin Lipids. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism

Elias

Williams

Holleran

et al. 2008

Journal of Lipid Research

181

172

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Novel EBP gene mutations in Conradi–Hünermann–Happle syndrome

Abstract: The strong phenotypic variability in our patients suggests that there is no clear genotype-phenotype correlation.

Cited by 27 publications

References 20 publications

Pathogenesis-Based Therapy Reverses Cutaneous Abnormalities in an Inherited Disorder of Distal Cholesterol Metabolism

Pathogenesis-Based Therapy Reverses Cutaneous Abnormalities in an Inherited Disorder of Distal Cholesterol Metabolism

Cholesterol homeostasis: Links to hair follicle biology and hair disorders

Thematic review series: Skin Lipids. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism

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