Disorders of keratinization and other genodermatoses
Anupam Das, Sumit Sethi in Concise Dermatology, 2021
The epidermis is the outermost layer of the skin and is composed almost entirely of keratinocytes with a few other cells, like melanocytes, Merkel cells, and Langerhans cells interspersed. The epidermis, particularly the stratum corneum, acts a barrier to physical, chemical, and microbiological insult. Epidermal differentiation and keratinization are complex processes, and various genetic mutations can disrupt the usual course of maturation. This is the commonest form of ichthyosis and is inherited in an autosomal dominant fashion. In the epidermis, this results in the accumulation of cholesterol sulfate, leading to abnormal desquamation. Subsequently, the individual may develop large, plate-like scales without any redness of skin or generalized fine white scaling with erythroderma. Large, plate-like scales, as seen in lamellar ichthyosis, are usually absent. The condition is classically associated with autosomal recessive ichthyosis but may be the presenting feature in certain other keratodermas and Gaucher's disease. Ichthyosis may sometimes develop later in life, secondary to various systemic causes.
Disorders of keratinization and other genodermatoses
Ronald Marks, Richard Motley in Common Skin Diseases, 2019
keratinization is a differentiation process in which basal epidermal cells gradually mature and transform into stratum corneum cells. During keratinization, a tough, chemically resistant, cross-linked protein band is laid down just inside the plasma membrane and the whole cell flattens to a thin disc. The stratum corneum is the major barrier to water loss from the skin and to the penetration of chemical agents that come into contact with the skin. The term ichthyosis is unfortunate, as the scale of ‘modern’ fish is, in fact, mesodermal rather than ectodermal in origin. Xeroderma is seen in many patients with atopic dermatitis. Non-bullous ichthyosiform erythroderma is inherited as a rare, autosomal recessive disorder. Epidermolytic hyperkeratosis is a rare, autosomal dominant disorder of keratinization. Lamellar ichthyosis is a rare, autosomal recessive disorder of keratinization, characterized by a striking degree of hyperkeratosis but not much erythema. Tuberous sclerosis is a rare, autosomal dominant condition in which many abnormalities occur.
Genotype and Anterior Segment Phenotype in a Cohort of Turkish Patients with Lamellar Ichthyosis
Published in Ophthalmic Genetics, 2015
Melis Palamar, Huseyin Onay, Ilgen Ertam, Esra Arslan Ates, Tugrul Dereli, Ferda Ozkinay, Ayse Yagci
Purpose: To evaluate the ocular surface and topography findings of lamellar ichthyosis, and to investigate the correlation of these findings with mutations in TGM1, CYP4F22 and NIPAL4 genes. Methods: Twelve patients with lamellar ichthyosis were evaluated. Routine ophthalmic examination including Schirmer 1, tear break-up time and ocular surface staining score, topography, and genetic evaluation for coding exons of TGM1, NIPAL4 and CYP4F22 genes were performed. Results: The mean age of the patients was 19.75 ± 9.15 (range, 4–31) years. Mean Schirmer 1 scores of the right and the left eyes were similar (18.75 ± 3.10 mm). Mean tear break-up time of the right and the left eyes were 6.58 ± 2.74, 6.58 ± 3.02 seconds, respectively. Mean ocular surface staining grade was 0.36 ± 0.20 in the right, and 0.39 ± 0.17 in the left eyes. Keratoconus was detected in two patients. Two patients with bilateral cataract formation were found. Genetic sequencing revealed that one case had homozygous R326X mutation in the CYP4F22 gene, two cases had homozygous A176D mutation in the NIPAL4 gene, and three had homozygous M1T mutation in the same gene. Mutations were detected in patients with keratoconus and in a patient with bilateral cataract formation. Conclusions: In lamellar ichthyosis, eyelid malformations together with decreased tear break-up time might cause sight-threatening complications. Genetic counseling for mutations might enable the physician to predict the possibility of upcoming ocular problems in lamellar ichthyosis patients.
Clinical investigation of acitretin in children with severe inherited keratinization disorders in China
Published in Journal of Dermatological Treatment, 2008
Xi‐Bao Zhang, Quan Luo, Chang‐Xing Li, Yu‐Qing He, Xiao Xu
Objective: Investigation into the clinical efficacy, side effects and safety of oral acitretin on severe inherited disorders of keratinization in children. Methods: Acitretin was given as a treatment dose of 0.77–1.07 mg/kg·per day (mean 0.86±0.11) and maintenance dose of 0–0.94 mg/kg·per day (mean 0.33±0.26) to 28 children with severe inherited disorders of keratinization. Body height and weight were chosen as the monitoring indexes to evaluate the growth and development and other common side effects as the safety evaluation of the children for a follow‐up of 2–36 months. Results: After 2–4 months of treatment, the clinical cure rate was 82.1% and the effective rate was 17.9%. Most cases, such as bullous ichthyosiform erythroderma, lamellar ichthyosis, pityriasis rubra pilaris, and inflammatory linear verrucous epidermal nevus showed remarkable therapeutic response; non‐bullous ichthyosiform erythroderma was also effective. Two cases with Darier's disease were previously shown to be resistant to acitretin therapy, but improved after 6 months of treatment. No previous investigation had been made on a negative effect on the growth and development of such children. Conclusion: Acitretin showed a satisfactory therapeutic effect on severe inherited disorders of keratinization in children.
The roles of ABCA12 in keratinocyte differentiation and lipid barrier formation in the epidermis
Published in Dermato-Endocrinology, 2011
ABCA12 is a member of the large superfamily of ATP-binding cassette (ABC) transporters, which bind and hydrolyze ATP to transport various molecules across limiting membranes or into vesicles. The ABCA subfamily members are thought to be lipid transporters. ABCA12 is a keratinocyte transmembrane lipid transporter protein associated with the transport of lipids in lamellar granules to the apical surface of granular layer keratinocytes. Extracellular lipids, including ceramide, are thought to be essential for skin barrier function. ABCA12 mutations are known to underlie the three main types of autosomal recessive congenital ichthyoses: harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma. ABCA12 mutations lead to defective lipid transport via lamellar granules in the keratinocytes, resulting in malformation of the epidermal lipid barrier and ichthyosis phenotypes. Studies of ABCA12-deficient model mice indicate that lipid transport by ABCA12 is also indispensable for intact differentiation of keratinocytes.