Netherton syndrome is an uncommon autosomal recessive disorder characterized by congenital ichthyosis with defective cornification, bamboo hair, and severe atopic manifestation. It is caused by mutations in
In 1958, Netherton described the bamboo-like deformity in the fragile hairs in a girl with erythematous scaly dermatitis. In 1985, Greene and Muller emphasized the triad of Netherton syndrome: ichthyosis, atopy, and trichorrhexis invaginata. In 2000, Chavanas
In this session, we summarize (1) the clinical features of Netherton syndrome, (2) the genetic relationship of
2. The clinical features of Netherton syndrome
Netherton syndrome is an uncommon autosomal recessive disease characterized by ichthyosis linearis circumflexa and/or congenital ichthyosiform erythroderma, hair shaft defects including trichorrhexis invaginata, trichorrhexis nodosa and pili torti and atopic manifestations with an elevated IgE level, frequent asthma and food allergies. It is caused by mutations in
The infants with Netherton syndrome commonly show a generalized erythroderma covered by fine, translucent scales, which can be difficult to distinguish clinically from erythrodermic psoriasis, non-bullous congenital ichthyosiform erythroderma, or other infantile erythrodermas. Electron microscopy is useful for diagnosis. It illustrates premature lamellar body secretions and foci of electron-dense materials in the intercellular spaces of stratum corneum. Patients with a mild phenotype of ichthyosis linearis circumflexa on the palms and soles will have mutations located downstream near the C-terminal end, while a severe erythrodermic phenotype will be associated with nucleotide changes with early truncations in
Trichorrhexis invaginata (bamboo hair) is a focal defect of the hair shaft that produces development of torsion nodules and invaginated nodules. Invagination of affected hairs is caused by softness of the cortex in the keratogenous zone because of an incomplete formation of disulfide bonds.
Lack of LEKTI causes stratum corneum detachment secondary to epidermal proteases hyperactivity. This skin barrier defect favors allergen absorption and is generally regarded as the underlying cause for atopic dermatitis-like lesions in Netherton syndrome. Uncontrolled kallikreins (KLK)s activity in Netherton syndrome epidermis can trigger atopic dermatitis-like lesions, independently of the environment and the adaptive immune system.
3. The genetic relationship of
SPINK5to atopic dermatitis
Atopic dermatitis is a chronic and relapsing inflammatory skin disorder caused by multiple genetic and environmental factors. A recent genome-wide association studies for atopic dermatitis identified susceptibility loci at 1q21.3 (
4. The molecular functions
The epidermis consists of the basal layer, the spinous layer, the granular layer and the cornified layer. The hair follicle is constructed by the inner root sheath, the outer root sheath and the hair bulb. LEKTI is expressed in the granular layer of the epidermis and in the inner root sheet of hair follicle and acts as an inhibitor of multiple serine proteases.4 LEPTI contains fifteen serine protease inhibitor domains and its proteolytic fragments inhibit epidermal proteases.22-28 LEPTI can inhibit the epidermal serine protease KLK5, KLK6, KLK7, KLK13 and KLK14.29 LEKTI-domain 6 was shown to specifically inhibit KLK5 and KLK7 in the mid-to-high nanomolar range. Thus, protease inhibitors such as LEPTI are crucial players for controlling protease activity.
KLK5 can cleave desmoglein 1, inducing the detachment of stratum corneum and subsequent severe skin barrier defect which is associated with high permeability of various allergens. Unrepressed KLK5 activity can be present in loss-of-functional mutation in
KLK7 is involved in stratum corneum desquamation via the disruption of corneodesmosomes and the cell-cell adhesion junctions of corneocytes by hydrolyzing the two mayor cadherins (corneodesmosin and desmocollin 1) in the extracellular region of the junctions.
Matriptase is a transmembrane tripsin-like serine protease having the capacity of autoactivation and subsequent occurrence of proteolytic cascade reactions.[33, 34] Sales
The functional loss or insufficiency of LEKTI induces relative excess activation of serine protease toward severe skin allergy.
Recently, studies for the interaction between proteases and protease inhibitors are focused on the elucidation of pathogenesis of Netherton syndrome, atopic dermatitis, asthma, and food allergies. Atopic manifestation with an elevated IgE level in Netherton syndrome prompted researches to investigate the genetic relationship between atopic dermatitis and genetic polymorphisms. LEKTI encoded by functionally decreased polymorphisms can alter proteolytic activation and protease deregulation. The relationship between atopic dermatitis and improper cornification has been focused not only in model mice of Netherton syndrome but also in flaky tail mice with double filaggrin and loricrin deficiencies. Further study will discover more precise mechanism in cornification, which would provide novel strategies for effective treatment for Netherton syndrome and atopic dermatitis.