Introduction:
Ichthyosis covers a wide spectrum of diseases affecting the cornification of the skin. All forms of ichthyosis are characterized by extensive scaling, hyperkeratosis, and often inflammation of the skin, resulting in erythroderma. (Joosten, “New developments in the molecular treatment of ichthyosis: review of the literature” Orphanet J. of Rare Diseases, 2022)
Ichthyosis refers to a set of inherited and acquired disorders of keratinization in which the skin is covered by an excessive amount of scales, resulitng in a thick yet dysfunctional skin barrier. (Kurban, US 11,382,888B2)
Ichthyosis differs form simple dry skin (xeroderma) by its association with a systemi disorder or medication, heritability, severity, or a combination. Ichthyosis can also be much more severe than xeroderma. Inherited ichthyoses are characterized by excessive accumaltion of dry, scaly, and thickened skin, and may involve most of the body surface area. They are classified according to clinical and genetic ceriteria. Pruritus, peeling, skin tightness and occasionally blistering can occur. Acquired ichthyosis typically presents in adulthood. It can be associated with systemic disoders (e.g., leprosy (Hansen disease), hypothyroidism, lymphoma, late-stage HIV multiple myeloma, systemic lupus erythematosus, dermatomyositis, systemic sclerosis. Some medicaitons also cause ichthyosis (e.g., nicotinic acid, triparanol, butyrophenones)(MERCK MANUAL)
Disease Subtypes:
X-linked recessive ichthyosis (XI): is caused by mutations in the steroid sulfatase (STS) gene and is usually present soon after birth. It is characterized by hyperkeratosis and generalized polygonal brown scales.
Autosomal recessive congenital ichthyosis (ARCI): described a spectrum of ichthyosis including lamellar ischthyosis (LI), congenital ichthyosiofrm erythroderma (CIE) and Harlequin ichthyosis (HI). The pehnotpye of each subtype differs. Children are often born with a colodion membrane.
—lamellar ischthyosis (LI): is characterized by rough, dark brown scaling, palmoplantar keratoderma and scarring alopecia.
—congenital ichthyosiofrm erythroderma (CIE): expresses as erythroderma with fine white scaline.
—Harlequin ichthyosis (HI): presetns itself at birth with a very thick and rigid collodion membrane causing ectropion, eclabium, restriction of movements, and high risk o mortality.
Epidermolytic ichthyosis (EI): is a form of ichthyosis that is characterized by congenital erythroderma, hyperkerotosis and blisering.
Congenital reticular ichthyosiform erythroderma (CRIE): results in a reticular ichthyosiform phenotype with yellow-brown scaling and erythroderma. It is due to autosomal dominant mutaitons in the tail regions of KRT1 and KRT10 gene, also cuasing collapse of KIF network.
Netherton syndrome (NS): is characterized by congenital scaly erythroderma, evolving into typical erythematous patches with peripheral scaling (ich-thyosis linearis circumflexa, hair saft abnormalities (trichorrhexis invaginata/bamboo hair) and atopic manifestation. It is an autosoaml recessive disorder caused by mutations int he Spink5 gene. This gene encodes for lympho-pithelial Kazal-type related inhibitor (LEKT1) which is a serine protease inhibitor and regualtes the degradation of corneodesmosomes by kallikrein-related peptidases 9KLKs).
Sjögren-Larsson syndrome: is an autosomal ressive disorder involving the skin, eyes and CNS. The ALDH3A2 gene encodes for fatty aldehyde dehydrogenase (FALDH). This enzyme catalyzes the oxidation of fatty aldehyde from various lipid pathways. Mutations in the ALDH3A2 gene, lead to a FALDH deficiency. The fatty alcohols will accumulate and are diverted to other lipids, which may interefere with normal formation of lamellar body membranes in keratinocytes and lead to abnormal stratum corneum membrane.
SAM syndrome: stands for severe dermatitis, multiple allergies and metabolic wasting syndrome. This congenital form of ichthyosis is due to mtuations in th desmoglein-1 (DSG1) or the desmoplakin (DSP) gene, encoding for desmoglein-1 and desmoplakin, respectively. Both proteins are curcil components of desmosomes, necessary to connect the cell surface to the KIF cytoskeleton. Mutations in the DSG1 or DSP gene cause loss of cell-to-cell adhesion and differentation disturbances.
Peeling skin sydnrome type 1 (PSS1): has clinically some resemblances with NS, PSS1 is characterized by erythroderma and superficial peeling of the skin. It is casued by mutations in the corneodesmosin gene (CDSN). Lack of corneodesmosin results in subcorneal splitting and detachment of corneocytes.
Keratitis-ichthyosis-deeafness (KID) syndrome: includes a vascularizing keratitis, erythrokeratoderma skin lesions and a sensorineural hearing loss. It is casued by mutations in teh connexin-26 (Cx26) gene. Gap junctions reulgate cellualr communicaiton and activiteis, and are composed of multiple connexins. Cx26 is one of these connexins and is expressed in many epithelial organs, including the inner ear and the skin.
CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects): is a cutaneous mosaicism, caused by mutaitons in the NAD(P)H steroid mosaicism, casued by mutations in the NAD(P)H steroid dehydrogenase-like (NSDHL) gene, which is involved in the process of cholesterol synthesis.
Pathology:
Gene Mutations: New advances in understanidng the pathophysiology of ichthyosis have been made. Mutations in over 50 genes are known to cuase an ichthyosis phenotype. Four processes in skin cornificaiton can be invovled in the pathophysiology; (1) the process of desquamation, (2) impariement in the keratin synthesis, (3) imparment in the synthesis of the cornified envelope or (4) impairment in the organizaiton of the stratum corneum extracellular lipid matrix. (Joosten, “New developments in the molecular treatment of ichthyosis: review of the literature” Orphanet J. of Rare Diseases, 2022)
Keratin-1 (KRT1) or Keratin-10 (KRT10) gene: EI is caused by autosomal dominant mutations in KRT1 or KRT10 gene, encoding for keratin 1 and keratin 10 proteins. These mutations indcue clumping of the ekratin intermediate filament network in suprabasal kertinocytes, and cellular collapse. The mutations may also interfere with lamellar body secretion and thus the lipid membrane formation, causing impaired barrier function.
Trans-gluatminase-1 (TGM1): The genetic defect in ARCI is based on mutations in numerous genes. The most common form of ARCI is caused by mtuations in the trans-gluatminase-1 (TGM1), genes, which encodes for the transglutaminase-1 (TG1) protoein. TG1 mediates crosslinking of cytoplasmic proteins onto the plasma membrane to form the cornified envelope.
Treatment:
Current treatment for ichthyosis is focused on symptom relief and includes emollients, keratolytics, and oral retinoids. The efficacy of these treatments is moderate and is usually not effective on inflammation of the skin. (Joosten, “New developments in the molecular treatment of ichthyosis: review of the literature” Orphanet J. of Rare Diseases, 2022)
Promising development have been made in pathogenesis based therapies, such as enzyme replacement therapy and gene therapy, and recent findings concerning the immune profile of ichthyosis patients hve given new ground to repurpose biologicals. (Joosten, “New developments in the molecular treatment of ichthyosis: review of the literature” Orphanet J. of Rare Diseases, 2022)
Biological Therapy: includes monocloanl antibodies that target specific molecuels like TNF-alpha, IL-13, IL-17 and IL-23. There is substantail experience in teh usage of biologics in inflammatory skin diseases such as psoriasis and atopic dermatitis. Accordingly, these drugs are commercially availabe and dermatologists are experience in their usage. The path for clinical testing can accordingly be rather rapaid.
–ixekizumab: targets IL-17A.
–Secukinumab: is a recombinant human mAb that targets IL-17A.
–Ustekinumab: inibits IL-17 by targeting IL-12 and IL-23.
Small Molecules: are used to inhibit certain proteins, such as protein kinases. Becasuse of their size and properrties, they are able to interact with specific parts of the targeted prtoein and thus inhibit it wihtout disrupting th pathways of other poteins. They are currently used to treat inflammatory skin diseases, such as apremilast in psoriasis and baricitinib for atopic dermatitis. Samll molecuesl could be applicable in NS, where the dysfunctional SPINK5 leads to an unopposed KLK5 activity.
Gene Therapy: aims to restore the WT gye fucntion.
Enzyme Replacement Therapy: entails the replacement of a deficient structural protein or enzyme. It has been used for over 20 years for lysosoaml storage disoders. For ichthyosis, it could be applicable for recessive forms, where a deficiency of a specific protein leads to the phenotype.
Lipid Replacement:
Lipid replacementcould be effective for CHILD syndrome, which is caused by a deficiency in builk cholesterol. Application of lovastatin and cholesterol has been reported beneficial for two CHILD affective individuals, who displayed ichthy-osiform plaquest.
–Topical Cholesterol Replacement: has been used with variable success , in the managemetn of x-linked ichthyosis casued by mutaitons in the steroid sulfatase gene. (Kurban, US 11,382,888B2)
Cholesterol is an integral component of all cell membranes. It contributes to the barrier function of the epidermis. The “cholesterol sulfate cycle” is also essentail for the development and maturation of keratinocytes. In the lower epidermis, cholesterol is sulfated by the enzyme cholesterol sulfotransferase to form cholesterol sulfate, which is then desulfated by the eznyme steroid sulfatase in the outer epidermis.
-Cholesterol and Lovastatin: (Kurban, US 11,382,888B2) discloses a combination of cholesterol at about 2% by with and lovastatin at about 2% by weight in a cream base and another cream of either glycolic acid at about 10% by weight or about 20% by weight.
Inhibitors of Cholesterol Synthesis:
Naphtali (US 6126947A) discloses that several skin disorders such as: acne, seborrhea, rosacea, atopic dermatitis, contact dermatitis, ichthyosis and rhinophyma can be treated by one topical application of one of a plurality of cholesterol synthesis inhibitors.
Moisturization and Keratolytics:
In any ichthyosis, there is impared epidermal barrier funciton and moisturizers should be applied immedaitely after bathing.
–Emollients are the mainsay of therapy for all patients with ichthyosis. Preferred agents include plain petrolatum or minieral oil, which sould be applied twixe daily, expecially after bathing while the skin is still wet. Other useful topical agents include dexpanthenol, certamid-based creams, and a mixture of hydrophilic petrolatum and water (in equal parts).
–Topical Keratolytics: are used to their excess scale and to promote peeling of the statum corneum. Ichthyosis typically responds well to the topical keratolytic proylene glycol. To remove scale (e.g., if icthyosis is severe)k patients can apply a preparation containg 40-60% proylene glycol in water under oculusion (e.g., a thin palstic fim or bag worn overnight) everyt ight after hydrotating the skin (e.g., by bathing or showering). (MERC Manual)
Retinoids: are effective in treating inherited ichthyoses. They have been shwon to reduce scaling and thus improve skin texture. Oral synthetic retinoids are effective for most ichthyosis. (MERC Manual)
Experiments show that RA treated skin result in hyperproliferation of basal keratinocytes and thickining of the epidermis, followed by clincial peeling and desquamation. At the molecuels level, RA binds nuclear steroidogenic receptors which regualte the expression of genes for cell growth control and ligands for EGF. (Kurban, US 11,382,888B2)