Ichthyosis – Ypatent

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) (see below):

Autosomal recessive congenital ichthyosis (ARCI): (See discussion below) described a spectrum of ichthyosis including lamellar ischthyosis (LI), congenital ichthyosiofrm erythroderma (CIE) and Harlequin ichthyosis (HI). The phenotpye of each subtype differs. Children are often born with a colodion membrane.

Kurban, (US 20200345678A1) discloses a method of treating a skin disease that such as ARCI by administering a combination of cholesterol at about 2% and a statin such as lovastatin at about 2% in a cream base and glycolic acid between about 10%-20%.

—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.

CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects) → usually pathogenic variants in NSDHL, affecting cholesterol biosynthesis.

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.

Ichthyosis Vulgaris: IV is characterised by whitish scales on non-erthrodermic skin of the leg.

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.

Icthyosis Vulgaris:

Introduction:

Icthyosis vulgaris is an inherited disorder of keratinization that results in asteatotic scales on extensor surfaces of the arm, legs, and trunk. (Bellew, “overcoming the barier treatment of ichthyosis a combination-therapy approach” J Clin Aesthetic Dermatol. 2010; 3(7): 49-53)

IV is an inherited, non-syndromic form of ichthyosis that presents with skin problems. Making up more than 95% cases of ichthyosis, IV is caused by heeterozygous loss-of-funciton mutaiton of the fillaggrin gene, raising the fragility and permeability of the stratum corneum. It typically presents in infancy as xerosis, skin lesions, keratosis pilaris, palmoplantar hyper linearity, scaly dermatosis and erythroderma, clearly identified by age 5. Although majority of patients have a normal lifespan, possible complicaitons include a vitamin D deficiency and auditory problems, due to scaling int he ears, besides a drop in quality of life due to dermatological changes. (Jaffar, “Ichthyosis vulgaris: An updated review” Skin Health Dis. 2023).

Pathology:

IV is an autosomal semidominant inherited disorder of keratinization characterized by dry, fine scales on the extremities and trunk with sparing of the flexural surfaces. IV is associated with FLG mutation leading to altered profillaggrin produciton and subsequent decreases in filaggrin. Bellew, “overcoming the barier treatment of ichthyosis a combination-therapy approach” J Clin Aesthetic Dermatol. 2010; 3(7): 49-53)

–-FLG deficiency: rasies the fragility and permeability of the statum corneum. The disruption of the mechanical barreir increases trans epidermal water loss and worsens the immunological battier against allergens and microorganisms. Water loss exacerbates skin eleasticity, while the change in pH affects the keratinocyte differentiation process. The patient is more prone to allergens, thereby increasing risk of AD, hand eczema, allergic contact dermatitis, and irritant contact dermatitis. Jaffar, “Ichthyosis vulgaris: An updated review” Skin Health Dis. 2023).

Treatment:

Urea-based creams with 10% urea, ceramides, and other ceramides are often the first line therapy in ichythyosis vulgaris. There is no known curative treatment but lifelong reamtent can allevaite the symptoms. Urea-based creams are highly therapeutic whereas ammonium lactate 12% lotion with a physiological lipid-based repair ream can help with caling and dryness. There is also evidence in favour of porylene glycol solutions. (Jaffar, “Ichthyosis vulgaris: An updated review” Skin Health Dis. 2023).

–EpiCeram: Physical examination of a patient exhibited dry, fine, scaly patches on the trunk and both the upper and lwoer extremities with sparing of the flexural surfaces, including the popliteal, antecubital, axillary, and inguinal regions. A diagnosis of ichthyosis vulgaris (IV) was made and the pateint was treatment with a combiantion regimen including ammonium lactate (AL) 12% lotion (Lac-Hydrin 12% Loiton, Ranbaxy Laboratores, Jacksonville, Florida), followed by a physiological lipid-based barrier repair cream containing ceramides, cholesterol, and free fatty acids in a 3:1:1 ratio designed to simulate the normal intercellular lipid biolay (EpiCeram Skin Barrier Emulsion, Promius Pharma LLC, Bridgewater, NJ). The combination therapy approach with a physiological lipid-based barrier repair topical emulsion and ammonium lactat 12% lotion applied topically was shown to be effective at 4 week follow up without any untoward side effects. The combination therapy addresses the importance of caring for both the corneocytes (“brinks”) and the intercelullar lipid biolay (“mortar”) for optimal benefit. (Bellew, “overcoming the barier treatment of ichthyosis a combination-therapy approach” J Clin Aesthetic Dermatol. 2010; 3(7): 49-53)

–Anti-IL23: Risankizumab, an anti-IL23 drug is under investigation. Jaffar, “Ichthyosis vulgaris: An updated review” Skin Health Dis. 2023).

Congenital Ichthyoses:

Introduction:

Six major distinct clinical subtypes are known in hereditary non-syndromic ichthyoses, o.e., harlequein ichthyosis (HI), lamellar ichthyosis (LI), non-bullous congenital ichthyosiform erythroderma (NBCIE), bullous congenital ichthyosiform erythroderma (BCIE). (Akyama “An update on molecualr aspects of the non-syndromic ichthyoses” Experimental Dermatology, 17, 373-382 (2008).

Autosomal recessive congenital ichthyosis (ARCI): describes a spectrum of ichthyosis including lamellar ischthyosis (LI), congenital ichthyosiofrm erythroderma (CIE) and Harlequin ichthyosis (HI). The phenotpye of each subtype differs. Children are often born with a colodion membrane.

ARCI is a genetically and phenotypically heterogenous group of disorders that includes lamellar ichthyosis (LI) and non-bullous congentical ichthyosiform erythroderma (NCIE). The incident of ARCI cases has been estimated at about 1 in 200k birthrss. Infants affected by LI and NCIE are generally born with a shinny, waxy layer of skin (called a collodion membrane) that is typically shed within the first few weeks of lie. For LI patients, the skin beneatht he collodion membrane is red and scaly, and typically develops into the alrge, dark, plate-like scales covering the skin which are characteristic of the disease. For NCIE patients, the skin beneath the collodion membrane is red and covered ith fine, white scales, and skin abnormalities (such s s thickening of the skin on the palms and the soles of the feet) may persist into adulthood. (Krishnan, US 2019/0314430A1)

The management of ARCI is a life-long endeavor and is generally supportive. It commonly focuses on reducing scaling and/or skin lubrication. A first-line therapy typically includes hydration and lubrication of the skin accomplished by creams and ointments containing low concentrations of salt, urea, or glycerol, which may increase water binding capacity of the stratum corneum. Tpopical or oral retinoid therapy may be recommended for those with severe skin involvement but are presecribed with caution. (Krishnan, US 2019/0314430A1)

—Lamellar ichthyosis (LI): LIS is characterized by large, dark grey to black scales on the legs. (Akyama “An update on molecualr aspects of the non-syndromic ichthyoses” Experimental Dermatology, 17, 373-382 (2008).

Lamella Ichthyosis (LI) is a clinically heterogenous autosomal recessive disorder, which causes abnormalities of the cornified envelope (CE) and persons with the severe LI phenotype often present at birth encased in a translucent colloidion membrane. Soon after brith, this thick membrane dries and cracks and, over time, these persons develop large, brown, plat-like scales in a generalized distribution. (Steinert, US 2003/0072795A1)

The locus for LI has been mapped to chromosome 14q11 and a complete linkage with the gene encoding transglutaminase 1 (TGase 1). Furth, point mutations in TGase1 were identified, and these mutations are hypothesized to adversely affect the formation of cross-links essential in the produciton of the CE. To form a healthy CE, specialized keratinocyte proteins are expressed and subsequently made insoluble by cross-linking by both disulfide bonds and isopeptide bonds formed by transglutaminases (TGases). Investigators believe that the protein composition of CEs varies widely between epithelia and even different body sites of epithelia such as the epidermis. The principle function of the enzyme is to attach ceramide lipids for compelte protein/lipid barrier funciton in the skin. Additionally, TGase 1 enzyme can can perform a transesterificaiton reaction between specific glutaminyl residues of human involucrin. (Steinert, US 2003/0072795A1)

Steinert, (US 2003/0072795A1) discloses compositions that include TGase 1 and a synthetic lipid vesicle and methods that provide stabilized transglutaminase 1 enzyme and other molecules necessary for the assembly of the cell envelope to skin cells. The invention provides enzyme in a stable active form, synthetic ceramide analogs that can function the same way as normal skin ceramides and synthetic lipid vesicles that can stably carry both the enzyme and synthetic ceramide analog to the skin. One effect is that the lipid barrier function in normal skin is improved and it can be applied to affected ARI skin for treatment. A mouse model lacking the TGase 1 gene for lamellar ichthyosis was used.

(Krishnan, US 2019/0314430A1) discloses a herpes virus that includes a polynucleotide encoding a transglutaminase (TGM) polypeptide.

Jin (US 2025/0120887A1) discloses skin moisturizing compositions that include a ceramide, a cholesterol and a fatty acid to treat skin diseases accompanied by abnormalities in the skin barrier function including lamellar ichthyosis.

—Congenital ichthyosiform erythroderma (CIE) (NBCIE — non-bullous congenital ichthyosiform erythroderma (NCIE)):

—Harlequin ichthyosis: is characterized by plate-like scales covering the entir body surface. (Akyama “An update on molecualr aspects of the non-syndromic ichthyoses” Experimental Dermatology, 17, 373-382 (2008).

The most severe form of ichthyoses spectrum is Harlequin Ichthyosis which is casued by mutations in ABCA12, a putative lipid transport protein of the ATP binding cassette (ABC) family. HI is a rare but very severe skin disease, with 50% noenatal lethality. For those patients who do survive beyond birth, a modest improvement in disease pehnotypes is observed, although a lifetime regime of frequent bathing, removal of scales and frequent applciation of emollient oils is required to manage the disorder. (Smyth, US 20180263940A1)

Smyth, (US 20180263940A1) disclsoes a method of treating a skin condition with lipid dysfunction that includes adminsitering aminosalicylic acid (ASA).

CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects) → usually pathogenic variants in NSDHL, affecting cholesterol biosynthesis.

Epidermolytic ichthyosis (EI) (BCIE — bullous congenital ichthyosiform erythroderma):

X-linked ichthyosis: 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.

Topical cholesterol replacement has been used, with variable success, in the management of x-linked ichthyosis casued by mutations in the steroid sulfatase gene. In particular, a combiantion of lovastain, 2% and cholesterol 2%, cream has been used for teh treatment of cutaneous manifestations in a rare ichthyosiform condition known as SHILD syndrome (gocngeital hemidhysplasia icthyosis and limb defects). The lovastatin serves to inhibit local 3-hydroxy-3-methyyl-gluatryl-coenzyme A reducatase enzyme activity and thus the production of toxic metaobolites, and the cholesterol compensates for the endogenous cholesterol noramlly produced in the skin. (Mazen, US 20200345678A1)

Superficial epidermolytic ichthyosis (SEI) (Ichthyosis bullosa of Siemens (IBS)):

Pathology Of Icthyosiform Diseases:

Abnormal barrier Function in the Stratum Corneum:

Many icthyosiform diseases (e.g., auttosomal recessive lamellar icthyosis and recessive congenital nonbullous ichthyosiform erythroderma) are caused by improper or incomplete plipid barrier function. (Steinert, US 2003/0072795A1)

A majority of cases show primary abnormal phenomena that are associated with barrier function in the SE. The skin barrier of the SC has 3 major components and mechanisms of pathogenesis of ichthyosis are thought to be associated with at least one of them. One is the intercellular lipid layers in the SC. Another is the cornified cell envelope of the stratum corneum cells. The other is keratin-filaggrin degradaiton products, filling the cytoplasm of cornified cells in the SC. (Akyama “An update on molecualr aspects of the non-syndromic ichthyoses” Experimental Dermatology, 17, 373-382 (2008).

Impaired skin barrier function causes or increases the risk of skin disorders such as infectious diseases, atopic dermatitis and ichthyosis. The stratum corneum (SC), which constitutes the otermost layer of the epidermis, plays a central role in skin barrier formation. In SC, two lipid structures -the lipid lamellae, which are multilayered lipid structures existing outside corneocytes, and the corneocyte lipid envelope (CLE), which covers the surfaces of corneocytes, play especially important roles. The major components of the lipid lamellae are free (non-protein-bound) cermides, cholesterol and free atty acids, while the CLE is primarily composed of protein-bound ceramides, which bind covalently to corneocyte surface proteins. (Akiyama, “correlations between skin condition parameters and ceramide profites in the Stratum Corneum of healthy individuals” Int. J. Molecular Sciences, 25, 9291, 2024).

There are several skin diseases in which the lipid composition in the intercellular matrix of the stratum corneum is different from that of healthy human skin. It has been shown that patients suffering from atopic dermatitis have a reduced ceramide content in the SC, whereas in the SC of lamelar ichthyosis patients, the amount of free fatty acids is decreased and the ceramide profile is latered. Both patient groups also show elevated levels of transepidermal water loss indicative of an impaired barrier function. (Pilgram, Aberrant lipid organization in stratum corneum of patients with atopic dermatitis and lamellar ichthyosis” Soceity for Investigative Dermatology2000)

Gene Mutations: Ichtyosis patients typically have defects in proteins involved in lipid metabolism and epidermal keratinocyte terminal differentiation and formation of the stratum corneum, causing impaired permeability barrier function. In ARCI, most affected gene products were linked to a common metabolic pathway required for the processing of epidermal acylceramides, which are essential for the assembly of the epidermal cornified lipid envelope (CLE) and barrier formation. Chunha, “hiPSC-derived epidermal keratinocytes form ichthyosis patients show altered expression of cornification markers” Intent. Molecular Sciences, 22, 1785, 2021)

New advances in understanding the pathophysiology of ichthyosis have been made. Mutations in over 50 genes are known to cause 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 induce clumping of the keratin 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.

Mutations in patatatin-like phospholipase domain-contain 1 (PNPLA1): casue autosomal recessive cognital ichthysois, but the mechanism invovled remains unclear. PNPLA1, an enzyme expressed in differentiated keratinocytes, plays a crucil role in the biosyntehsis of w-O-acryleramide, a lipid component essential for skin barrier. (Hirabayashi, “PNPLA1 has a crucial role in skin barrier funciton by directing acylceramide biosynthesis” Nature Communicaitons2017)

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.

Disease Models:

Induced Pluripotent Stem Cells (hiPSCs):

Inherited ichtoyosis represents a large heterogenous group of skin disorders characterized by impaired epidermal barrier function and disturbed cornification. Current knowledge about disease mechanisms has been uncovered mainly through the use of mouse models or human skin organotypic models. However, most mouse lines suffer form severe epidermal barrier defects causing neonatal death and human keratinocytes have very limited proliferation ability in vitro. Thus, development of disease models based on patient derived human induced pluripotent stem cells (hiPSCs) is highly relevant. (Chunha, “hiPSC-derived epidermal keratinocytes form ichthyosis patients show altered expression of cornificaiton markers” Intent. Molecular Sciences, 22, 1785, 2021).

Chunha, “hiPSC-derived epidermal keratinocytes form ichthyosis patients show altered expression of cornification markers” Intent. Molecular Sciences, 22, 1785, 2021) generated hiPSCs from patients with congenital ichthyosis, either non-syndromic autosomal recessive congenital ichtyosis (ARCI) or the ichthyosis syndrome trichothiodystrophy (TTD). Several hiPSC lines were generated by reprogramming of dermal fibroblasts form patients diagnosed with congenital ichthyosis, namely ARCI and TTD1. hiPSCs were successfully differentiated into basal keratinocyte-like cells (hiPSC-bKs), with high expression of epidermal keratins. The hiPSCs were successfully differentiated into epidermal keratinocytes using BMP-4 and ATRA for the initial induction into epithelial fate, complemented with KGF/FGF7 during the differentaiton process. In the presence of higher calcium concentration, terminal differentiation of hiPSC-bKs was induced and markers KRT1 and IVL expressed. TTD1 hiPSC-bKs cshowed reduced expression of FLG, SPRR2b and lipoxygenase genes. ARCI hiPSC-bKs showed more severe defects, with downregulation of several cornificaiton genes. The application of hiPSC technology to TTD1 and ARCI demonstrates the successful generaiton of in vitro models mimicking the disease phenotypes, proving a valuable system both for fruther molecualr investigations and drug development for ichthyosis patients.

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 (e.g., Ceramide/choelsterol and Fatty acid) Replacement:

Lipid replacement could 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)