No approved-drug candidate for superficial epidermolytic ichthyosis is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Superficial epidermolytic ichthyosis (SEI), previously called ichthyosis bullosa of Siemens, is a rare genetic skin condition characterised by superficial blisters and hyperkeratosis. It is caused by mutations in the K2e gene. A 2012 report of two families noted that SEI can be easily confused with epidermolytic ichthyosis (EI, also called epidermolytic hyperkeratosis) and that genetic testing can help differentiate them. A 2025 report of two siblings described the clinical features as superficial blistering, hyperkeratosis predominantly involving flexures and joints, and the Mauserung phenomenon (the shedding of sheets of scale). On ultrastructural studies, epidermolytic hyperkeratosis is seen. The 2025 authors stated that very few families with SEI are described in the literature and that its exact prevalence in the Indian population is undetermined.
A 2021 case report described a 5-year-old Filipino girl with EI (not SEI specifically) who had hyperkeratotic scales sparing the palms and soles. Histopathology showed epidermolytic hyperkeratosis. She was treated with isotretinoin at 0.3 mg/kg/day together with keratolytic agents, urea lotion and lactic acid lotion. This resulted in a marked decrease in the thickness of the scales and odour. However, rebound effects were noted when the dose was increased to 0.6 mg/kg/day. The authors noted that EI presents with more skin fragility than non-EHK ichthyosis and suggested there may be a smaller treatment window for patients with EI, notably lower than the dose recommended for ichthyosis in general. The 1999 review of ichthyosis stated that use of oral retinoids in epidermolytic hyperkeratosis is associated with mixed results; sometimes blistering increases while scale decreases.
The 1999 review also described that in epidermolytic hyperkeratosis (now called EI), the incidence is about 1 in 300,000, it is autosomal dominant, and it is caused by errors in keratins 1 and 10. Newborns present with red, scaly lesions and widespread denuded skin. After the neonatal period, blistering lessens but does not disappear, and hyperkeratosis becomes more obvious with a distinctive porcupine-like quill scale involving the entire body, especially flexures, face and scalp. The palms and soles become thick. Bullae form underneath the quills, often become purulent and secondarily infected, and produce an extremely foul odour. The review noted that life expectancy is normal but chronic problems include blistering and odour, and that the combination of odour and unusual skin increases the prevalence of psychological problems. A 2003 Swedish review of 127 cases of congenital ichthyosis classified 21 patients as having bullous ichthyosis (epidermolytic hyperkeratosis) and related disorders due to keratin mutations.
What is still missing for SEI specifically are large-scale prevalence data, controlled trials of any systemic therapy, and a clear understanding of the optimal dose and safety of retinoids given the narrow treatment window suggested by the single case report. No trial has established a standard of care, and patient stratification by genotype (K2e mutation) has not been linked to treatment response in any published study.
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Dermatologica · 2009 · 84 citations
Retinoids in Disorders of Keratinization: Their Use in Adults
AbstractHereditary disorders of keratinization may be a considerable handicap. Oral treatment with retinoids has been shown to be effective in many of these diseases. In the group of ichthyoses, the best results can be obtained in the various types of nonbullous congenital ichthyosis (erythrodermic autosomal recessive lamellar ichthyosis, nonerythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant lamellar ichthyosis). It should be borne in mind, however, that retinoid therapy alone cannot lead to a complete response of these forms of ichthyosis and that this treatment cannot replace an appropriate topical treatment. During continuous treatment with etretinate a reduction of the dosis to 0.5 mg/kg is often necessary. Etretinate treatment of bullous congenital ichthyosiform erythroderma is more difficult, and it is advisable to begin with a low dosis of 0.25-0.5 mg/kg. The epidermolytic form of palmoplantar keratoderma is in our opinion no indication for retinoid treatment which seems to result inevitably in large erosions. Good or excellent results have been seen in other forms of palmoplantar keratoderma including mal de Meleda, Papillon-Lefèvre syndrome, erythrokeratodermia variabilis, verrucous epidermal nevi, Darier disease and pityriasis rubra pilaris. In patients with Darier disease it is wise to begin with a relatively low dosage of 0.5 mg/kg and to adjust the dosage to the further course of the disease. The same is true for the ichthyosis seen in the Netherton syndrome, which may be either a diffuse hyperkeratosis or ichthyosis linearis circumflexa. In view of the fact that any inherited keratinization disorder requires long-term treatment, the risk of bone toxicity should be carefully weighed against the benefit of this therapy. The results so far obtained indicate that the effect of etretin is comparable to that of etretinate in the treatment of inherited keratinization disorders. Intermittent therapy should be tried whenever possible. A combination therapy seems reasonable in pityriasis rubra pilaris of the adult type. We have seen good results by combination with PUVA treatment. Autosomal dominant ichthyosis vulgaris and X-linked recessive ichthyosis are inappropriate to treat with oral retinoid therapy because these diseases are too mild. Papillomatous epidermal nevi should also be excluded because they do not respond to the drug. Hailey-Hailey disease may even be worsened by this treatment. According to our experience, oral retinoid therapy has no effect in monilethrix.
https://doi.org/10.1159/000248867Acta Dermato Venereologica · 2003 · 30 citations · open access
The Clinical Spectrum of Congenital Ichthyosis in Sweden: A Review of 127 Cases
AbstractCongenital ichthyosis comprises a rare group of usually monogenetic diseases that present at birth as a collodion phenotype or as variable degrees of ichtHyosiform erythroderma, with or without superficial blisters. Depending on which gene mutation causes the disease, the skin problems later in life may range from a severe lamellar or bullous ichthyosis to mild or only focally expressed hyperkeratotic lesions. It is obviously important, but sometimes painstakingly difficult, to make a correct diagnosis already in infancy. Fortunately, recent advances in our understanding of the molecular genetics of ichthyosis have led to several new diagnostic tools that are continuously being updated. Based on this development, and on our own 5 years of experience in a national genodermatosis centre, we describe 127 cases of congenital ichthyosis examined in childhood or adulthood. Applying a combination of phenotypic and genotypic criteria, the patients were classified into three main groups: 1) Bullous ichthyosis (epidermolytic hyperkeratosis) and related disorders due to keratin mutations (n = 21); 2) Non-bullous ichthyosiform erythroderma and lamellar ichthyosis mainly due to transglutaminase 1 mutations (n = 80); 3) Syndromic ichthyosis, i.e. systemic (multi-organ) diseases due to many different causes (n = 26). Each group could be further stratified into 4-11 entities using mutation analysis, electron microscopy of epidermis and various other techniques. Our findings are discussed in relation to recent data in the literature emphasizing the clinical usefulness of various diagnostic procedures for ichthyosis.
https://doi.org/10.1080/00015555-0370Pediatrics in Review · 1999 · 25 citations
Ichthyosis in a Nutshell
AbstractAfter completing this article, readers should be able to: The ichthyoses are a heterogeneous group of diseases that share one presentation: scaly skin. Not too long ago, all patients who exhibited this characteristic were lumped into one group. In reality, there are differences ranging from localized to generalized scaling; spiny to flat scales; tiny to huge and plate-like scales; and blistering or redness beneath the scale. Careful observation,histopathology, genetics, and biochemistry allow ichthyoses to be categorized into several classes. The term “ichthyosis” comes from the Greek, meaning fish. To understand the ichthyoses, one must be familiar with the internal to external progression of normal skin.Ichthyoses represent abnormalities in the formation and desquamation of the keratinocytes, the most common epidermal cell. The epidermis is arranged in four layers: basal cell, squamous cell (or spiny), granular, and horny. As keratinocytes progress from the basal layer to the horny layer, different keratin proteins are manufactured. Keratins form a structural framework inside the cell that holds the shape similarly to steel girders inside a blimp. As skin tissue matures and moves outward, the keratin proteins are manufactured in a predictable sequence, but mutations can lead to keratins that have different size, shape, and assembly defects, which can affect the size and shape of the cell. At the basal layer, keratin types 5 and 14 are expressed, and as the cell moves up, keratins 1 and 10 are expressed in the spinous and granular layers. Depending on where the genetic error in keratin coding exists, the same skin can show very different phenotypes from epidermolysis bullosa to ichthyoses.Intercellular excretion of enzymes is necessary to release the bonds between cells, which allows sloughing of the top layer when appropriate. Errors in the manufacturing of these proteins, their packaging, and/or their release will cause cells to stick together far longer than normal. Basal cells form a layer of single columnar cells attached to each other by desmosomes and to the underlying dermal-epidermal junction and lamina densa via hemidesmosomes. The epidermal cells divide and move up layer by layer, taking 26 to 42 days to travel from the basal cell layer to the granular layer.Innumerable keratohyalin granules at the granular layer give it its name. This area marks the end of viable squamous cells. The cells flatten out, lose their nuclei, and abruptly keratinize. Lysosomal enzymes then are released, which are crucial for allowing the cells to desquamate. This is done via “membrane coating granules” (also known as Odland bodies or lamellar bodies), which are discharged from the granular cells into the intercellular space. These organelles excrete lipids that establish a barrier to water loss and mediate stratum corneum cell dissolution by excreting proteases. It takes an additional 14 days for the lowermost horny cells to reach the top of the epidermis.Defects in intercellular enzymes lead to diseases like X-linked ichthyosis or congenital ichthyosiform erythroderma. Defects in the cells themselves due to keratin defects (or the enzymes used to crosslink the keratins) can lead to diseases such as epidermolytic hyperkeratosis or lamellar ichthyosis.Ichthyosis vulgaris means common “fish-like” scaly skin. This common condition occurs in approximately 1:250 to 1:500 people. In many patients it appears only in dry climates. It is inherited in an autosomal dominant fashion; if both parents have very dry skin, the children are guaranteed to have dry and scaly skin.Standard skin biopsies of IV stained with hematoxylin and eosin(H&E) show little to no granular layer. On electron microscopy,decreased or tiny keratohyalin granules are seen. This correlates with reduced profilaggrin expression. Profilaggrin (the major protein of the keratohyalin granule) is broken down into filaggrin and is believed to serve as scaffolding along which the keratin filaments align. No gene defect for reduced profilaggrin expression has been found to date.IV is a clinical continuum, with common dry skin at the mild end and lizard-like scaling with erythema and itching at the severe end. Those who are mildly affected have dry skin, usually on the lower legs(Fig. 1, Table 1) and lower back, especially in dry climates or seasons. Children who have full-blown IV have fine white scales from neck to ankles, sparing the folds (where the humidity is higher) and the face (where the sebaceous glands help control the scaling). The scales are similar to small bran flakes, especially on the lower back. On the lower legs, the scaling can have a lizard-like appearance, although it is less than that seen in lamellar ichthyosis. The palms often are dry and show multiple additional lines, referred to as “hyperlinear palms.” The hair, teeth, and nails are normal.IV frequently is seen in association with atopic dermatitis. There are no systemic or laboratory abnormalities. Keratosis pilaris often accompanies IV and can be seen on the sides of the lower cheeks, neck,dorsum of the upper arms, buttocks, and anterior thighs. These are small, pointed, flesh-colored to red, perifollicular papules.As with other genetic diseases, IV can be controlled but not cured. The initial step is to hydrate the stratum corneum and seal in the moisture, then reapply the moisturizing grease as often as necessary to control the condition (Table 2) Simple soaking in warm water followed quickly by application of a thick, greasy moisturizing cream or ointment is sufficient for most patients. Soaking twice a day is preferable, as long as sufficient moisturing cream or ointment is applied immediately after the bath.Moisturizers that are available in jars and are scooped out with the fingers work best, including petroleum jelly and even vegetable shortening. More elegant solutions include mild keratolytic agents(salicylic acid), alpha hydroxy acids, or propylene glycol. Keratolytics help loosen the upper layer of scales and promote shedding. Alpha hydroxy acids (lactic, citric, glycolic) are simple,organic, hydroscopic acids that both hydrate the skin and cause the skin cells to detach. Ammonium lactate holds many times its weight in water and works well for dry, scaly skin. It is important to note that alpha hydroxy acids sting and that most children do not tolerate them. When applied to the entire cutaneous surface, any “acid”preparation can cause acidosis in neonates and, therefore, should not be used. Propylene glycol (40% to 60% in water) works as a hydroscopic agent. Urea creams (10% to 20%) act as humectants,producing a more pliable stratum corneum.There are many myths regarding the treatment of dry skin(Table 3) Warm, moist climates do help, as does humidifying the home. If children live in a geographic area in which there are four distinct seasons, the condition will improve during the summer. With sufficient humidity year round, IV may occur only when visiting dry climates.This uncommon form of ichthyosis affects 1:2,000 to 1:6,000 males. It is reported worldwide and has no ethnic or racial predominance. The patient’s mother is an obligate heterozygote.RXLI is due to a deficiency of the enzyme steroid sulfatase, which is carried on the X chromosome. About 90% of the cases are due to steroid sulfatase gene deletions, with about one third of the cases being “contiguous gene syndrome” deletions.Desquamation or a pronounced peeling is seen within a few weeks or months of birth. This is followed by persistent, dark brown scaling on the arms, legs, trunk, and especially the sides of the neck (Fig. 2Table 4) The scales are tightly adherent to the underlying skin. A mother often will exclaim, “I can’t get his neck clean.” The scales are noted on the extensor surface of the arms and encroach on the flexural sides much more than with IV. The central face is spared, but scaling can be seen around the ears and lateral cheeks. The classic areas of involvement are the lower abdomen (belt buckle area) and the sides of the neck. Marked seasonal variation is seen. Palms, soles, hair, nails, teeth,and mucosa are not involved.Placental sulfatase is needed for labor to progress. Some mothers report prolonged labor or failure to initiate labor when carrying these patients.Cryptorchidism is noted in as many as 25% of patients (see section on contiguous gene syndrome that follows). About 50% of adults who have RXLI exhibit asymptomatic punctate corneal opacities. This is also seen in carrier mothers, but not reliably enough to use as a screening test.The decrease in steroid sulfatase can be measured via three primary methods: 1) enzyme assays, 2) cholesterol sulfate accumulation in various tissues, and 3) fluorescent in situ hybridization (FISH)test. The blood test for excess cholesterol sulfate is the most reliable method for affected males. If the gene deletion is known, then the FISH test is useful for prenatal diagnosis. The original finding of fast migrating beta-low-density lipoprotein on lipoprotein electrophoresis is a difficult test to obtain and has been replaced by newer technologies. Contact the support group “FIRST” (see section on support groups) for test sites and availabilities.The phenomenon of different syndromes caused by deletions along the same gene at slightly different neighboring sites is called the contiguous gene syndrome. RXLI, chondrodysplasia punctata(Conradi-Hünermann syndrome), and Kallmann syndrome are linked by propinquity on the X chromosome. They share overlapping symptoms that include ichthyotic scaling, stippling of the long bones on radiography, anosmia, and cryptorchidism.Patients in whom RXLI is suspected should have cholesterol sulfate levels measured. They also should be evaluated for sense of smell and descended testes. The scale can be treated as noted previously for IV. Genetic counseling should be offered.RXLI is a lifelong condition that changes little with age. Seasonal variations can be expected. It is not debilitating and should not affect normal life activities adversely.EH used to be known as bullous congenital ichthyosiform erythroderma. It is caused by an error in keratin synthesis and is labeled more appropriately as a keratinopathy. The incidence is rare,probably 1:300,000. It affects all races and both genders and is autosomal dominant.EH is due to an error in synthesis of keratins 1 and 10, which are found in the upper spinous to granular layer. The phenotypes differ slightly depending on the defect, with keratin 1 defects causing palm and sole bullae. The intraepidermal blistering seen in EH is due to abnormal keratin filament formation that leads to an abnormal cytoskeleton, resulting in mechanical fragility. In addition, the desmosomal attachments are imperfect, which leads to blister formation.Newborns present with red, scaly lesions and widespread areas of denuded skin. The blisters are superficial (in the upper epidermis)and, therefore, do not scar. Neonatal hyperkeratosis may be present, but it can be subtle. After the neonatal period, the blistering lessens (but does not disappear), and the hyperkeratosis becomes more obvious. The scale in EH is a distinctive porcupine-like quill (albeit short) that involves the entire body (Figs. 3 and 4, Table 5). It especially involves all the flexures, face, and scalp, causing formation of furrowed ridges of spiny skin. The palms and soles become thick, as if covered by wax.After the newborn period, bullae form underneath the quills. These often become purulent and secondarily infected, and then the epidermis sloughs. The exposed underlying skin is red and looks relatively normal temporarily until the quills regrow. The fissures between the quills harbor aerobic and anaerobic bacteria; this plus any infected bullae produce an extremely foul odor. The foul odor is the most distressing part of this disease and the most difficult aspect to control.Sweating can be decreased in those who have EH because of blocked sweat ducts, which can lead to heat intolerance in hot climates. Staphylococcal infection in the bullae can become systemic.The biopsy of EH is very distinctive, showing a thickened epidermis with areas of cellular “clear spaces” and breakdown. Hence, the term epidermolytic hyperkeratosis, which is simply a description of the pathology. There is a markedly thickened granular layer, with irregular kerato-hyalin granules corresponding to the desmosomal problems mentioned previously. The bullae arise within the epidermis due to separation and breakdown of the edematous cells.Newborns who exhibit bullae can have problems with fluid and electrolyte imbalances as well as with sepsis. Careful handling is necessary to prevent further blistering.Beyond the neonatal period, hyperkeratosis and foul odor are the two primary problems. Simple soaking in water, scrubbing, and after-bath greasing can soften and remove many quills. Topical retinoic acids and/or alpha-hydroxy acids (10% glycolic acid lotions) are helpful, but the large body surface areas that must be treated and expense make these therapies prohibitive. Topical propylene glycol (10% to 50% in water) is a less expensive alternative. It is applied under occlusion if possible, and the saturated scales fall off in the next bath. Use of oral retinoids is associated with mixed results; sometimes blistering is increased while scale is decreased.The foul odor can be ameliorated by frequent, thorough bathing and use of antibacterial soap. Adding a capful of bleach or sufficient betadine to the bath water kills most bacteria. It is important to treat the secondary staphylococcal infections as well. The odor can be masked by applying a few drops of essential oils (eg, cloves or wintergreen) on clothing each day. Finally, air deodorizers (commercial or hospital type) can be purchased in small spray bottles and sprayed around the patient to neutralize the odor temporarily.EH is a lifelong condition. Life expectancy is normal. Chronic problems include blistering and odor. The foul odor makes life especially difficult for children during school years. The combination of odor and unusual skin increases the prevalence of psychological problems.Lamellar means arranged in multiple layers or plate-like. These are the most recognizable ichthyoses, with the skin appearing as it does in alligators. Old names include ichthyosis congenita and nonbullous congenital ichthyosiform erythroderma (Table 6). Congenital ichthyosiform erythroderma simply means “red scaly skin present at birth.” These two conditions have a certain overlap in phenotypes, and early literature often addresses them as one entity. Now that the gene defect is known, the term autosomal recessive primary ichthyosis has been applied to encompass both conditions. The incidence is believed to be approximately 1 per 100,000 to 300,000 live births. Males and females are affected equally, with no ethnic preponderance.LI (the severe phenotype) is due to mutations in the transglutaminase 1 gene. Tranglutaminases are a large group of enzymes that catalyze transamidation of glutamine residues. This is necessary in a variety of processes, including blood clotting, cytoplasmic destruction of the skin cells(apoptosis), formation of hair follicles, fertilization, and keratinization of skin. Transglutaminase controls the cross-linkage of the cell envelope precursor proteins. This matrix of insoluble proteins forms a dense, insoluble cell envelope called the“marginal band.” Keratin filaments are connected to the inside and impart rigidity to the cell. Transglutaminase mediates the attachment of these proteins to the inner part of the cell wall. At least three gene loci have been found for transglutaminase, which could account for the large variety of phenotypes seen in LI.CIE (the milder phenotype) is probably a defect of the lamellar granules in which the transglutaminase is packaged. These lamellar granules(Odland bodies) package enzymes and lipids that are excreted from within the keratinocytes into the intercellular space. The excreted lipids provide a barrier to water loss, and the enzymes mediate cell release from the upper layer. Steroid sulfatase, one such packaged enzyme, removes the lipids from the upper stratum corneum and allows the cells to desquamate (see the previous section on RXLI). In CIE, the lamellar granules are present but arranged irregularly. We infer from this that the packaged enzymes are not delivered to the right place at the right time. Indeed, recent have abnormal accumulation of transglutaminase 1 in skin. In addition, there is less enzyme between that seen with normal skin and that seen with who have are the most 5). They are with with and that to The scaling affects the entire cutaneous The scales are and tightly is by and that are out, causing corneal and problems. The red of the along the lower is distinctive, the a hair becomes down and are and can lead to can be and soles show In of the the skin is fissures the as the causing and superficial skin also with but when the underlying skin is red with fine The scale to be white and a (Fig. plate-like scales sometimes on the lower The of these plate-like scales is which for the in to between and and are not seen with is less and is not The is with less affected patients appearing may account for of out Careful will scaling, including in the is a clinical There is sometimes with and soles show but to a than with problems with and with fluid and electrolyte They are at for In addition, the the body to is a due to may be in and levels should be red children who have may protein and to of a markedly thickened stratum corneum but normal of only mild have in for transglutaminase 1 on skin such test is which can abnormal of transglutaminase in is useful in the or of the The is in many cases of but is present in to the skin is the of acids, and propylene glycol can be used. are needed several times because the has a surface area to of body of creams can cause systemic retinoids provide for They help the but do not the underlying genetic pathology. of use and of retinoids should be only by who are with their and of these conditions are with little but affects or the psychological of body are there is no that patients be of are several ichthyoses have been These include and further the in is the of the with transglutaminase 1 have been in the to severe have both clinical and in the only a few cell retinoids many of the problems associated with the ichthyoses, but systemic long in the and especially the 90% of (in widespread More are under mother who has to a who has severe ichthyosis to the for of is to the of the skin to obtain the is not The skin does not until in the and and skin biopsy have In addition, many ichthyoses normal in the water bath of the and the of life to the distinctive can be used if the gene defect is This can be early in the via is a very group for any patient who has ichthyosis or who is these patients. In addition, certain laboratory can be done them of for and to and for and on this
https://doi.org/10.1542/pir.20-1-5Pediatric Dermatology · 2012 · 11 citations
Superficial Epidermolytic Ichthyosis: A Report of Two Families
AbstractSuperficial epidermolytic ichthyosis (SEI), previously known as ichthyosis bullosa of Siemens, is a rare genetic skin condition, characterized by blisters and hyperkeratosis. It can be easily confused with epidermolytic hyperkeratosis, known now as epidermolytic ichthyosis, and genetic testing can be helpful in differentiating between the two conditions. We describe two children with SEI confirmed by genetic testing, including one with a novel mutation. We also describe other affected family members with SEI.
https://doi.org/10.1111/j.1525-1470.2012.01750.xDermatology Online Journal · 2015 · 2 citations · open access
Unilateral hyperkeratotic plaques along blaschko lines
AbstractEpidermolytic ichthyosis (or epidermolytic hyperkeratosis) classically presents with erythroderma and increased fragility (blistering) at birth or soon thereafter. In later life, erythroderma and blistering improve gradually and the clinical picture is dominated by hyperkeratotic plaques in flexures and around joints. Linear epidermolytic hyperkeratosis is a unique, uncommon clinical variant and the absence of erythroderma and blistering are its hallmark. Linear lesions may be localized or generalized andunilateral or bilateral. Herein we report a 6-year-old girl with unilateral epidermolytic ichthyosis.
https://doi.org/10.5070/d3217028137Acta Medica Philippina · 2021 · 1 citations · open access
Recalibrated Scales: The Use of Low-dose Isotretinoin in a Case of Epidermolytic Ichthyosis-NPS1 in a Filipino Child
AbstractEpidermolytic Ichthyosis (EI) is a rare non-syndromic keratinopathic ichthyosis without definitive treatment. This is a case of EI in a 5-year-old Filipino female who presented with hyperkeratotic scales sparing the palms and soles. Histopathology revealed epidermolytic hyperkeratosis. A trial of treatment with isotretinoin 0.3 mg/kg/day, together with keratolytic agents, urea lotion and lactic acid lotion, resulted in a marked decrease in the thickness of the scales and odor. Interestingly, rebound effects were noted at 0.6 mg/kg/day. Taking into account that EI presents with more skin fragility compared to non-EHK ichthyosis, the authors surmise that there may be a smaller treatment window for patients with EI, which is notably lower than recommended for ichthyosis in general.
https://doi.org/10.47895/amp.v55i5.2893Pediatrics in Review · 1999 · 0 citations
Ichthyosis in a Nutshell
AbstractAfter completing this article, readers should be able to: The ichthyoses are a heterogeneous group of diseases that share one presentation: scaly skin. Not too long ago, all patients who exhibited this characteristic were lumped into one group. In reality, there are differences ranging from localized to generalized scaling; spiny to flat scales; tiny to huge and plate-like scales; and blistering or redness beneath the scale. Careful observation,histopathology, genetics, and biochemistry allow ichthyoses to be categorized into several classes. The term “ichthyosis” comes from the Greek, meaning fish. To understand the ichthyoses, one must be familiar with the internal to external progression of normal skin.Ichthyoses represent abnormalities in the formation and desquamation of the keratinocytes, the most common epidermal cell. The epidermis is arranged in four layers: basal cell, squamous cell (or spiny), granular, and horny. As keratinocytes progress from the basal layer to the horny layer, different keratin proteins are manufactured. Keratins form a structural framework inside the cell that holds the shape similarly to steel girders inside a blimp. As skin tissue matures and moves outward, the keratin proteins are manufactured in a predictable sequence, but mutations can lead to keratins that have different size, shape, and assembly defects, which can affect the size and shape of the cell. At the basal layer, keratin types 5 and 14 are expressed, and as the cell moves up, keratins 1 and 10 are expressed in the spinous and granular layers. Depending on where the genetic error in keratin coding exists, the same skin can show very different phenotypes from epidermolysis bullosa to ichthyoses.Intercellular excretion of enzymes is necessary to release the bonds between cells, which allows sloughing of the top layer when appropriate. Errors in the manufacturing of these proteins, their packaging, and/or their release will cause cells to stick together far longer than normal. Basal cells form a layer of single columnar cells attached to each other by desmosomes and to the underlying dermal-epidermal junction and lamina densa via hemidesmosomes. The epidermal cells divide and move up layer by layer, taking 26 to 42 days to travel from the basal cell layer to the granular layer.Innumerable keratohyalin granules at the granular layer give it its name. This area marks the end of viable squamous cells. The cells flatten out, lose their nuclei, and abruptly keratinize. Lysosomal enzymes then are released, which are crucial for allowing the cells to desquamate. This is done via “membrane coating granules” (also known as Odland bodies or lamellar bodies), which are discharged from the granular cells into the intercellular space. These organelles excrete lipids that establish a barrier to water loss and mediate stratum corneum cell dissolution by excreting proteases. It takes an additional 14 days for the lowermost horny cells to reach the top of the epidermis.Defects in intercellular enzymes lead to diseases like X-linked ichthyosis or congenital ichthyosiform erythroderma. Defects in the cells themselves due to keratin defects (or the enzymes used to crosslink the keratins) can lead to diseases such as epidermolytic hyperkeratosis or lamellar ichthyosis.Ichthyosis vulgaris means common “fish-like” scaly skin. This common condition occurs in approximately 1:250 to 1:500 people. In many patients it appears only in dry climates. It is inherited in an autosomal dominant fashion; if both parents have very dry skin, the children are guaranteed to have dry and scaly skin.Standard skin biopsies of IV stained with hematoxylin and eosin(H&E) show little to no granular layer. On electron microscopy,decreased or tiny keratohyalin granules are seen. This correlates with reduced profilaggrin expression. Profilaggrin (the major protein of the keratohyalin granule) is broken down into filaggrin and is believed to serve as scaffolding along which the keratin filaments align. No gene defect for reduced profilaggrin expression has been found to date.IV is a clinical continuum, with common dry skin at the mild end and lizard-like scaling with erythema and itching at the severe end. Those who are mildly affected have dry skin, usually on the lower legs(Fig. 1, Table 1) and lower back, especially in dry climates or seasons. Children who have full-blown IV have fine white scales from neck to ankles, sparing the folds (where the humidity is higher) and the face (where the sebaceous glands help control the scaling). The scales are similar to small bran flakes, especially on the lower back. On the lower legs, the scaling can have a lizard-like appearance, although it is less than that seen in lamellar ichthyosis. The palms often are dry and show multiple additional lines, referred to as “hyperlinear palms.” The hair, teeth, and nails are normal.IV frequently is seen in association with atopic dermatitis. There are no systemic or laboratory abnormalities. Keratosis pilaris often accompanies IV and can be seen on the sides of the lower cheeks, neck,dorsum of the upper arms, buttocks, and anterior thighs. These are small, pointed, flesh-colored to red, perifollicular papules.As with other genetic diseases, IV can be controlled but not cured. The initial step is to hydrate the stratum corneum and seal in the moisture, then reapply the moisturizing grease as often as necessary to control the condition (Table 2) Simple soaking in warm water followed quickly by application of a thick, greasy moisturizing cream or ointment is sufficient for most patients. Soaking twice a day is preferable, as long as sufficient moisturing cream or ointment is applied immediately after the bath.Moisturizers that are available in jars and are scooped out with the fingers work best, including petroleum jelly and even vegetable shortening. More elegant solutions include mild keratolytic agents(salicylic acid), alpha hydroxy acids, or propylene glycol. Keratolytics help loosen the upper layer of scales and promote shedding. Alpha hydroxy acids (lactic, citric, glycolic) are simple,organic, hydroscopic acids that both hydrate the skin and cause the skin cells to detach. Ammonium lactate holds many times its weight in water and works well for dry, scaly skin. It is important to note that alpha hydroxy acids sting and that most children do not tolerate them. When applied to the entire cutaneous surface, any “acid”preparation can cause acidosis in neonates and, therefore, should not be used. Propylene glycol (40% to 60% in water) works as a hydroscopic agent. Urea creams (10% to 20%) act as humectants,producing a more pliable stratum corneum.There are many myths regarding the treatment of dry skin(Table 3) Warm, moist climates do help, as does humidifying the home. If children live in a geographic area in which there are four distinct seasons, the condition will improve during the summer. With sufficient humidity year round, IV may occur only when visiting dry climates.This uncommon form of ichthyosis affects 1:2,000 to 1:6,000 males. It is reported worldwide and has no ethnic or racial predominance. The patient’s mother is an obligate heterozygote.RXLI is due to a deficiency of the enzyme steroid sulfatase, which is carried on the X chromosome. About 90% of the cases are due to steroid sulfatase gene deletions, with about one third of the cases being “contiguous gene syndrome” deletions.Desquamation or a pronounced peeling is seen within a few weeks or months of birth. This is followed by persistent, dark brown scaling on the arms, legs, trunk, and especially the sides of the neck (Fig. 2Table 4) The scales are tightly adherent to the underlying skin. A mother often will exclaim, “I can’t get his neck clean.” The scales are noted on the extensor surface of the arms and encroach on the flexural sides much more than with IV. The central face is spared, but scaling can be seen around the ears and lateral cheeks. The classic areas of involvement are the lower abdomen (belt buckle area) and the sides of the neck. Marked seasonal variation is seen. Palms, soles, hair, nails, teeth,and mucosa are not involved.Placental sulfatase is needed for labor to progress. Some mothers report prolonged labor or failure to initiate labor when carrying these patients.Cryptorchidism is noted in as many as 25% of patients (see section on contiguous gene syndrome that follows). About 50% of adults who have RXLI exhibit asymptomatic punctate corneal opacities. This is also seen in carrier mothers, but not reliably enough to use as a screening test.The decrease in steroid sulfatase can be measured via three primary methods: 1) enzyme assays, 2) cholesterol sulfate accumulation in various tissues, and 3) fluorescent in situ hybridization (FISH)test. The blood test for excess cholesterol sulfate is the most reliable method for affected males. If the gene deletion is known, then the FISH test is useful for prenatal diagnosis. The original finding of fast migrating beta-low-density lipoprotein on lipoprotein electrophoresis is a difficult test to obtain and has been replaced by newer technologies. Contact the support group “FIRST” (see section on support groups) for test sites and availabilities.The phenomenon of different syndromes caused by deletions along the same gene at slightly different neighboring sites is called the contiguous gene syndrome. RXLI, chondrodysplasia punctata(Conradi-Hünermann syndrome), and Kallmann syndrome are linked by propinquity on the X chromosome. They share overlapping symptoms that include ichthyotic scaling, stippling of the long bones on radiography, anosmia, and cryptorchidism.Patients in whom RXLI is suspected should have cholesterol sulfate levels measured. They also should be evaluated for sense of smell and descended testes. The scale can be treated as noted previously for IV. Genetic counseling should be offered.RXLI is a lifelong condition that changes little with age. Seasonal variations can be expected. It is not debilitating and should not affect normal life activities adversely.EH used to be known as bullous congenital ichthyosiform erythroderma. It is caused by an error in keratin synthesis and is labeled more appropriately as a keratinopathy. The incidence is rare,probably 1:300,000. It affects all races and both genders and is autosomal dominant.EH is due to an error in synthesis of keratins 1 and 10, which are found in the upper spinous to granular layer. The phenotypes differ slightly depending on the defect, with keratin 1 defects causing palm and sole bullae. The intraepidermal blistering seen in EH is due to abnormal keratin filament formation that leads to an abnormal cytoskeleton, resulting in mechanical fragility. In addition, the desmosomal attachments are imperfect, which leads to blister formation.Newborns present with red, scaly lesions and widespread areas of denuded skin. The blisters are superficial (in the upper epidermis)and, therefore, do not scar. Neonatal hyperkeratosis may be present, but it can be subtle. After the neonatal period, the blistering lessens (but does not disappear), and the hyperkeratosis becomes more obvious. The scale in EH is a distinctive porcupine-like quill (albeit short) that involves the entire body (Figs. 3 and 4, Table 5). It especially involves all the flexures, face, and scalp, causing formation of furrowed ridges of spiny skin. The palms and soles become thick, as if covered by wax.After the newborn period, bullae form underneath the quills. These often become purulent and secondarily infected, and then the epidermis sloughs. The exposed underlying skin is red and looks relatively normal temporarily until the quills regrow. The fissures between the quills harbor aerobic and anaerobic bacteria; this plus any infected bullae produce an extremely foul odor. The foul odor is the most distressing part of this disease and the most difficult aspect to control.Sweating can be decreased in those who have EH because of blocked sweat ducts, which can lead to heat intolerance in hot climates. Staphylococcal infection in the bullae can become systemic.The biopsy of EH is very distinctive, showing a thickened epidermis with areas of cellular “clear spaces” and breakdown. Hence, the term epidermolytic hyperkeratosis, which is simply a description of the pathology. There is a markedly thickened granular layer, with irregular kerato-hyalin granules corresponding to the desmosomal problems mentioned previously. The bullae arise within the epidermis due to separation and breakdown of the edematous cells.Newborns who exhibit bullae can have problems with fluid and electrolyte imbalances as well as with sepsis. Careful handling is necessary to prevent further blistering.Beyond the neonatal period, hyperkeratosis and foul odor are the two primary problems. Simple soaking in water, scrubbing, and after-bath greasing can soften and remove many quills. Topical retinoic acids and/or alpha-hydroxy acids (10% glycolic acid lotions) are helpful, but the large body surface areas that must be treated and expense make these therapies prohibitive. Topical propylene glycol (10% to 50% in water) is a less expensive alternative. It is applied under occlusion if possible, and the saturated scales fall off in the next bath. Use of oral retinoids is associated with mixed results; sometimes blistering is increased while scale is decreased.The foul odor can be ameliorated by frequent, thorough bathing and use of antibacterial soap. Adding a capful of bleach or sufficient betadine to the bath water kills most bacteria. It is important to treat the secondary staphylococcal infections as well. The odor can be masked by applying a few drops of essential oils (eg, cloves or wintergreen) on clothing each day. Finally, air deodorizers (commercial or hospital type) can be purchased in small spray bottles and sprayed around the patient to neutralize the odor temporarily.EH is a lifelong condition. Life expectancy is normal. Chronic problems include blistering and odor. The foul odor makes life especially difficult for children during school years. The combination of odor and unusual skin increases the prevalence of psychological problems.Lamellar means arranged in multiple layers or plate-like. These are the most recognizable ichthyoses, with the skin appearing as it does in alligators. Old names include ichthyosis congenita and nonbullous congenital ichthyosiform erythroderma (Table 6). Congenital ichthyosiform erythroderma simply means “red scaly skin present at birth.” These two conditions have a certain overlap in phenotypes, and early literature often addresses them as one entity. Now that the gene defect is known, the term autosomal recessive primary ichthyosis has been applied to encompass both conditions. The incidence is believed to be approximately 1 per 100,000 to 300,000 live births. Males and females are affected equally, with no ethnic preponderance.LI (the severe phenotype) is due to mutations in the transglutaminase 1 gene. Tranglutaminases are a large group of enzymes that catalyze transamidation of glutamine residues. This is necessary in a variety of processes, including blood clotting, cytoplasmic destruction of the skin cells(apoptosis), formation of hair follicles, fertilization, and keratinization of skin. Transglutaminase controls the cross-linkage of the cell envelope precursor proteins. This matrix of insoluble proteins forms a dense, insoluble cell envelope called the“marginal band.” Keratin filaments are connected to the inside and impart rigidity to the cell. Transglutaminase mediates the attachment of these proteins to the inner part of the cell wall. At least three gene loci have been found for transglutaminase, which could account for the large variety of phenotypes seen in LI.CIE (the milder phenotype) is probably a defect of the lamellar granules in which the transglutaminase is packaged. These lamellar granules(Odland bodies) package enzymes and lipids that are excreted from within the keratinocytes into the intercellular space. The excreted lipids provide a barrier to water loss, and the enzymes mediate cell release from the upper layer. Steroid sulfatase, one such packaged enzyme, removes the lipids from the upper stratum corneum and allows the cells to desquamate (see the previous section on RXLI). In CIE, the lamellar granules are present but arranged irregularly. We infer from this that the packaged enzymes are not delivered to the right place at the right time. Indeed, recent have abnormal accumulation of transglutaminase 1 in skin. In addition, there is less enzyme between that seen with normal skin and that seen with who have are the most 5). They are with with and that to The scaling affects the entire cutaneous The scales are and tightly is by and that are out, causing corneal and problems. The red of the along the lower is distinctive, the a hair becomes down and are and can lead to can be and soles show In of the the skin is fissures the as the causing and superficial skin also with but when the underlying skin is red with fine The scale to be white and a (Fig. plate-like scales sometimes on the lower The of these plate-like scales is which for the in to between and and are not seen with is less and is not The is with less affected patients appearing may account for of out Careful will scaling, including in the is a clinical There is sometimes with and soles show but to a than with problems with and with fluid and electrolyte They are at for In addition, the the body to is a due to may be in and levels should be red children who have may protein and to of a markedly thickened stratum corneum but normal of only mild have in for transglutaminase 1 on skin such test is which can abnormal of transglutaminase in is useful in the or of the The is in many cases of but is present in to the skin is the of acids, and propylene glycol can be used. are needed several times because the has a surface area to of body of creams can cause systemic retinoids provide for They help the but do not the underlying genetic pathology. of use and of retinoids should be only by who are with their and of these conditions are with little but affects or the psychological of body are there is no that patients be of are several ichthyoses have been These include and further the in is the of the with transglutaminase 1 have been in the to severe have both clinical and in the only a few cell retinoids many of the problems associated with the ichthyoses, but systemic long in the and especially the 90% of (in widespread More are under mother who has to a who has severe ichthyosis to the for of is to the of the skin to obtain the is not The skin does not until in the and and skin biopsy have In addition, many ichthyoses normal in the water bath of the and the of life to the distinctive can be used if the gene defect is This can be early in the via is a very group for any patient who has ichthyosis or who is these patients. In addition, certain laboratory can be done them of for and to and for and on this
https://doi.org/10.1542/pir.20.1.5Nepal Journal of Dermatology Venereology & Leprology · 2025 · 0 citations · open access
Superficial Epidermolytic Ichthyosis: Clinical and Histopathological Features in Two Siblings
AbstractSuperficial epidermolytic ichthyosis (SEI), a type of keratinopathic ichthyosis (KPI) caused by mutations in the K2e gene, is clinically characterized by superficial blistering, hyperkeratosis predominantly involving flexures and joints, Mauserung phenomenon and epidermolytic hyperkeratosis (EHK) on ultrastructural studies. Though it has been known to mankind for ages, very few families afflicted with this disease are described in the literature and its exact prevalence in the Indian population is yet undetermined. Through this case report, we wanted to highlight its various peculiar manifestations and reiterate the importance of meticulous clinical evaluation and clinicopathological correlation, especially in resource-limited settings, for effective patient management.
https://doi.org/10.3126/njdvl.v23i1.69921Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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