Ichthyosis is a skin disease characterized by abnormalities in keratinocyte differentiation and epidermal barrier function, and is characterized clinically by scaly skin all over the body. It can be divided into acquired ichthyosis and hereditary ichthyosis, among which hereditary ichthyosis is more common, with various modes of inheritance, including autosomal dominant, autosomal recessive and X chromosome – chain inheritance.
[Etiology].
According to the cause, ichthyosis can be divided into two categories: hereditary and acquired. Hereditary ichthyosis is usually caused by mutations in genes related to keratinocyte differentiation and epidermal barrier function. Acquired ichthyosis has a complex and diverse etiology, and any factor that affects the activity of key metabolic enzymes in the formation and breakdown of the stratum corneum may lead to the development of acquired ichthyosis, especially factors that affect the synthesis and metabolic processes of filoproteins, the most common of which are systemic malignancies, especially Hodgkin’s disease. Certain autoimmune diseases, HIV infection, nutritional deficiencies, and some drugs that affect cholesterol metabolism can also trigger acquired ichthyosis.
I. Common type ichthyosis
The most common keratotic disease. The prevalence is 1/250 and is inherited in a semidominant manner. The disease shows incomplete epistasis in heterozygous patients and exhibits different phenotypes within and between family lines.
[Pathogenesis].
During the terminal differentiation of keratin-forming cells, filoproteinogen (the main protein of keratin hyaline granules) is broken down into filoprotein polypeptides that can aggregate keratin intermediate filaments, and filoproteinogen and keratin intermediate filaments are cross-linked to the keratinocyte envelope to form an epidermal barrier. In common ichthyosis, the keratinization process is abnormal due to the reduction or deletion of filoproteins caused by genetic mutations. The increased adhesion to the stratum corneum and the formation of scales are thought to be caused by the lack of water-retaining amino acids, the metabolite of filoprotein breakdown.
Clinical manifestations
Dryness and mild to moderate flaking of the skin often appear a few months after birth. Late onset ichthyosis vulgaris may also be seen in young children, with no lesions due to moist groin and flexural areas. The disease mostly affects the extensor aspect of the lower leg, with large scales that are fixed centrally and raised peripherally. Deepening of the skin lines is common. In severe cases, the scales may spread to the trunk, scalp, forehead and cheeks and may be accompanied by pruritus. In addition, palmoplantar involvement is more pronounced, often leading to deepening of the heel furrow or painful cracking. Clinical symptoms and severity are seasonal and climate-dependent, decreasing in summer and with increased humidity and worsening in dry and cold environments. Although ichthyosis vulgaris progresses gradually during childhood, it usually improves with age.
Common ichthyosis is often accompanied by peri-hair keratosis and the atopic triad (asthma, cushings fever and atopic dermatitis). 20% to 50% of patients with ichthyosis have atopic dermatitis, which can mask the absence of lesions on the flexural side of the body in ichthyosis.
[Differential diagnosis].
The line between dry skin and mild ichthyosis vulgaris is blurred, and differentiation is based on subjective experience. In men with ichthyosis, X-linked ichthyosis is usually larger and darker in scale, with involvement of the neck and other flexural areas, a history of delayed or delayed delivery in the mother, cryptorchidism and X-linked genetic features, which can be distinguished from common ichthyosis. Biochemical, cytogenetic (fluorescence in situ hybridization) or molecular biology tests can exclude steroid sulfate enzyme deficiency. Acquired ichthyosis with late onset of malnutrition, infectious disease (e.g., leprosy), tumor (e.g., lymphoma), or inflammatory disease (e.g., sarcoidosis) is easily differentiated. Atopic dermatitis can develop alone.
[Treatment].
The aim of treatment is to reduce scaling through the continuous application of emollients and keratin softeners, and there is evidence that lipid cream treatment containing ceramide is effective. Agents containing urea and keratolytic agents such as alpha-hydroxy acids, lactic acid and salicylic acid are effective, and care must be taken to prevent salicylic acid toxicity. Topical application of retinoic acid is effective, but can cause skin irritation. Vitamin D-based drugs are not effective. Systemic use of Avitamin or Isotretinoin has therapeutic effect, but side effects are more pronounced. Moisturizing cleansers and moisturizers help in treatment.
II. X-linked ichthyosis
The worldwide incidence rate of males is 1/2000 to 1/9500, inherited from female carrier to the next generation, with X-linked inheritance pattern, only males develop.
[Pathogenesis].
In 90% of affected patients, the steroid sulfate esterase (STS) gene located on chromosome Xp22.31 is completely absent, resulting in diminished or complete absence of steroid sulfate esterase activity, and 10% of patients are caused by inactivating mutations in this gene. The abnormal hydrolysis of steroid sulfate esterase and dehydroepiandrosterone sulfate, followed by the accumulation of 3-sulfate cholesterol in the epidermis. elevated 3-sulfate cholesterol can inhibit transglutaminase-1, which could explain the partial overlap of clinical symptoms with lamellar ichthyosis. However, the exact pathological mechanism of this disease is still poorly understood.
Clinical manifestations]
In 90% of affected male patients, X-linked ichthyosis appears in the first week of life with mild erythroderma and generalized scaling or shedding of large transparent scales. The large, polygonal, dark brown scales that typically adhere to the skin appear in late infancy and are symmetrically distributed over the extremities, trunk, and neck. Sometimes the lower extremities are more scaly and light gray or white in color. The flexors of the body may or may not be involved, but the neck is almost always involved. Thin scales of the scalp are seen in young children and decrease as they grow. The palmoplantar and facial areas are not characteristically involved, except for the preauricular area. It tends to improve in summer, but unlike common ichthyosis, it does not diminish with age.
Asymptomatic corneal clouding may occur in 10% to 50% of male patients and some female carriers, and other visual abnormalities are relatively rare, such as green color blindness. The incidence of cryptorchidism increases 20-fold in affected male patients, independent of the development being poorly descended testes, with an increased risk of developing testicular cancer and hypogonadism. Other concomitant symptoms such as epileptiform seizures, reactive psychological disorders, pyloric hypertrophy, congenital defects of the abdominal wall and acute lymphoblastic leukemia are rarer. Although steroid sulfate esterase activity is reduced by 85% in female carriers, the remaining activity appears to be sufficient to prevent the appearance of skin lesions.
[Diagnosis].
Laboratory tests for steroid sulfate esterase deficiency or STS gene deletion can rule out other types of ichthyosis. Clinically, common ichthyosis with no involvement of the flexural side of the body and neck, often with increased palmoplantar dermatoglyphic lines and peripapillary keratosis, can be differentiated from X-linked ichthyosis. In male patients with continuous Xp microdeletion syndrome, X-linked recessive punctate chondrodysplasia or hypogonadotropic hypogonadism syndrome with loss of smell (Kallmann syndrome) has a similar clinical presentation to X-linked ichthyosis. Ichthyosis with hypogonadism (ichthyosis-like erythrodermic dwarf syndrome, Rud’s syndrome) may not be an independent disease, but may be caused by submicroscopic deletions of the terminal mitoses of the short arm of the X chromosome. Differential diagnosis with the above diseases, karyotype analysis, fluorescence in situ hybridization or microdot analysis is necessary to detect X/Y chromosome translocations and X chromosome deletions in patients.
[Treatment].
Emollients (especially propylene glycol), topical keratolytics and retinoids are effective alone or in combination, while vitamin D drugs are unsatisfactory and can cause skin irritation. Systematic application of retinoids is usually not necessary.
Laminar ichthyosis
The incidence is worldwide and is estimated to be between 1/200,000 and 1/300,000 in live newborns, although it may be more prevalent in some regions such as Norway (1/91,000) or in consanguineous groups. The disease is usually genetically heterogeneous and shows autosomal recessive inheritance in most families, and occasionally autosomal dominant inheritance is found.
Pathogenesis]
Most patients with LI are caused by mutations in both heterozygous TGM1 genes, resulting in a defect in transglutaminase-1. Transglutaminase-1 catalyzes calcium-dependent protein cross-linking by forming NE(glutamyl)lysine heteropeptide, and this enzyme is distributed in the upper differentiated layer of the epidermis, which induces a large number of structural proteins to cross-link with each other to form non-water-soluble protein envelopes and also facilitates the formation of lipid molecular membranes. Therefore, the pathological mutation of TGM1 gene severely disrupts the complex process of keratinization and exfoliation. The currently reported mutations in ABCA12 are all distributed in five exons (28-32) that encode the first nucleotide-binding region in the ABC transporters of lamellar vesicles, a site that plays an important role in the energy-dependent transmembrane transport of lipid substrates. the CYP4F22 gene encodes a cytochrome P450 enzyme that functions in the lipoxygenase pathway, and it was recently found that mutations in this gene have been associated with an LI phenotype accompanied by increased palpebral lines. The etiology of nearly half of the patients with LI is still unknown.
Clinical presentation
Patients present with severe symptoms that are apparent at birth and persist throughout their lives. Most of the children are born wrapped in a fire wool gelatinous membrane with occult erythroderma. The typical skin lesions of LI are characterized by large, gray, discoid scales that are mosaic or dendritic in appearance, with or without mild erythrodermic manifestations. The scales are centrally attached with free edges, thus predisposing the skin surface to chapping. Swimsuit ichthyosis is a specific phenotype of lamellar ichthyosis (caused by a specific mutation in the TGM1 gene), which is characterized by involvement of the trunk and scalp only, with tension pulling on the facial skin often leading to lid ectropion, lip ectropion, and nasal and auricular cartilage dysplasia. Severe lid ectropion can also lead to eyelash loss, conjunctivitis, and incomplete eyelid closure secondary to keratoconjunctivitis. Tension and compression of the skin can also lead to scarring baldness, most severely in the peripheral areas of the scalp. The hair shaft is normal but often surrounded by a thickened keratin layer. The severity of palmoplantar keratosis varies, ranging from aggravation of the palmoplantar skin texture to severe keratinous thickening with fissures and cracking. Secondary nail dystrophy due to nail plate thickening and longitudinal nail ridges due to inflammation of the nail folds are not uncommon. Constriction of the sweat ducts in the epidermis can cause severe heat intolerance, and the accumulation of scales can also lead to occlusion of the external ear canal, harboring bacteria and recurrent ear infections.
Differential diagnosis
In the neonatal period, there is considerable clinical overlap with other congenital ichthyosis phenotypes with pyroglossal membranes, especially CIE, self-healing pyroglossal-like children and Sjö;gren-Larsson syndrome. As the disease progresses, LI exhibits characteristic large gray discoid scales, lid ectropion and indistinguishable erythroderma, so it is easy to differentiate from other ichthyosis.
Treatment
Children with severe disease often need to be treated systematically with retinoids from early childhood. It can effectively reduce hyperkeratosis and scaling. Treatment usually starts with a small dose and is gradually adjusted to the lowest effective dose depending on the course of the disease and the severity of the disease. Treatment may also help to improve ectropion, thereby avoiding ocular complications and eyelid surgical reconstruction. However, the potential toxic effects of retinoids must be weighed against the long-term use of systemic therapy. In cases where topical treatment is required in the presence of severe desquamation and impairment of skin barrier function, keratolytic agents are usually contraindicated because of their skin irritation and increased risk of systemic absorption, especially in children. Topical application of vitamin D3 derivatives and tazarotene, as well as creams containing lactic acid and propylene glycol in the base, have been shown to be effective. For heat intolerance poor palliative therapy is often used for relief, such as frequent use of water or application of air conditioning and humidifiers to keep the skin moist.
IV. Herpetic congenital ichthyosis vulgaris-like erythroderma
The prevalence of this disease is estimated to be 1/300,000~1/200,000 worldwide, and it is an autosomal dominant disease with equal probability for men and women. About 50% of the cases are disseminated, suggesting de novo mutations.
Pathogenesis
BCIE is caused by heterozygous mutations in the genes encoding keratin 1 (KRT1) and keratin (KRT10) located on chromosomes 12q13.3 and 17q21.2, respectively. These keratins are expressed in the granular and upper basal layers of the epidermis, the site of pathogenesis. kRT1 mutations are usually associated with severe palmoplantar keratosis, whereas with kRT10 mutations, the palmoplantar is not involved, as the kRT10 gene is not expressed in the palmoplantar region. Most of the mutations are non-conservative amino acid substitution mutations that accumulate at the border of the α-helical rod region and can affect keratin alignment, oligomerization and keratin filament assembly, therefore weakening the cytoskeleton and compromising the mechanical strength and cellular integrity of the epidermis, causing cell lysis and blistering. Hypertrophy and hyperkeratosis of the epidermal spine layer may be caused by hyperproliferation, decreased desquamation and other factors. The barrier function of the skin is significantly disrupted, causing increased transepidermal water loss and colonization of the stratum corneum by bacterial bacteria. Mutations on the outer side of the spiral border are rare and have a mild clinical presentation.
[Clinical manifestations].
Erythroderma, vesicles, desquamation and large skin peeling are present at birth. Skin hyperkeratosis can also appear at birth, or in infancy, with age, skin fragility, blistering and erythroderma diminish or decrease, and skin hyperkeratosis is already present. The clinical presentation varies widely between patients and between families and includes at least six known clinical phenotypes with or without palmoplantar involvement. For example, in NPS types 1-3, bulging along the dermatome on the flexor side of the body and hyperkeratosis forming a cobblestone-like appearance on the extensor side of the joint are commonly seen. The clinical phenotype and course of the disease are relatively consistent within members of the family.
Cyclic ichthyosis with epidermolysis bullosa and cyclic epidermolysis bullosa are rare types of BCIE, caused by mutations in the KRT1 and KRT10 genes, respectively. The course of BCIE is long, with perinatal morbidity and mortality in affected neonates associated with sepsis and disturbed water-electrolyte balance, and chronic pain from blistering and secondary infections. Patients often present with large epidermal peels and basal flushing with a distinctive foul odor, occasionally causing postural and gait abnormalities. Other concomitant symptoms include keratoconjunctivitis and scalp involvement, which leads to encrustation of the hair shaft and hair loss.
Differential diagnosis
BCIE with macules, vesicles and localized skin defects appearing in the neonatal period can be distinguished from non-maurotic congenital ichthyosis. Clinically, it should be distinguished from all types of herpetic epidermolysis bullosa, staphylococcal scald-like skin syndrome and toxic epidermolysis bullosa. The identification requires observation of skin biopsy tissue from fresh blister margins using light and electron microscopy, in addition to bacterial culture. BCIE with macules, vesicles and localized skin defects presenting in the neonatal period can be distinguished from non-maurotic congenital ichthyosis. Clinically, it has to be differentiated from all types of herpetic epidermolysis bullosa, staphylococcal scald-like skin syndrome and toxic epidermolysis bullosa. It needs to be identified by observation of skin biopsy tissue from fresh blister margins with light microscope and electron microscope, in addition to bacterial culture.
Treatment]
The main treatment is symptomatic. In the neonatal phase, the patient should be isolated and protected against dehydration, electrolyte disturbances, and multiple epidermal infections. The presence of sepsis must be treated with broad-spectrum antibiotics. Careful handling of the neonate and the use of pads and emollient oils will allow skin erosions and defects to heal as quickly as possible. In children and adults, treatment is aimed at reducing hyperkeratosis formation, removing scabs and softening the skin. Keratolytic creams and lotions containing urea, salicylic acid and alpha-strength acids are effective and are usually not easily tolerated by patients, especially children, due to the burning and stinging sensation of the medications. Large topical applications of highly concentrated salicylic acid preparations should be avoided to prevent systemic salicylic acid toxicity. Topical topical retinoic acid and vitamin D preparations are effective, but can cause skin irritation. Frequent use of emollients and skin soothing and a combination of water and action on keratinized skin (e.g., mucoid soaking) and mechanical rubbing (e.g., gentle scrubbing with a soft brush, sponge, etc.) will be effective. Bacterial skin infections are common and can cause macules, which require topical or systemic antibiotic treatment. The use of antiseptics such as antibacterial soap or chlorhexidine can help control bacterial colonization. Continuous prophylactic treatment (oral or topical antibiotics) should be avoided because antibiotic resistance can occur. It is also important to prevent mechanical injury, which may make the skin more brittle (e.g., by wearing soft clothing and shoes). Synthetic oral retinoids can completely reduce the frequency of hyperkeratosis and pancytopenia BCIE infections, but also increase the fragility of the epidermis and the frequency of blistering. Therefore, it is recommended to start with a low initial dose and gradually increase the dose and monitor it carefully until the minimum maintenance dose is determined.
Congenital ichthyosiform erythrodermatitis
Congenital ichthyosis erythrodermicus (CIE) is more common than lamellar ichthyosis, and its incidence is about 1/200000. in the majority of families, CIE shows autosomal recessive inheritance characteristics, and occasionally it is reported to be autosomal dominant.
Clinical manifestations
Patients with CIE are usually born with pyogranulomatous membranes and then develop generalized erythroderma and persistent desquamation, with lifelong, mildly variable symptoms. In severe cases, CIE is typically characterized by severe, extensive erythrodermic symptoms with diffuse white, powdery, fine scales, which may be accompanied by ectropion and scarring alopecia. Larger, darker discoid scales may be present on the extensor side of the lower extremities.
Patients with CIE often have severe diffuse chapped palmoplantar keratosis, while the rest of the body presents with fine, clear scales. Patients with milder forms present with only milder erythroderma, but still have generalized scaling and varying degrees of palmoplantar involvement. Obstruction of sweat ducts and sweat holes can lead to hypersweating and heat intolerance, and secondary nail dystrophy and onychomycosis are also common in patients. Although most patients with CIE have normal growth and development, severe exfoliative erythroderma may cause high impact metabolic stress and chronic dysplasia in children during the growth period.
Differential diagnosis
Netherton’s syndrome is similar to this disease, with histopathological psoriasis-like changes, but Netherton’s syndrome is similar to this lesion, with psoriasis-like histopathology, but is often combined with marked developmental arrest, recurrent skin or systemic infections, self-induced pruritus, markedly elevated plasma IgE levels, and hair stem abnormalities. Congenital ichthyosis vulgaris-like ichthyosis has specific clinical and histologic features, including multiple vesicles with a flexural focus at birth, recurrent blistering and no lid ectropion. In common ichthyosis, the lesions are more limited and the flexors are generally not involved and the face does not show tightness.
Treatment
We can refer to the treatment plan of lamellar ichthyosis, and pay special attention to replenishing sufficient fluids and calories for erythrodermic patients, and intake iron and protein to replace the substances lost through the skin. Systematic treatment with oral retinoids can reduce flaking, but has little effect on the control of erythroderma.
[Prevention].
Given that there is a certain chance that the above hereditary ichthyosis will be passed on to the next generation, it is important to conduct genetic diagnosis to identify the mutation loci of the patient. In addition, prenatal diagnosis of pregnant women with known pathogenic loci can clarify whether the fetus carries the pathogenic mutation, thus helping to reduce the prevalence of the disease and guiding eugenic reproduction.