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Ichthyosis Vulgaris

Ichthyosis Hystrix Gravior

Ichthyosis vulgaris or hereditary ichthyosis vulgaris is a genetic disorder, characterized by the presence of dry, scaly skin on the arms and legs. This is a separate disease entity from the non-heritable condition called acquired ichthyosis vulgaris, which has a different etiology.    


Presentation

History

Hereditary ichthyosis
The skin appears normal at birth, but scaling occurs in the first few years. Only the arms and legs are affected, and none in the diaper area. Scales may likewise be found on the forehead and cheeks which disappear later. Symptoms usually improve in summer. Information on family history is not consistent due to heterogeneity and alleviation of symptoms with time.

Atopy (asthma, eczema, hay fever) accompanies hereditary ichthyosis in many patients. Some family members may experience atopic conditions, with or without symptoms of ichthyosis vulgaris. Atopic manifestations have been documented in 50% of patients in one study, 41% among them with at least one affected relative.

Acquired ichthyosis
Acquired ichthyosis has the same clinical manifestations as hereditary ichthyosis but affects adults with a different etiology. The symptoms of ichthyosis may precede or follow the onset of the underlying systemic disease with which it is associated. It follows that the severity of acquired ichthyosis will vary with the clinical course of the co-existing condition.

Conditions that are associated with acquired ichthyosis include: thyroid disease, leprosy, chronic renal failure, HIV infection, cancer (especially lymphoma), sarcoidosis, primary cutaneous CD30+ lymphoproliferative disorders, other neoplasms including osseous hemangiopericytoma, hyperparathyroidism, nutritional disorders, and bone marrow transplantation. Autoimmune diseases are also involved, such as dermatomyositis and systemic lupus erythematosus. Systemic sclerosis and SLE was reportedly in a patient.

Cancers are also linked with acquired ichthyosis. These include: leiomyosarcoma, Kaposi's sarcoma, myeloma, Hodgkin disease, non-Hodgkin lymphoma (including mycosis fungoides), and carcinomas of the lung, breast, ovary, and cervix.

Medications that predispose to acquired ichthyosis include: cimetidine, dixyrazine, triparanol, nicotinic acid, butyrophenones, and clofazimine.

Bathing suit ichthyosis or congenital ichthyosis, due to an autosomal recessive gene, is characterized by the presence of scaly skin on the bathing suit areas but not on the extremities and the face. Bathing suit ichthyosis phenotype is temperature dependent and is caused by transglutaminase-1 deficiency.

Physical characteristics

Both hereditary ichthyosis vulgaris and acquired ichthyosis are characterized by the presence of symmetrical scaly skin which may be slightly rough and dry in texture or may appear as thick, hard scabs. Scales are small, polygonal, curled at the edges, flaky, white to dirty gray to brown, and measuring 1 mm-1 cm in diameter. Scales vary in appearance from different locations, in the same individual. Most scales are in the extensor surface of the extremities, markedly delimited from surrounding areas.

Scaling occurs on the lower extremities more than the upper extremities and scales on the shins are more prominent, arranged in a mosaic fashion, and resembling "lizard skin" during winter time. Scales are found more in the back than the abdomen. The face is rarely affected possibly due to increased sebaceous secretions. Scales may appear on the cheeks and forehead in hereditary ichthyosis in the young child.

The scalp is uniformly affected by dry scaling but not the flexural folds (e.g., neck, axillae, antecubital and popliteal fossae) because of the warmth and moisture in these areas. Hereditary ichthyosis vulgaris generally improves during warm weather conditions.

Hyperkeratosis often appears on the hands and feet looking dirty. Fissures may be present which are painful and prone to infection especially in summer.

Keratosis pilaris (follicular hyperkeratosis) is found on the cheek and neck, the upper arms, buttocks, and thighs, with or without inflammation. The condition consists of spiny protruberances that are cushiony to touch. Dried skin at the core is whitish and resembles pus. Keratosis pilaris may be found in family members with a history of hereditary ichthyosis vulgaris. Correlation with the absence of sebaceous glands is being considered as an early stage in the pathogenesis of keratosis pilaris. Dry skin is itchy causing the patient to scratch and leading to erythema of the affected area.

Dental Caries
  • Herein we reported a case of pycnodysostosis, showing short stature with widening of the sutures, unfused anterior and posterior fontanelles, crowding of teeth with dental caries and typical radiological features associated with ichthyosis vulgaris and[ncbi.nlm.nih.gov]
Unilateral Epiphora
  • Papillomas of the lacrimal canaliculus are very rare tumors and, when encountered in clinical practice, usually present with unilateral epiphora due to obstruction of the lacrimal drainage system.[ncbi.nlm.nih.gov]
Skin Thickening
  • Symptoms may include any of the following: Dry skin, severe Scaly skin ( scales ) Possible skin thickening Mild itching of the skin The dry, scaly skin is usually most severe on the legs.[nlm.nih.gov]
  • Symptoms Dry skin, severe Scaly skin ( scales ) Possible skin thickening Mild itching of the skin The dry, scaly skin is usually most severe on the legs. But it can also involve the arms, hands, and middle of the body.[nicklauschildrens.org]
  • Symptoms Symptoms may include any of the following: Dry skin, severe Scaly skin ( scales ) Possible skin thickening Mild itching of the skin The dry, scaly skin is usually most severe on the legs.[account.allinahealth.org]
Withdrawn
  • Three patients were withdrawn prematurely because of itching and burning sensation after DC application (1 patient) or URx application (2 patients).[ncbi.nlm.nih.gov]
  • , Trial Phase, Sponsor Type and End point status The report reviews top companies involved and enlists all trials (Trial title, Phase, and Status) pertaining to the company The report provides all the unaccomplished trials (Terminated, Suspended and Withdrawn[gii.co.jp]

Workup

Procedures

Biopsy samples may be taken from areas where the scales are thickest such as the anterior aspect of the lower leg. Mild scales may not be suitable for histopathologic examination as these may be difficult to distinguish from normal skin. Specimens can be examined by light and electron microscopy.

Histologic findings

Hereditary ichthyosis and acquired ichthyosis are histologically similar. Solid hyperkeratosis and sometimes thin plates are seen in the stratum corneum. Follicular plugs when present are associated with keratosis pilaris. The granular layer is either absent or one layer thick. Acquired ichthyosis patients may have ichthyosiform sarcoid with noncaseating granulomas in the dermis.
Electromicrographs show reduced or absence of keratohyalin granules, thus the granular layer appears spongy due to a defect in keratohyalin synthesis. Normal keratin pattern is seen in the hyperkeratotic portions of the stratum corneum.

Trichophyton Rubrum
  • These lesions were resistant to topical corticosteroid and emollient cream treatments and were found to be caused by Trichophyton rubrum.[ncbi.nlm.nih.gov]

Treatment

Although hereditary ichthyosis vulgaris, a chronic disorder, usually improves with age, continuous therapy may still be required for good measure. Meanwhile, recovery from acquired ichthyosis depends on the amelioration of the associated systemic disease. Treatment of both conditions consists of adequate hydration of the skin and minimizing evaporation with an ointment. This facilitates normal desquamation by accelerating hydrolytic enzyme activity and serving as a physical barrier while improving the flexibility of the skin. Topical retinoids can be used.

Alpha-hydroxy acids (e.g., lactic, glycolic, or pyruvic acids) are hydrating agents which disperse the corneocytes forming the lower layer of the stratum corneum. Lactic acid (5-10% formulation) in a suitable carrier can be applied twice a day as recommended.

Scales can be removed with keratolytics such as salicylic acid (commercially available as 6% gel), which disaggregate corneocytes in the upper stratum corneum. Moisturizers, also available commercially, contain urea (10-20%) or propylene glycol. Propylene glycol absorbs water through the stratum corneum, promoting hydration. Moisturizers containing urea in lower strengths (10-20%), acting as a humectant, can soften the stratum corneum. Urea topical formulation can be applied to hyperkeratotic and dry skin.

Topical retinoids (e.g., tretinoin, tazarotene) help spread out epithelial cells, stimulate cell proliferation and inhibit keratin synthesis. Although steroids are not effective against ichthyosis vulgaris, itching may be relieved by a mild topical steroid. Various topical emollients are being tested for the treatment of ichthyosis vulgaris. Acquired ichthyosis vulgaris improves with treatment of the concomitant systemic condition. Various topical emollients are being tested for the treatment of ichthyosis vulgaris.

Prognosis

Prognosis is good for hereditary ichthyosis vulgaris. Symptoms improve as the patient grows older. On the other hand, recovery from acquired ichthyosis vulgaris is determined by the nature and clinical outcome of the co-existing systemic disease.

Etiology

Hereditary ichthyosis vulgaris is caused by an autosomal dominant gene mutation in the expression of profilaggrin, an intermediate product in the synthesis of filaggrin. Filaggrin is a structural protein that is essential for epidermal viability. The mutation alters the structure and function of the keratinocytes in the stratum corneum (outer skin barrier), leading to scaling and desquamation. Acquired ichthyosis is usually associated with a concomitant disease or altered immune response to an underlying disorder as in multiple myeloma [7] or systemic lupus erythematosus [8].

Epidemiology

Hereditary ichthyosis vulgaris occurs globally but data vary among countries. One case in 250 children examined was reported in Berkshire, England. The overall incidence in the United States is 1 in 300,000 people. There is no predilection for age, gender and ethnic origin. Children and adolescents may experience embarrassing problems with cosmesis. Cracked skin on the hands and feet may become infected. Ichthyosis vulgaris has been diagnosed in children aged 1-5 years, peaks during adolescence, and wanes with age.

Sex distribution
Age distribution

Pathophysiology

Ichthyosis vulgaris exemplifies retention hyperkeratosis from the the accumulation of keratin in the stratum corneum instead of undergoing normal desquamation, hence, subsequent thickening of the stratum corneum. Mutations in the human gene encoding profilaggrin (FLG) is the molecular basis of the development of ichthyosis. Profilaggrin, precursor of filaggrin, is converted to filaggrin through successive posttranslational reactions in the epidermis. Filaggrin is essential in maintaining skin moisture because of its hygroscopic property. Deficiency in the synthesis of filagrrin leads to the altered state of the stratum corneum in ichthyosis as well as the predisposition to water loss (xerosis). Disruption of the hydration-dehydration cycle adversely affects normal desquamation. Filaggrin is also the first line of defence of the skin against environmental substances that trigger aberrant immune responses. 

In ichthyosis vulgaris, the expression of profilaggrin is abolished or diminished in the epidermis, resulting in 50% reduction of profilaggrin mRNA and 90% reduction of profilaggrin protein. This accounts for the decrease in keratohyalin granules and progression of disease.  Loss of posttranscriptional regulation leads to instability of profilaggrin mRNA.

FLG is part of several genes on 1q21, called epidermal differentiation complex, including an adjoining region on 1q22, which determines the biosynthesis of structural proteins [9][10]. The relevance of this complex to the pathophysiology of ichthyosis remains to be studied in human and mouse models.

Null mutations in FLG lead to ichthyosis vulgaris and susceptibility to secondary allergic diseases, including atopic dermatitis  [11] [12] [13]. Common European mutations evolved from variants carried on conserved haplotypes. Fifteen of these are nonesense mutations associated with the absence of filaggrin production. Mutations p.R501X and c.2282del4 were found in ichthyosis vulgaris patients [14]. 

Fifteen of 21 patients with FLG mutations and prominent scaling were evaluated, including 8 family members from 4 successive generations. Results showed that heterozygous patients with mutant genes p.R501X and c.2282del4 exhibited the same distinct phenotype. Mutations p.R501X and c.2282del4 were likewise found in German ichthyosis vulgaris patients, but these might have specific population or familial origins [15].

FLG mutation c.3321delA was linked to ichthyosis vulgaris and atopic dermatitis in a Korean patient [16]. Ichthyosis vulgaris in 3 Chinese pedigrees was attributed to 2 novel FLG null mutations, c.477-478insA and c.6218-6219delAA) and mutation c.3321delA [17]. The proband of one pedigree was compound heterozygous for these mutations, but with a mild phenotype. FLG mutations were also found in European and Japanese populations with ichthyosis vulgaris and atopic dermatitis [18] [19]. Mutations at any site within FLG may be responsible for the lack of genotype-phenotype correlation observed in patients with FLG mutations [20]. Symptoms were less severe in heterozygotes than in homozygotes and compound heterozygottes, indicating semidominant inheritance with incomplete penetrance.

FLG mutant gene was 74% in patients with only ichthyosis vulgaris disorder versus 43% in patients with combined atopic dermatitis–ichthyosis vulgaris [21]. These suggest that factors other than FLG gene mutations may be involved in disrupting profilaggrin/filaggrin expression, leading to the ichthyosiform phenotype in terms of atopic dermatitis. Meanwhile, complete filaggrin deficiency has been linked with minor disruption of the transepidermal hydration-dehydration cycle [22].

Prevention

Precautionary measures include:

  • Avoiding the use of scented soaps and perfumes  as they may irritate the skin and worsen dryness. Use only mild or non-allergenic soaps, with added fats and oils.
  • Avoiding medications that can trigger acquired ichthyosis.

Proper care of the skin includes:  

  • Soaking in warm bath to soften the skin, and gently rubbing the skin with a soft towel to remove the scales. 
  • Patting the skin gently after bathing, leaving moisture on the skin. 
  • Applying emollients, such as petroleum jelly, while the skin is still damp to conserve the moisture. 
  • Humidify the room to prevent dryness of the skin.

Summary

Hereditary ichthyosis vulgaris is widespread, constituting more than 95% of all ichthyosis cases reported in some studies [1] [2]. The most prominent manifestation of the disease is the presence of flaky skin on the extensor surface of the extremities, so called because of the resemblance to fish scales. Ichthyosis, meaning "fish" in Greek, has been cited in medical literature two centuries ago. Robert Wilan first described the disease in England in 1808.

The trait is inherited from either one parent or both via an autosomal dominant mutant gene which has lost its function to determine the normal development of the epidermis. When both parents are carriers of the trait, the clinical manifestation on the child will be severe. Ichthyosis vulgaris is not synonymous with acquired ichthyosis vulgaris, which is not hereditary, uncommon as it is, and with a different etiology [3]. However, both are dermatological disorders of keratinization, with similar histological profiles and clinical manifestations.

Hereditary ichthyosis vulgaris occurs in young children and is due to errors in the biosynthesis of profilaggrin, an epidermal calcium-binding protein and the precursor of filaggrin. Filaggrin is essential to the maintenance of epidermal integrity and flexibility. Mutations in the profilaggrin gene (FLG) occurs in 10% of the population [4]. Mutation leads to scale formation and peeling of skin, and constitutes a risk factor for atopic dermatitis [5]. This finding in 2006 has advanced knowledge on ichthyosis as it is today [6].

On the other hand, acquired ichthyosis is rare, if at all, affects adults and is associated with systemic disease, such as HIV and malignancy [7] [8]. Certain medications may cause acquired ichthyosis.

Ichthyosis vulgaris occurs worldwide but prevalence varies among countries. Treatment is straightforward, in other words keeping the skin moist and warm and infection-free with the use of non-allergenic dermatologicals and antimicrobials. Counselling may be required if the child is bothered by the appearance of the skin to restore self-confidence.

Patient Information

Ichthyosis vulgaris is a skin disorder in which the skin becomes dry and flaky due to the accumulation of dead epidermal cells in certain areas of the body. The overall appearance of affected skin resembles fish scales, hence, the term ichthyosis, meaning "fish" in Greek. Affected parts of the body are the arms and legs, sometimes, the back, neck and face. Most cases are mild.
Ichthyosis vulgaris or hereditary ichthyosis is clinically similar to acquired ichthyosis but the two have different manner of causation. Therefore, the terms ichthyosis vulgaris and acquired ichthyosis (sometimes written as acquired ichthyosis vulgaris) are not synonymous.

Ichthyosis vulgaris is a hereditary disorder, meaning that the trait or defect is passed on to the offspring in the genes of either one parent or both. If both parents are positive for the trait the symptoms will be more severe in the child. The cause is actually a mutation in the autosomal dominant gene in which the function of maintaining the integrity of the skin is abolished or absent. The particular part of the skin or epidermis that is affected is the outermost layer, the stratum corneum, which becomes dry and scaly. The disorder becomes manifested in the infant and disappears spontaneously later in the young child.

Ichthyosis vulgaris may be accompanied by other skin disorders (e.g., eczema and keratosis pilaris). Eczema causes itchy skin rashes in which the skin is thick and flaky. Keratosis pilaris appears as red and white skin protuberances on the arms, thighs or buttocks. presenting as rough patches of skin.

On the other hand, acquired ichthyosis vulgaris affects adults. It is rare, non-hereditary, and is usually associated with a systemic disease such as cancer, autoimmune disease, chronic kidney failure, and thyroid disease.

Symptoms of ichthyosis vulgaris are more pronounced in winter because of the dry and cold climate. The appearance of ichthyosis vulgaris includes: dry, thickened and itchy skin; flaky scalp; polygonal shaped brown, gray or white scales.

Areas of dry skin are found on the elbows and lower legs, and dark, thick segments on the shins. In severe cases, deep, painful fissures that are prone to infection may develop on the palms and soles.

The disorder is diagnosed and treated by a dermatologist who is a specialist in skin diseases. The doctor will need information on family history, patient's biodata and experience with other skin conditions. Physical examination, laboratory tests, and skin biopsy will be required to establish the diagnosis by microscopy.

Treatment is based mainly on keeping the skin moist with emollients, removing the scales, preventing secondary infection, and relieving inflammation and pruritus, if any. Proper care of the affected skin includes avoiding scented soaps, perfumes and allergenic cosmetics. Moisturizers usually contain urea or propylene glycol with a non-allergenic carrier. Sometimes petroleum jelly suffices.

Topical treatment includes:

Ichthyosis can cause embarrassment and loss of self-confidence, especially among children because of the unsightly appearance. Counselling should be sought from professionals for both cosmetic remedies and mental health. Individual initiative is important in coping with the situation and in helping oneself
achieve complete cure.

References

Article

  1. Bolognina JL, Jorizzo JL, Rapini RP. Dermatology: 2-Volume Set. St. Louis: Mosby; 2007.
  2. Freedberg, Eisen AZ, Wolff K, et al. Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill; 2003.
  3. James WD, Berger T, Berger D. Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders; 2005.
  4. Thyssen JP, Godoy-Gijon E, Elias PM. Ichthyosis vulgaris - the filaggrin mutation disease. Br J Dermatol. 2013 Jan 10. 
  5. McGrath JA, Uitto J. The filaggrin story: novel insights into skin-barrier function and disease. Trends Mol Med. 2008 Jan. 14(1):20-7. 
  6. Brown SJ, McLean WH. One remarkable molecule: filaggrin. J Invest Dermatol. 2012 Mar. 132(3 Pt 2):751-62.
  7. Dar NR, Raza N, Khan A, Amin MU. Paraneoplastic Addisonian pigmentation and acquired ichthyosis as presenting features of multiple myeloma. J Coll Physicians Surg Pak. 2011 Jan. 21(1):40-2. 
  8. Biver-Dalle C, Gil H, Meaux-Ruault N, et al. [Acquired ichthyosis and livedoid palmoplantar keratoderma: Two unusual skin manifestations of systemic lupus erythematosus open link.]. Rev Med Interne. 2011 Mar 21.
  9. Zhong W, Cui B, Zhang Y, et al. Linkage analysis suggests a locus of ichthyosis vulgaris on 1q22. J Hum Genet. 2003. 48(7):390-2. 
  10. Liu P, Yang Q, Wang X, et al. Identification of a genetic locus for ichthyosis vulgaris on chromosome 10q22.3-q24.2. J Invest Dermatol. 2008 Jun. 128(6):1418-22.
  11. Hanifin JM. Evolving concepts of pathogenesis in atopic dermatitis and other eczemas. J Invest Dermatol. 2009 Feb. 129(2):320-2. 
  12. Winge MC, Hoppe T, Berne B, et al. Filaggrin genotype determines functional and molecular alterations in skin of patients with atopic dermatitis and ichthyosis vulgaris. PLoS One. 2011. 6(12):e28254.
  13. Sandilands A, Terron-Kwiatkowski A, Hull PR, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet. 2007 May. 39(5):650-4. 
  14. Gruber R, Janecke AR, Fauth C, Utermann G, Fritsch PO, Schmuth M. Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris. Eur J Hum Genet. 2007 Feb. 15(2):179-84.
  15. Oji V, Seller N, Sandilands A, et al. Ichthyosis vulgaris: novel FLG mutations in the German population and high presence of CD1a+ cells in the epidermis of the atopic subgroup. Br J Dermatol. 2009 Apr. 160(4):771-81.
  16. Kang TW, Lee JS, Oh SW, Kim SC. Filaggrin mutation c.3321delA in a Korean patient with ichthyosis vulgaris and atopic dermatitis. Dermatology. 2009. 218(2):186-7.
  17. Xiong Z, Luo S, Xu X,  et al. Novel FLG mutations associated with ichthyosis vulgaris in the Chinese population. Clin Exp Dermatol. 2012 Mar. 37(2):177-80.
  18. Nomura T, Sandilands A, Akiyama M, et al. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol. 2007 Feb. 119(2):434-40. 
  19. Nomura T, Akiyama M, Sandilands A, et al. Specific filaggrin mutations cause ichthyosis vulgaris and are significantly associated with atopic dermatitis in Japan. J Invest Dermatol. 2008 Jun. 128(6):1436-41.
  20. Akiyama M. FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics. Br J Dermatol. 2010 Mar. 162(3):472-7.
  21. Li M1, Cheng R, Shi M, et al. Analyses of FLG mutation frequency and filaggrin expression in isolated ichthyosis vulgaris (IV) and atopic dermatitis-associated IV. Br J Dermatol. 2013 Jun;168(6):1335-8.
  22. Perusquía-Ortiz AM, Oji V, Sauerland MC, et al. Complete filaggrin deficiency in ichthyosis vulgaris is associated with only moderate changes in epidermal permeability barrier function profile. J Eur Acad Dermatol Venereol. 2013 Dec;27(12):1552-8.

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Last updated: 2019-07-11 21:19