eMedicine Specialties > Dermatology > Pediatric Diseases

Ichthyosis Vulgaris, Hereditary and Acquired

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Jason F Okulicz, MD, Assistant Professor of Medicine, Uniformed Services University of the Health Sciences; Staff, Infectious Disease Service, Brooke Army Medical Center
Contributor Information and Disclosures

Updated: Jul 21, 2009

Introduction

Background

Hereditary ichthyosis vulgaris and acquired ichthyosis vulgaris, members of a group of cutaneous disorders of keratinization, appear similar both clinically and histologically. The term ichthyosis is derived from the ancient Greek root ichthys, meaning fish. Although the resemblance is rather fanciful, it nevertheless conveys the characteristic features of these diseases. References to ichthyosis have been found in ancient medical texts aged more than 2000 years. Robert Wilan first made the most accurate description of ichthyosis in the English literature in 1808. Later modifications classified the diseases into hereditary and acquired forms.

Hereditary ichthyosis vulgaris is an autosomal dominant genetic disorder first evident in early childhood. It is the most common form of ichthyosis, accounting for more than 95% of ichthyosis cases. It is caused by altered profilaggrin expression leading to scaling and desquamation. Visible scales are retained for longer periods and sloughed off in clumps. Hereditary ichthyosis is also associated with atopy. The protein filaggrin is important in maintaining effective skin barrier function. Loss-of-function mutations in the profilaggrin gene (FLG) are evident in up to 10% of the population, causing ichthyosis vulgaris and representing a major risk factor for the development of atopic dermatitis.¹

Acquired ichthyosis, usually appearing for the first time in adulthood, is a nonhereditary condition associated with internal disease. Acquired ichthyosis is rare and must be viewed as a marker of systemic disease, including malignancy. Cases have been attributed to the use of certain medications.

Other eMedicine articles on ichthyosis include the following:

• Ichthyosis Fetalis
• Ichthyosis Vulgaris, Hereditary and Acquired
• Ichthyosis, Lamellar
• Ichthyosis (ophthalmology focus)

Pathophysiology

Ichthyosis vulgaris is classified as a retention hyperkeratosis. The only known molecular marker affected by hereditary ichthyosis vulgaris is profilaggrin, a high molecular weight filaggrin precursor. Profilaggrin, synthesized in the granular layer of the epidermis, is a major component of keratohyalin granules. Through various posttranslational modifications, profilaggrin is converted to filaggrin, which aggregates keratin intermediate filaments in the lower stratum corneum. Filaggrin is proteolyzed and metabolized, producing free amino acids that may play a critical role as water-binding compounds in the upper stratum corneum. Normal cycles of skin hydration and dehydration contribute to normal desquamation. These cycles are disrupted in ichthyosis vulgaris.

Normal expression of the profilaggrin gene can be first detected in the granular layer. In ichthyosis vulgaris, the expression of profilaggrin is absent or reduced in the epidermis. This biochemical abnormality correlates with the decreased numbers of keratohyalin granules and the clinical severity of the condition. Analyses of cultured keratinocytes have shown reduced profilaggrin mRNA. Compared with normal amounts, one study found only 50% of the profilaggrin mRNA and 10% of the profilaggrin protein present. Research has shown that defective posttranscriptional regulation leads to decreased stability of profilaggrin mRNA.

The profilaggrin gene is part of a cluster of genes on 1q21 that encodes for structural proteins expressed in terminally differentiating epidermis. This complex, called the epidermal differentiation complex, involves many genes involved in this process. An adjacent region on 1q22 may also be involved.² The underlying molecular mechanisms contributing to the pathophysiology of this disease have not yet been determined. Studies are currently underway in humans and mouse models.

An association exists between filaggrin null mutations of ichthyosis vulgaris and atopic dermatitis.³ Two common filaggrin (FLG) null mutations cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. Comprehensive analysis of the gene encoding filaggrin uncovered prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.⁴ These common European mutations are ancestral variants carried on conserved haplotypes. Fifteen variants were described, including 7 that are prevalent, all being either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis.

Filaggrin mutations p.R501X and c.2282del4 were analyzed in patients with ichthyosis vulgaris.⁵ Homozygotes and compound heterozygotes may be severely affected, whereas heterozygotes showed mild disease or were asymptomatic, suggesting semidominant inheritance with incomplete penetrance in heterozygotes. The presence of FLG mutations in 15 of 21 ichthyosis vulgaris patients were studied with a marked generalized scaling phenotype, including 8 affected members of a 4-generation family. In this group, heterozygous patients for p.R501X and c.2282del4 also displayed a pronounced phenotype. Filaggrin mutation c.3321delA was identified in a Korean patient with ichthyosis vulgaris and atopic dermatitis.⁶ Mutations R501X and 2282del4 represent the most frequent genetic cause in German ichthyosis vulgaris  patients but are probably population and family specific.⁷

Mutations in the gene encoding filaggrin have been identified as the cause of ichthyosis vulgaris and shown to be major predisposing factors for atopic dermatitis both in European and Japanese populations.^8,9

Frequency

United States

Hereditary ichthyosis vulgaris is a common disease in the United States, with a prevalence of approximately 1 case in 300 persons. Because symptoms improve with age, the true prevalence is probably higher. Acquired ichthyosis is extremely rare. Its prevalence in the United States is unknown.

International

Hereditary ichthyosis vulgaris is found worldwide, and the prevalence depends on the location. One study in Berkshire, England, observed a frequency of 1 case in 250 schoolchildren. Acquired ichthyosis is extremely rare. Its prevalence worldwide is unknown.

Mortality/Morbidity

• Children and adolescents with hereditary ichthyosis vulgaris may experience some morbidity in terms of cosmesis. Secondary infections may occur in fissures of the hands and feet.
• The morbidity and mortality of acquired ichthyosis in adults is due to associated internal disease.

Race

• Hereditary and acquired ichthyosis vulgaris have no known racial predisposition.

Sex

• Hereditary and acquired ichthyosis occur equally in men and women.

Age

• Hereditary ichthyosis vulgaris typically is absent at birth. It appears in most patients during the first year of life and in the vast majority by age 5 years. The extent of scaling usually intensifies up until puberty and subsequently decreases with age.
• Acquired ichthyosis usually first appears in adulthood; however, age-associated systemic diseases do occur in children.

Clinical

History

• Although the skin in hereditary ichthyosis vulgaris looks and feels normal at birth, it gradually becomes rough and dry in early childhood.
  • Scaling tends to be most prominent on the extensor surfaces of the extremities and absent on the flexor surfaces.
  • The diaper area is usually unaffected.
  • The forehead and cheeks may be involved early on, but scaling usually diminishes in these areas with age.
  • A notable amelioration of symptoms occurs during the summer months.
  • A family history of hereditary ichthyosis vulgaris may be difficult to ascertain because of the varying degrees of penetrance and the general improvement of symptoms over time.
  • Many hereditary ichthyosis vulgaris patients have associated atopic manifestations (eg, asthma, eczema, hay fever). Atopic conditions can be found in many family members, with or without symptoms of ichthyosis vulgaris. One study noted atopic manifestations in almost half of all subjects enrolled, with 41% having at least one relative who also was affected.
• Acquired ichthyosis is clinically indistinguishable from hereditary ichthyosis; however, acquired ichthyosis is associated with various systemic diseases.
  • The appearance of ichthyosis in adulthood can occur before or after the diagnosis of a systemic condition.
  • Disease severity varies depending on the course of the associated systemic condition.
  • Acquired ichthyosis is associated with many systemic diseases, including cancer (especially lymphoma), sarcoidosis, leprosy, thyroid disease, hyperparathyroidism,¹⁰ nutritional disorders, chronic renal failure, bone marrow transplantation,¹¹ and HIV infection.¹² Autoimmune diseases, including systemic lupus erythematosus¹³ and dermatomyositis,¹⁴ are also linked. It was recently described in a patient with the overlap syndrome consisting of systemic sclerosis and systemic lupus erythematosus.¹³
  • The types of cancers most often found in association with acquired ichthyosis are Hodgkin disease, non-Hodgkin lymphoma (including mycosis fungoides), myeloma, Kaposi sarcoma, leiomyosarcoma, and carcinomas of the lung, breast, ovary,¹⁵ and cervix.¹⁶
  • The use of certain medications has been linked to acquired ichthyosis, namely nicotinic acid,^17,18 triparanol, butyrophenones, dixyrazine,¹⁹ cimetidine, and clofazimine.²⁰
  • Bathing suit ichthyosis is a striking and unique clinical form of autosomal recessive congenital ichthyosis characterized by marked scaling on the bathing suit areas but sparing of the extremities and the central face. Bathing suit ichthyosis, caused by transglutaminase-1 deficiency, displays evidence that suggests it is a temperature-sensitive phenotype.²¹

Physical

• Ichthyosis vulgaris (both hereditary and acquired) is characterized by symmetrical scaling of the skin, which varies from barely visible roughness and dryness to strong horny plates.

• Scales are small, fine, irregular, and polygonal in shape, often curling up at the edges to give the skin a rough feel.
• Scales vary in size from 1 mm to 1 cm in diameter and range from white to dirty gray to brown. Dark-skinned individuals often have darker scales.
• Different types of scaling may be found in different areas, even in the same patient.
• Most scaling occurs on the extensor surfaces of the extremities, with a sharp demarcation between normal flexural folds and the surrounding affected areas.
• The lower extremities generally are more affected than the upper extremities. Compared to other sites, the scales overlying the shins are thicker, darker, and arranged in a mosaic pattern. Patients often report "lizard skin" in these areas during the winter.
• If the trunk is involved, scaling tends to be more pronounced on the back than on the abdomen.
• Relative sparing of the face is seen, most likely because of increased sebaceous secretions, although the cheeks and forehead may be involved during early childhood in the hereditary form.
• Dry scaling is often observed uniformly over the scalp.
• Sparing of the flexural folds (eg, neck, axillae, antecubital and popliteal fossae) is attributed to the relative increase in temperature and humidity in these areas.
• Overall symptoms of ichthyosis vulgaris generally improve in the summer months or in warm climates.
• Hyperkeratosis is often present on the palms and soles, causing them to appear dirty.
  • Skin creases in these areas are more prominent and can lead to painful fissuring, especially during dry weather.
  • Secondary infections at fissure sites are common.
• Keratosis pilaris (follicular hyperkeratosis) occurs on the side of the cheek and neck, dorsum of the upper arms, buttocks, and thighs.
  • It consists of spiny parafollicular papules that when palpated resemble a cheese grater.
  • Dried skin in the central portion is often white and mistaken for pus.
  • Inflammation may or may not be present.
  • Keratosis pilaris, which can be present without scaling, may be the only finding in family members with hereditary ichthyosis vulgaris.
• Pruritus can be caused by dry skin, even if inflammation is not evident. As a result, itching and scratching may lead to erythema in affected areas.

Causes

• Hereditary ichthyosis vulgaris is an autosomal dominant genetic disorder first evident in early childhood.

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