Chapter 4 Disorders of keratinization
3. How common are the congenital ichthyoses? How are they inherited?
4. What features help differentiate the most common inherited ichthyoses?
Both clinical and histologic features are helpful in the diagnosis of ichthyoses (Table 4-1). Onset of symptoms, anatomic location of skin changes, birth history, and the condition of the infant’s skin at birth are helpful clues. In some instances, a skin biopsy can be diagnostic.
Ichthyosis vulgaris (Fig. 4-1A,B) usually develops around school age, and is characterized by generalized xerosis and scale, with characteristic sparing of the flexural skin. Additional findings include follicular accentuation (keratosis pilaris), hyperlinearity of palms and soles, and a personal or family history of atopy. Rare patients may have an associated palmar-plantar keratoderma. Skin biopsy demonstrates a decreased granular cell layer associated with moderate hyperkeratosis.
X-linked ichthyosis, in contrast, is usually present by one year of age, affects the posterior neck with “dirty”-appearing scales, and spares the palms and soles (Fig. 4-1C). The skin changes—gradually worsening with age—with the neck, face, and trunk ultimately developing thick, brown scales. The disease is caused by a defect in steroid sulfatase, an enzyme important in cholesterol synthesis and vital for normal development and function of the stratum corneum. Accumulation of cholesterol sulfate and a lack of tissue cholesterol ensue, leading to a disturbance in steroid hormone metabolism. Skin biopsy of X-linked ichthyosis is rarely diagnostic, and demonstrates a normal granular layer with hyperkeratosis.
5. What genetic defect is responsible for X-linked ichthyosis (XLI)?
Ninety percent of patients with XLI have deletions in the STS gene on chromosome Xp22.3, leading to steroid sulfatase deficiency and the classic phenotype of XLI. However, some patients have larger deletions at this site, encompassing neighboring genes. These patients present with more complicated forms of XLI representing contiguous gene deletion syndromes (OMIM [Online Mendelian Inheritance in Man] #308100).
9. What is a collodion baby?
A collodion baby is a newborn infant whose skin looks like a “baked apple,” with a shiny, tough, membrane-like covering. This term describes a phenotype that occurs in several types of ichthyosis. Although congenital ichthyosiform erythroderma is the most common underlying condition (Fig. 4-1D), lamellar ichthyosis, Netherton’s syndrome, Conradi’s syndrome and others may also present as a collodion baby. Collodion babies may also go on to have normal skin. These infants are at increased risk for infections and fluid and electrolyte imbalances due to cutaneous fissures and impaired barrier function of the skin. Treatment in a high-humidity environment with frequent application of petrolatum allows gradual sloughing of the collodion membrane. Manual debridement and keratolytics are not recommended.
10. What is a harlequin fetus?
The most severe manifestation of congenital ichthyosis, the harlequin fetus, is born with massive hyperkeratotic plates associated with limb deformities, rudimentary ears, ectropion, and eclabium (Fig. 4-2). These infants rarely survive beyond the first week of life. The use of acitretin in harlequin ichthyosis may be lifesaving, although side effects are numerous and may be severe.
11. Name several conditions associated with acquired ichthyosis.
See Table 4-3.
• Malignancy: The pathogenesis of the skin changes associated with malignancies is unknown, although reduced dermal lipid synthesis, malabsorption, and immunologic abnormalities have been identified.
• Nutritional and metabolic disorders: Many of nutritional problems involve abnormal vitamin A metabolism. Chronic renal failure may result in hypervitaminosis A, which produces rough, scaly skin. Hypovitaminosis A produces follicular hyperkeratosis and dry skin.
• Drugs and other therapies: Medications produce ichthyosis by various mechanisms. Niacin, triparanol, butyrophenones, dixyrazine, and nafoxidine alter cholesterol synthesis. Cimetidine and retinoids are antiandrogenic and reduce sebum secretion (Fig. 4-3).
Figure 4-2. Fatal case of harlequin fetus demonstrating large, fissured, keratotic platess.
(Courtesy of the Fitzsimons Army Medical Center teaching files.)
Figure 4-3. Acquired ichthyosis due to clofazimine.
(Courtesy of the Fitzsimons Army Medical Center teaching files.)
Homayoun A: Acquired ichthyosis and related conditions, Int J Dermatol 23:458–461, 1984.
12. Are laboratory tests helpful in the diagnosis of ichthyoses?
In general, no. However, with recent advancements in genetic testing and microarray analysis, genetic testing is becoming easier and more readily available for this group of disorders. In ichthyosis vulgaris, cultured keratinocytes demonstrate absent or reduced filaggrin keratohyalin granules, and fail to react to antifilaggrin monoclonal antibodies. The defective enzyme in X-linked ichthyosis, steroid sulfatase, can be assayed in cultured keratinocytes, fibroblasts, leukocytes, or skin scales. Low levels of cholesterol sulfate in blood can be detected by the increased mobility of low-density lipoproteins on serum protein electrophoresis. Female heterozygotes can be detected by Southern blot hybridization from peripheral blood leukocytes. The gene has been mapped to the short arm of the X chromosome (Xp22.3). Several of the rarer ichthyosiform syndromes are also associated with enzyme deficiencies detectable in cell cultures.
13. Is prenatal diagnosis of congenital ichthyosis possible?
Prenatal diagnosis is available for many of the congenital ichthyoses, if one is suspected, based on family history. Fetal skin biopsy performed at 19 to 21 weeks will demonstrate early development of a thickened stratum corneum, normally not present until 24 weeks. This is useful in lamellar ichthyosis, epidermolytic hyperkeratosis, Sjögren-Larsson syndrome, and harlequin fetus. Lamellar ichthyosis may also be detected via a transglutaminase activity assay from a fetal skin sample. Epidermolytic hyperkeratosis, known to result from mutations in keratins 1 and 10, can be detected by direct gene sequencing done on chorionic villus sampling in the second trimester. Cultured chorionic villi cells or amniocytes will demonstrate the enzyme deficiency in XLI, Sjögren-Larsson syndrome, and Refsum’s disease. A high ratio of maternal urinary estrogen precursors in a male fetus also suggests the diagnosis of XLI. Trichothiodystrophy can be identified by unscheduled DNA synthesis in cultured amniocytes exposed to ultraviolet light.
14. How is ichthyosis treated?
Acquired ichthyosis usually improves with treatment of the underlying condition. Congenital ichthyosis is difficult to treat, especially in its severe forms. Topical emollients containing glycolic acid, lactic acid, urea, or glycerin may partially improve dryness and scaling. Topical tretinoin (Retin-A) is effective but poorly tolerated due to irritation. Oral retinoids, including isotretinoin, etretinate, and acitretin, are very effective, but relapses after treatment cessation are common. The use of oral retinoids is limited by major side effects (including teratogenic effects), and chronic use, which is often required in congenital disorders, is associated with hyperostoses. Blistering may indicate bacterial infection and should be cultured and managed with oral antibiotics. The foul odor present in epidermolytic hyperkeratosis may be due to bacterial colonization and can be improved by the use of an antibacterial soap.
15. What is Hailey-Hailey disease?
Hailey-Hailey disease, also known as benign familial pemphigus, is an autosomal dominant condition in which mutations in the ATP2C1 gene result in abnormal intracellular calcium signaling. It is characterized histologically by acantholysis (loss of cohesion between keratinocytes) and clinically by patches of minute vesicles that break and form crusted erosions.
16. How does Hailey-Hailey disease present?
Skin changes consisting of localized patches of minute vesicles and erosions start in areas of friction, usually the neck, groin, and axilla (Figs. 4-4 and 4-5). Patches spread peripherally with serpiginous borders and show central healing with hyperpigmentation or granular vegetations. Onset of lesions is often delayed until the second or third decade. Associated symptoms include itching, pain, and foul odor.
19. How is Hailey-Hailey disease treated?
Topical steroids are generally helpful in relieving burning and itching. Both Staphylococcus aureus and Candida albicans infections may exacerbate lesions, requiring treatment with appropriate antibacterial and antifungal agents. Recalcitrant cases have been treated with localized steroid injections, carbon dioxide laser, dermabrasion, topical cyclosporine, dapsone, vitamin E, psoralen plus ultraviolet A (PUVA), methotrexate, thalidomide, and vitamin D analogs, with variable results.
Figure 4-5. Hailey-Hailey disease showing a patch of minute vesicles, erosions, and crusting in the antecubital fossa.
Key Points: Disorders of Keratinization
2. Congenital ichthyosiform erythroderma and lamellar ichthyosis are the two disorders of keratinization that are most likely to present as a collodion baby.
20. What is Darier’s disease?
Darier’s disease, also known as keratosis follicularis and Darier-White disease, is a dominantly inherited disorder of keratinization caused by mutations in the ATP2A2 gene, resulting in dysfunction of intracellular calcium signaling. Typically, the disease presents in the first or second decade of life. Microscopically, it is characterized by distinctive changes of both premature keratinization and acantholysis.
21. How is Darier’s disease diagnosed?
The diagnosis is based on clinical manifestations and histologic features. The primary lesions are flesh-colored papules that may coalesce into plaques and develop tan, scaly crusts (Fig. 4-6). These keratotic papules are located in “seborrheic areas,” such as the chest, back, ears, nasolabial folds, scalp, and groin. Thick, foul-smelling, warty masses can develop. Flat, wartlike papules may be seen on the dorsa of distal extremities, and 1- to 2-mm punctate keratoses may be present on the palms and soles. Oral and rectal mucosal surfaces often demonstrate small, cobblestone-like papules. The diagnosis can be confirmed by skin biopsies that reveal acantholytic dyskeratosis.
23. Is Darier’s disease difficult to treat?
Complete clearing of Darier’s disease is rare. Soothing moisturizers containing urea or lactic acid reduce scaling and irritation. Salicylic acid in a propylene glycol gel and topical retinoids are also effective in reducing crusts and scale, although retinoids may need to be initiated on an alternate-day schedule in combination with midpotency topical steroids to minimize irritation. Aggravating factors such as heat, humidity, sunlight, and lithium should be avoided. Infection should be prevented with antibacterial soaps and treated with antibiotics. Oral retinoids are effective, but toxicity limits their use; intermittent use may be preferable, such as starting the medication before a summer holiday to prevent sun-induced exacerbations. Recalcitrant verrucous lesions have been treated with dermabrasion, carbon dioxide laser vaporization, and surgery.
Burge SM: Management of Darier’s disease, Clin Exp Dermatol 24:53–56, 1999.
