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ICHTHYOSES AND GENERALIZED HYPERKERATOSIS

The ichthyoses represent a group of disorders in which the horny layer of the skin does not desquamate normally. Hyperkeratotic scaly skin results.

Ichthyosis vulgaris

Ichthyosis vulgaris is thought to be caused by a posttranslational defect in profilaggrin expression but, as of this writing, the causative gene or genes have not been identified. Severe xerosis and fine, white scaling, with onset in the first few months of life, are characteristic. In comparison with the other ichthyoses, the skin changes of ichthyosis vulgaris are mild. The disease is worse in the winter, worse on the legs, and may worsen with age (Fig.19.68). Inheritance is autosomal dominant, with variable expression within the family. Testicular cancer has been reported. An important feature histologically is an absence of the granular layer. Use of emollients and keratolytics is usually sufficient treatment. Ammonium lactate (12% lotion) or urea is often effective.

Figure 19.69 Collodion baby.

Collodion baby

A newborn infant covered with oiled parchment-like shiny skin is characteristic (Fig.19.69). The condition is not a single disease but a clinical finding. It may resolve spontaneously or evolve into various diseases, including lamellar ichthyosis and congenital ichthyosiform erythroderma (Table 19.3). Morbidity and mortality may occur secondary to impaired barrier function. Complications include infection, dehydration, and hypernatremia. Heat regulation may also be impaired (both hyper- and hypothermia).

Figure 19.70 (a,b) Non-bullous congenital ichthyosiform erythroderma.

    Intensive care, close temperature regulation, incubator, fluid status, and an emollient several times daily are important. One study showed an increased risk of infection with emollients, and the authors recommended a humidified incubator, with intravenous rehydration if necessary, instead of emollients.

Non-bullous congenital ichthyosiform erythroderma

    The term non-bullous congenital ichthyosiform erythroderma applies to a phenotypic presentation that may be caused by various gene mutations. Researchers have identified mutations in lipoxygenase-3 and 12(R)-lipoxygenase genes linked to chromosome 17, the transglutaminase gene, and a new gene called ichthyin on chromosome 5q33.

    The skin is diffusely erythematous with fine scaling in this group of autosomal recessive ichthyoses (Fig.19.70). It is distinguished from the other autosomal recessive, non-bullous ichthyosis, lamellar ichthyosis, by the plate-like scale of the latter. For treatment, acitretin has been used, and calcipotriene (calcipotriol) has shown a beneficial effect.

Lamellar ichthyosis

This is an autosomal recessive ichthyosis in which absent transglutaminase expression has been demonstrated, thereby separating it from other causes of non-bullous congenital ichthyosiform erythroderma (discussed earlier), which it may resemble. Transglutaminase is an enzyme that catalyzes the cross-linking of precursor proteins such as involucrin.

    Lamellar ichthyosis often presents as a collodion baby at birth. Later, the skin becomes ichthyotic with large, plate-like scales and variable erythroderma (Fig.19.71). Ectropion and PPK are frequently present.

    Retinoids (e.g. acitretin) are dramatically helpful in treating this disorder, but side effects limit their long-term use. Topical tazarotene was very helpful within weeks in one case report. Topical calcipotriene had a beneficial effect in one study.

Netherton syndrome

Congenital, exfoliative erythroderma is the first sign of this disorder; the clinically distinctive scale pattern termed ichthyosis linearis circumflexa (double-edged scale with a serpiginous border) may not become evident for several years. It has recently been reported to be caused by a mutation in the SPINK5 gene, encoding LEKTI, a 15-domain serine protease inhibitor. The diagnosis is confirmed or made by the finding of trichorrhexis invaginata (bamboo hair) of scalp, vellus, or eyelash hair. Infants may have failure to thrive, hypernatremia, diarrhea, recurrent infections, sepsis, and renal problems. Hairs at all body sites may be affected. Scalp hair may be dry and subject to trauma. Areas subject to friction may become bald. A golf tee hair, representing the proximal part of the invaginate node, may be the only microscopic sign. An atopic diathesis completes this triad of eczema, bamboo hair, and ichthyosiform dermatosis (Fig. 19.72).

    Patients with generalized exfoliative erythroderma–Netherton syndrome should not receive retinoids. Emollients and intermittent topical steroids may be given. Topical calcipotriol has been helpful in some patients.

Harlequin ichthyosis

Hard, keratotic plates cover the newborn in this rare disease. The exact genetic cause has not been elucidated, but in one case there was a deletion of chromosome 18q. The typical infant is usually premature and of low birth weight. Ectropion and eclabium are common (Fig.19.73). The ears, nose, fingers, and toes may be hypoplastic or rudimentary. The limbs may have limited mobility. Inheritance seems to be autosomal recessive.

Figure 19.71 Lamellar ichthyosis. (Courtesy of the Department of Dermatology, University of California, San Diego.)

    Most patients die within the first few weeks of life, with contributing factors including prematurity, abnormal temperature control, sepsis, and respiratory and feeding difficulties. Some children, however, have survived into the teenage years. When older, the skin is diffusely red and scaly or hyperkeratotic. The facial features are effaced with lack of scalp hair, eyebrows, and eyelashes. The pinna is small and misshapen. The intelligence may be normal in these children, or they may be learning-disabled. Hypothyroidism has been associated. Nutrition is of key importance.

Figure 19.72 Ichthyotic skin in a patient with Netherton syndrome. Note the eczematous skin and the sparse hair.

Figure 19.73 (a) Harlequin ichthyosis in a newborn. Note the apple crust scale and the ectropion. (b) Rarely, patients with harlequin ichthyosis may survive into childhood and even young adulthood. This is a picture of the feet of a prepubertal boy. (Courtesy of Angelito M. Arias, M.D.)

    For the newborn infant, acitretin, treatment in an intensive care unit with humidity control, regular feedings by tube or bottle, regular skin emolliation, eye drops, and monitoring for infection are important. For infants and children, acitretin (either continuously at low dose, or intermittently) is recommended, with yearly radiographic studies of long bones. Short stature and failure to thrive are common; some patients overcome this only with the help of tube feedings. Infants who have survived into childhood may be plagued by repeated infections (e.g. by Staphylococcus aureus ), which gain access through the defective skin. The parents should be informed that subsequent siblings may be affected.

Figure 19.74 Recessive X-linked ichthyosis. Note the sparing of the flexures.

Recessive X-linked ichthyosis

Mutations in the gene for steroid sulfatase cause recessive X-linked ichthyosis (RXLI). As a consequence of steroid sulfatase deficiency, its substrate, cholesterol sulfate, accumulates in the epidermis. This abnormal accumulation results in scaling and barrier dysfunction. Males are affected, although carrier females may exhibit mild features as well as failure to go into labor spontaneously (a family history of postmature births can be diagnostically useful). Corneal opacities may be found. Cryptorchidism and testicular cancer unassociated with cryptorchidism may occur. Male pattern baldness has been associated.

    The patient with RXLI presents with diffuse scale, but usually sparing the flexures. The scales are larger, darker, and thicker in RXLI than in many other ichthyoses (Fig.19.74). For treatment, emollients and keratolytics are used, including ammonium lactate (12% lotion). Oral retinoids (e.g. acitretin) have been used.

Erythrokeratoderma variabilis

Erythrokeratoderma variabilis is a rare keratoderma associated with mutations in the genes that code for connexin. Autosomal dominant inheritance occurs. Circumscribed erythematous, brownish to bright-red lesions that change shape over the course of several hours are characteristic (Fig.19.75). Exacerbation by cold, wind, heat, or emotional stress has been reported. Additionally, hyperkeratotic yellowish brown plaques are characteristic and may develop on normal or previously erythematous skin. The face, buttocks, and limbs are favored sites.

    The course is chronic and may persist throughout life. Topical retinoids may be tried, but the response is variable. Oral retinoids are very effective, but cumulative side effects may limit their long-term use. Oral antihistamines may reduce itch if necessary.

Epidermolytic hyperkeratosis

Epidermolytic hyperkeratosis (EH) is an autosomal dominantly inherited condition characterized by fragility, erosions, and later hyperkeratosis. Defects in the genes that code for keratins 1, 9, and 10 have been found. Patients with epidermal nevi that histologically show EH may give rise to offspring with classic, diffuse EH.

    DiGiovanna and Bale have separated this disease into distinct clinical phenotypes. The presence or absence of PPK is the most helpful distinguishing characteristic, with three PS types (severe palm and sole [PS] hyperkeratosis) and three non-PS types (those without severe palm and sole hyperkeratosis). The classification was always consistent within the families studied. In those families in which mutations were defined, the keratin 10 mutations resulted in a non-PS clinical phenotype, and the keratin 1 mutations, a PS type.

Figure 19.75  Erythrokeratoderma variabilis. Note the annular, red, scaly lesion with the trailing scale.

Clinical

The affected infant will have diffusely red, scaly skin with blister formation (which gave rise to the former name of bullous ichthyosiform erythroderma). Later, the skin becomes diffusely hyperkeratotic and verrucous (Fig.19.76). A very helpful diagnostic sign is the presence of areas of denudation (originally described in ichthyosis bullosa of Siemens, and termed the Mauserung phenomenon) and, later, normal skin adjacent to verrucous areas (Fig.19.77).

Treatment

Bacterial infections may be frequent and should be treated accordingly. Keratolytics such as salicylic acid and ammonium lactate may be helpful. Low-dose acitretin can be dramatically helpful in this chronic disease and may give disease-free periods, but its long-term use may cause skeletal hyperostosis. Radiographs (e.g. of the cervical and thoracic spine) should be obtained yearly if retinoids are used long term. Some patients have benefited from prolonged bathing with scrubbing, followed by emolliation.

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.