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Diagnosis: Lamellar Ichthyosis

Diagnosis: Lamellar Ichthyosis

The patient was diagnosed with bathing suit lamellar ichthyosis, a variant of lamellar ichthyosis often seen in South African blacks.1,2

Background and History

Originally derived from the Greek word ICQUS (ichthys), meaning fish, the ichthyoses are a heterogeneous group of skin disorders characterized by generalized scaling of the skin. Features of the ichthyoses are so distinct that early medical writings dating back to circa 200 BC from Indian and Chinese literature describe them as diseases resembling a snakeskin or the scales of a fish.3 And though all ichthyoses have scaling in common, their clinical manifestations vary widely. They can be inherited or acquired, present at birth or later in life, and limited to the skin or a part of a multisystem disorder. The term lamellar ichthyosis was first coined by Frost and Van Scott in 1966 and was used for all autosomal recessive forms of non-bullous congenital ichthyoses.4 Later, Williams and Elias further subdivided this group into what we know today as lamellar ichthyosis and nonbullous congenital ichthyosiform erythroderma.5

Epidemiology

Lamellar ichthyosis is a rare genodermatosis that occurs worldwide with an estimated prevalence of 1 in 300,000 live births, affecting females and males equally. However, it is seen more frequently in consanguineous communities and certain regions such as Norway where the prevalence approximates 1 in 91,000.6 Although previously thought to be solely autosomal-recessive in nature, Traupe et al recently reported on an autosomal-dominant form that is phenotypically indistinguishable from its autosomal recessive counterpart.7

Clinical Features

Lamellar ichthyosis is a severe and chronic disorder that presents at birth and persists throughout life. Most of those affected are born encased in a collodion membrane with underlying erythroderma, and associated ectropion and eclabium. Sometimes nail dystrophy and hypoplasia of nasal and auricular cartilages may be seen. Additionally, there may be hypohidrosis and hyperpyrexia in the neonatal period, giving rise to thermoregulatory problems and possible seizure activity, both of which may persist throughout life.8 Eventually, the collodion membrane is shed and large, plate-like, dark brown scales emerge, which are centrally attached with raised borders. Often, superficial fissures are noted between the plate-like scales.

Differential Diagnosis

The differential diagnosis for lamellar ichthyosis includes: epidermolytic hyperkeratosis, self-healing collodion baby, Sjörgen-Larssen syndrome, X-linked ichthyosis, congenital ichthyosiform erythroderma, Comèl Netherton’s syndrome, and trichothiodystrophy. In the neonatal period, there is considerable overlap with other congenital ichthyoses that present as a collodion baby. However, later in life, lamellar ichthyosis is usually distinguished from other forms of ichthyoses based on history and clinical findings, as mentioned above.6

Pathogenesis and Histopathology

Lamellar ichthyosis is a very heterogeneous disease with both homozygous and compound heterozygous mutations documented.9 Thus far, seven genes have been identified, with the vast majority of cases — approximately 40% — attributed to mutations in transglutaminase-1.2.10 Table 2 discusses each gene implicated and its function.11-18 The pathology of lamellar ichthyosis occurs in the cornified cell envelope. In particular, gene mutations result in decreased amounts of free fatty acids produced, and alterations of ceramide fractions 2, 3a, 3b, 4 and 5. This leads to atypical ratios of free fatty acid to ceramide and free fatty acid to cholesterol, which cause irregular cross-linking of the cornified cell envelope. Clinically, this causes abnormal hyperkeratosis of the stratum corneum, with an impaired skin barrier function and increased transepidermal water loss.19 Structurally, the irregular cross-linking can be appreciated via freeze fracture electron microscopy, which shows the lipids predominantly arranged in a hexagonal lattice pattern when viewed laterally. In comparison, normal stratum corneum lipids are arranged predominantly in an orthorhombic lattice-like pattern.20 By light microscopy, one sees marked hyperkeratosis and moderate acanthosis with a normal or thickened granular layer in those affected with lamellar icthyosis. In addition, mild papillomatosis and dermal capillary dilatation can sometimes be present.21

Laboratory Investigations

Since there is considerable variability in phenotypes, diagnostic testing is sometimes necessary. Prenatal diagnosis of lamellar ichthyosis can be achieved by electron microscopic examination of fetal skin biopsies or amniotic fluid cells obtained via fetoscopy.6 DNA-based molecular genetic testing is commercially available for TGM1, ABCA12, ALOXE3 and ALOX12B.22 Alternatively, skin biopsies may be examined by light microscopy and electron microscopy for histological features, or for detection of in situ TGM1 expression and activity.

Prognosis and Complications

Although life expectancy is normal, it has been reported that those affected with lamellar ichthyosis have impaired growth due to a defective skin permeability barrier with increased chronic losses of water and calories.23 The tight adhesion of plate-like scales constricts and obstructs sweat ducts, causing heat intolerance, which further contributes to caloric expenditure and water loss. Moreover, tight adhesion and excess accumulation of scale in areas such as the external ear canal predispose those affected to bacterial colonization and recurrent ear infections.6 Other complications seen in lamellar ichthyosis include: scarring alopecia occurring at the periphery of the scalp, secondary nail dystrophy with thickened nail plates and ridging due to chronic inflammation of the nail folds, and palmoplantar keratoderma.6 However, the most worrisome complication is ectropion. Usually, it is of the cicatricial type and can be severe. Ectropion can lead to corneal ulceration, vascularization and corneal scarring with subsequent blindness if not treated promptly.21

Treatment

In regard to treatment, moisturizers are the mainstay of therapy during the neonatal period and throughout life. Moisturizers increase the flexibility of the epidermis, hydrate and restore the epidermal barrier function, and aid in covering and removal of the scale.24

For infants. In addition to moisturization, neonates should be monitored for fluid and electrolyte imbalances and temperature regulation. Infants should be referred to ophthalmology for ectropion management and otorhinolaryngology for external ear cleaning and auditory testing.

After age 1. After the first year of life, mechanical removal of scale with microfiber washcloths, and urea may be started. Urea, a humectant, binds water and facilitates epidermal barrier regeneration with additional keratolytic and antimicrobial effects. However, salicylic acid, although a keratolytic too, is contraindicated in infants and children due to increased systemic absorption and the risk of metabolic acidosis.25

Older children and adults. In older children and adults, moisturizers and keratolytics are the mainstay of topical therapy. Salicylic acid too can be used in this population for localized refractory areas.25 However, topical retinoids and topical calcipotriene have been used with some success, and with little systemic absorption. 26-29

Systemic therapy. Oral retinoids appear to be most effective in treating the non-bullous congenital ichthyoses, particularly lamellar ichthyosis. Although retinoids have a profound effect on epidermal differentiation, the most likely mechanism of action in regard to treating the ichthyoses is thinning of the stratum corneum and accelerated epidermal turnover. However, the side effects, teratogenicity and the risk management program iPLEDGE severely limit its use.30-31 Emerging therapy with retinoic acid metabolism blocking agents, such as talarozole and liarozole, show promise with all advantages of the retinoid effects but with fewer side effects and a shorter post-treatment teratogenicity period.32 Hopefully, gene therapy will be on the horizon in the near future.

Dr. Briley is a third-year dermatology resident at St. John’s Episcopal Hospital in Far Rockaway, NY. Dr. Sirota-Rozenberg is the assistant director of the dermatology residency program at St. John’s Episcopal Hospital in Far Rockaway, NY. Dr. Khachemoune, the Section Editor of Derm Dx, is with Department of Dermatology, State University of New York, Brooklyn, NY.

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