Chapter 650 Disorders of Keratinization
Disorders of cornification (ichthyoses) are a primary group of inherited conditions characterized clinically by patterns of scaling and histopathologically by hyperkeratosis. They are usually distinguishable on the basis of inheritance patterns, clinical features, associated defects, and histopathologic changes (Table 650-1).
Harlequin ichthyosis is caused by mutations in the ABCA12 gene. Mutation in the gene leads to defective lipid transport and ABCA12 activity is required for the generation of long-chain ceramides that are essential for the development of the normal skin barrier.
At birth, markedly thickened, ridged, and cracked skin forms horny plates over the entire body, disfiguring the facial features and constricting the digits. Severe ectropion and chemosis obscure the orbits, the nose and ears are flattened, and the lips are everted and gaping. Nails and hair may be absent. Joint mobility is restricted, and the hands and feet appear fixed and ischemic. Affected neonates have respiratory difficulty, suck poorly, and are subject to severe cutaneous infection. Most die within the first days to weeks of life, but patients occasionally survive beyond infancy and have severe ichthyosis usually resembling lamellar ichthyosis or congenital ichthyosiform erythroderma.
Initial treatment includes high fluid intake to avoid dehydration from transepidermal water loss and use of a humidified heated incubator, emulsifying ointments, careful attention to hygiene, and oral retinoids (1 mg/kg/day). Prenatal diagnosis has been accomplished by fetoscopy, fetal skin biopsy, and microscopic examination of cells from amniotic fluid.
Collodion baby is not a single entity but a newborn phenotype that is most often seen in babies who will eventually demonstrate lamellar ichthyosis or congenital ichthyosiform erythroderma. Less commonly, collodion babies evolve into babies with other forms of ichthyosis or Gaucher disease. A small subset become otherwise healthy babies without chronic skin disease.
Collodion babies are covered at birth by a thick, taut membrane resembling oiled parchment or collodion (Fig. 650-1), which is subsequently shed. Affected neonates have ectropion, flattening of the ears and nose, and fixation of the lips in an O-shaped configuration. Hair may be absent or may perforate the abnormal covering. The membrane cracks with initial respiratory efforts and, shortly after birth, begins to desquamate in large sheets. Complete shedding may take several weeks, and a new membrane may occasionally form in localized areas.
Neonatal morbidity and mortality may be due to cutaneous infection, aspiration pneumonia (squamous material), hypothermia, or hypernatremic dehydration from excessive transcutaneous fluid losses as a result of increased skin permeability. The outcome is uncertain, and accurate prognosis is impossible with respect to the subsequent development of ichthyosis.
Lamellar Ichthyosis and Congenital Ichthyosiform Erythroderma (Nonbullous Congenital Ichthyosiform Erythroderma)
Lamellar ichthyosis and congenital ichthyosiform erythroderma (nonbullous congenital ichthyosiform erythroderma) are the most common types of autosomal recessively inherited ichthyosis. Both forms are present soon or shortly after birth. Most infants with these forms of ichthyosis present with erythroderma and scaling; but among collodion babies, most turn out to have one of these ichthyosis variants.
Three genes have been identified that cause lamellar ichthyosis (LI). These are LI1 (TGM1), LI2 (ABCA12), and LI3 (CYP4F22). Other genes have also been linked to LI, but they have not yet been identified. Transglutaminase mutations lead to abnormalities in the cornified envelope, whereas defects in ABCA12 cause abnormal lipid transport and those in CYP4F22 produce abnormal lamellar granules.
Three mutations have also been identified as the causes of congenital ichthyosiform erythroderma. These are TGM1, ALOX12B, and ALOX3. The ALOX genes encode for lipoxygenases the function of which is not definitively known. These lipoxygenases are likely to play a role in epidermal barrier formation by affecting lipid metabolism.
After shedding of the collodion membrane, if present, lamellar ichthyosis evolves into large, quadrilateral, dark scales that are free at the edges and adherent at the center. Scaling is often pronounced and involves the entire body surface, including flexural surfaces (Fig. 650-2). The face is often markedly involved, including ectropion and small, crumpled ears. The palms and soles are generally hyperkeratotic. The hair may be sparse and fine, but the teeth and mucosal surfaces are normal. Unlike in congenital ichthyosiform erythroderma, there is little erythema.
In congenital ichthyosiform erythroderma, erythroderma tends to be persistent, and scales, although they are generalized, are finer and whiter than in lamellar ichthyosis (Fig. 650-3). Hyperkeratosis is particularly noticeable around the knees, elbows, and ankles. Palms and soles are uniformly hyperkeratotic. Patients have sparse hair, cicatricial alopecia, and nail dystrophy. Neither form includes blistering.
A markedly thickened stratum corneum and mild, irregular epidermal thickening characterize lamellar ichthyosis. Congenital ichthyosiform erythroderma involves more epidermal thickening with parakeratosis but less hyperkeratosis and hypergranulosis than in lamellar ichthyosis.
Pruritus may be severe and responds minimally to antipruritic therapy. The unattractive appearance of the child and the bad odor from bacterial colonization of macerated scales may create serious psychological problems. A high-humidity environment in winter and air conditioning in summer reduce discomfort. Generous and frequent applications of emollients and keratolytic agents such as lactic or glycolic acid (5-12%), urea (10-40%), tazarotene (0.1% gel), and retinoic acid (0.1% cream) may lessen the scaling to some extent, although these agents produce stinging if applied to fissured skin. Oral retinoids (1 mg/kg/day) have a beneficial effect in these conditions but do not alter the underlying defect and, therefore, must be administered indefinitely. The long-term risks of these compounds (teratogenic effects and toxicity to bone) may limit their usefulness. Ectropion requires ophthalmologic care and, at times, plastic surgical procedures.
Autosomal dominant or recessive mutations in the filaggrin gene cause ichthyosis vulgaris. Filaggrin is a filament-aggregating protein that assembles the keratin filament cytoskeleton, causing collapse of the granular cells into classic flattened squamous cell shape. Mutations in filaggrin lead to absence or marked reductions in keratohyalin granules.
Ichthyosis vulgaris is the most common of the disorders of keratinization, with an incidence of 1/250 live births. Onset generally occurs in the 1st yr of life. In most cases, it is trivial, consisting only of slight roughening of the skin surface. Scaling is most prominent on the extensor aspects of the extremities, particularly the legs (Fig. 650-4). Flexural surfaces are spared, and the abdomen, neck, and face are relatively uninvolved. Keratosis pilaris, particularly on the upper arms and thighs, accentuated markings, and hyperkeratosis on the palms and soles, and atopy are relatively common. Scaling is most pronounced during the winter months and may abate completely during warm weather. There is no accompanying disorder of hair, teeth, mucosal surfaces, or other organ systems.
The histopathologic changes in ichthyosis vulgaris differ from those of other types of ichthyosis in that the hyperkeratosis is associated with a decrease or absence of the granular layer. Abnormally small and crumbly keratohyalin granules are found in epidermal cells on electron microscopy.
X-linked ichthyosis involves a deficiency of steroid sulfatase, which hydrolyzes cholesterol sulfate and other sulfated steroids to cholesterol. Cholesterol sulfate accumulates in the stratum corneum and plasma. In the epidermis this accumulation causes malformation of intercellular lipid layers, leading to barrier defects and delay of corneodesmosome degradation, resulting in corneocyte retention.