Etiology/Pathogenesis

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.

Clinical Manifestations

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.

Histology

Common morphologic abnormalities include hyperkeratosis, accumulation of lipid droplets within corneocytes, and absence of normal lamellar granules.

Treatment

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.

Etiology

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.

Clinical Manifestations

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.

Figure 650-1 Typical appearance of a collodion baby.

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.

Histology

Biopsy reveals a thickened stratum corneum with compact orthokeratotic hyperkeratosis.

Treatment

A high-humidity environment and application of nonocclusive lubricants facilitates shedding of the membrane.

Etiology/Pathogenesis

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.

Mutations in the gene encoding ichthyn may cause either lamellar ichthyosis or congenital ichthyosiform erythroderma. The function of icthyn is unknown.

Clinical Manifestations

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.

Figure 650-2 Generalized scaling of lamellar ichthyosis.

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.

Figure 650-3 Prominent erythema and scale in congenital ichthyosiform erythroderma.

Histology

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.

Treatment

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.

Etiology/Pathogenesis

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.

Clinical Manifestations

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.

Figure 650-4 Scale over the shin in ichthyosis vulgaris.

Histology

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.

Treatment

Scaling may be diminished by daily applications of an emollient or a lubricant containing urea (10-40%), salicylic acid, or an α-hydroxy acid such as lactic acid (5-12%).

Etiology/Pathogenesis

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.

Clinical Manifestations

Skin peeling may be present at birth but typically begins at 3-6 mo of life. Scaling is most pronounced on the sides of the neck, lower face, preauricular areas, anterior trunk, and the limbs, particularly the legs. The elbow (Fig. 650-5) and knee flexures are generally spared but may be mildly involved. The palms and soles may be slightly thickened but are also usually spared. The condition gradually worsens in severity and extent. Keratosis pilaris is not present, and there is no increased incidence of atopy. Deep corneal opacities that do not interfere with vision develop in late childhood or adolescence and are a useful marker for the disease because they may also be present in carrier females. Some patients have larger deletions on the X chromosome that encompass neighboring genes, generating contiguous gene deletion syndromes. These include Kallmann syndrome (KAL1 gene), which consists of hypogonadotrophic hypogonadism and anosmia, X-linked chondroplasia punctata (ARSE gene), short stature, and ocular albinism. The rate of testicular cancer may be increased in patients with coexistent Kallmann syndrome. There is also an increased risk of attention deficit hyperactivity disorder and autism owing to a contiguous gene defect in neuroglin 4.

Figure 650-5 Sparing of the antecubital fossa in X-linked ichthyosis.

Reduced steroid sulfatase enzyme activity can be detected in fibroblasts, keratinocytes, and leukocytes and, prenatally, in amniocytes or chorionic villus cells. In affected families, an affected male can be detected by restriction enzyme analysis of cultured chorionic villus cell DNA or amniocytes or by in situ hybridization, which identifies steroid sulfatase gene deletions prenatally in chorionic villus cells. A placental steroid sulfatase deficiency in carrier mothers may result in low urinary and serum estriol values, prolonged labor, and insensitivity of the uterus to oxytocin and prostaglandins.

Histology

Histologic findings in X-linked ichthyosis consist of hyperkeratosis of the stratum corneum, a well-developed granular layer, and a hyperplastic epidermis.

Treatment

Daily application of emollients and a urea-containing lubricant (10-40%) are usually effective. Glycolic or lactic acid (5-12%) in an emollient base and propylene glycol (40-60%) in water with occlusion overnight are alternative forms of therapy.

Etiology/Pathogenesis

Epidermolytic hyperkeratosis is an autosomal dominant trait that has been shown to be due to defects in either keratin 1 or keratin 10. These keratins are required to form the keratin-intermediate filaments in cells of the suprabasilar layers of the epidermis.

Clinical Manifestations

The clinical manifestations are initially characterized by the onset at birth of widespread blisters and erosions on a background of generalized erythroderma (Fig. 650-6). Recurrent blistering may be widespread in neonates and may cause diagnostic confusion with other blistering disorders. With time, the blister formation ceases, erythema decreases, and generalized hyperkeratosis develops. The scales are small, hard, and verrucous. Distinctive, parallel hyperkeratotic ridges develop over the joint flexures, including the axillary, popliteal, and antecubital fossae, and on the neck and hips. Palmoplantar keratoderma is associated with keratin 1 defects. The hair, nails, mucosa, and sweat glands are normal. Malodorous secondary bacterial infection is common and requires appropriate antibiotic therapy.

Figure 650-6 Superficial erosions and hyperkeratosis in epidermolytic hyperkeratosis.

Pathology

The histopathology is diagnostic of epidermolytic hyperkeratosis, consisting of hyperkeratosis, degeneration of the epidermal granular layer with an increased number of keratohyalin granules, clear spaces around nuclei, and indistinct cellular boundaries of cells in the upper epidermis. On electron microscopic examination, keratin-intermediate filaments are clumped, and many desmosomes are attached to only one keratinocyte instead of connecting neighboring keratinocytes. Localized forms of the disease may resemble epidermal nevi or keratoderma of the palms and soles but share the distinctive histopathologic changes of epidermolytic hyperkeratosis.

Treatment

Treatment of epidermolytic hyperkeratosis is difficult. Morbidity is increased in the neonatal period as a result of prematurity, sepsis, and fluid and electrolyte imbalance. Bacterial colonization of macerated scales produces a distinctive bad odor that can be controlled somewhat by use of an antibacterial cleanser. Intermittent oral antibiotics are generally necessary. Keratolytic agents are often poorly tolerated. Oral retinoids (1 mg/kg/day) may produce significant improvement. Prenatal diagnosis for affected families is possible by examination of DNA extracts from chorionic villus cells or amniocytes, provided that the specific mutation in the affected parent is known.

Etiology/Pathogenesis

An autosomal dominant disorder, erythrokeratoderma variabilis (EKV) is caused by mutations in connexins 31 and 30.3. Connexins are proteins that form gap junctions between cells that allow for transport and signaling between neighboring epidermal cells.

Clinical Manifestations

EKV usually manifests in the early months of life, progresses in childhood, and stabilizes in adolescence. It is characterized by two distinctive manifestations: sharply demarcated, hyperkeratotic plaques (Fig. 650-7A) and transient figurate erythema (Fig. 650-7B). The distribution is generalized but sparse; sites of predilection are the face, buttocks, axillae, and extensor surfaces of the limbs. The palms and soles may be thickened, but hair, teeth, and nails are normal.

Figure 650-7 Erythrokeratoderma variabilis. A, Fixed, hyperkeratotic plaques, B, Migratory, erythematous lesion.

Histology

Histopathology demonstrates hyperkeratosis, papillomatosis, and irregular hyperplasia of the epidermis.

Treatment

There are case reports that topical tazarotene gel 0.1% and oral retinoids (1 mg/kg/day) are effective for treatment of EKV.

Etiology/Pathogenesis

Symmetric progressive erythrokeratoderma is an autosomal dominant disorder caused by mutations in the gene encoding loricrin. Loricrin is a major component of the epidermal cornified cell envelope.

Clinical Manifestations

The disorder manifests in childhood as large, fixed, geographic and symmetric, fine, scaling, hyperkeratotic, erythematous plaques primarily on the extremities, buttocks, face, ankles, and wrists. The primary feature distinguishing this disorder from EKV is the lack of variable erythema seen in the latter condition.

Histology

There is papillated epidermal hyperplasia with hypergranulosis, parakeratosis and orthokeratosis.

Treatment

Symmetric progressive erythrokeratoderma is a very rare disorder, but reports of response to topical and oral retinoids (1 mg/kg/day) exist.

Sjögren-Larsson Syndrome

Netherton Syndrome

Clinical Manifestations

Netherton syndrome is characterized by ichthyosis (usually ichthyosis linearis circumflexa but occasionally the lamellar or congenital types of ichthyosiform erythroderma), trichorrhexis invaginata and other hair shaft anomalies, and atopic diathesis. The disorder manifests at birth or in the first few months of life as generalized erythema and scaling. The trunk and limbs have diffuse erythema and superimposed migratory, polycyclic, and serpiginous hyperkeratotic lesions (Fig. 650-8), some with a distinctive double-edged margin of scale. Lichenification or hyperkeratosis tends to persist in the antecubital and popliteal fossae. The face and scalp may remain erythematous and scaling. Many hair shaft deformities, most notably, trichorrhexis invaginata, have been described in most patients with Netherton syndrome.

Figure 650-8 Serpiginous, erythematous, hyperkeratotic lesions of ichthyosis linearis circumflexa.

The ichthyosis is present in the first 10 days of life and may be especially marked around the eyes, mouth, and perineal area. The erythroderma is often intensified after infection. Infants may suffer from failure to thrive, recurrent bacterial and candidal infections, elevated serum immunoglobulin (Ig) E values, and marked hypernatremic dehydration. The most frequent allergic manifestations are urticaria, angioedema, atopic dermatitis, and asthma. Scalp hair is sparse and short and fractures easily (Fig. 650-9); eyebrows, eyelashes, and body hair are also abnormal. The characteristic hair abnormality can be identified with light microscopy; in the newborn, it may best be identified in eyebrow hair.

Figure 650-9 Very short scalp hair and thick scale in Netherton syndrome.

Refsum Syndrome (Chapters 80.2 and 605.5)

Chondrodysplasia Punctata (Chapter 80.2)

Other Syndromes with Ichthyosis

A number of other rare syndromes with ichthyosis as a consistent feature include the following: keratitis with ichthyosis and deafness (KID syndrome, connexin 26 gene), ichthyosis with defective hair having a banded pattern under polarized light and a low sulfur content (trichothiodystrophy), multiple sulfatase deficiency, neutral lipid storage disease with ichthyosis (Chanarin-Dorfman syndrome/CGI58 gene), and CHILD syndrome (Fig. 650-10; congenital hemidysplasia with ichthyosiform erythroderma and limb defects; NSDHL gene).

Figure 650-10 Limb dysplasia and ichthyosiform eruption in CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome.