CIE, congenital ichthyosiform erythroderma; CHH, Conradi–Hünermann–Happle syndrome; EI, epidermolytic ichthyosis; CHILD, congenital hemidysplasia with ichthyosiform nevus and limb defects; IFAP, ichthyosis follicularis with atrichia and photophobia; KID, keratitis–ichthyosis–deafness syndrome; NLSD, neutral lipid storage disease; SLS, Sjögren–Larsson syndrome; TGM-1, transglutaminase-1; TTD, trichothiodystrophy.

• A few ichthyoses have characteristic histologic features (e.g. epidermolytic ichthyosis; see below).

• For conditions with a known molecular etiology, genetic testing can confirm the diagnosis in the patient and affected relatives as well as provide the basis for prenatal/preimplantation testing.

Ichthyosis Vulgaris (IV)

• The most common disorder of cornification, with a prevalence of at least 1 in 200.

• Autosomal semidominant inheritance – mild ichthyosis with a heterozygous filaggrin (FLG) mutation and more severe ichthyosis with mutations in both FLG alleles.

• Filaggrin deficiency results in impaired formation of cornified keratinocytes, increased transepidermal water loss, and a propensity for an inflammatory response upon exposure to irritants or allergens; this explains the pathogenic role of FLG mutations in atopic dermatitis as well as IV.

• Typically becomes apparent during infancy or early childhood and improves by adulthood; worsens in a cold, dry environment.

• Mild to moderate scaling favors the extensor extremities (Fig. 46.1), ranging from fine white scales to larger adherent scales (especially on the lower legs); the trunk, scalp, and forehead are occasionally affected, and flexural sites are characteristically spared.

Fig. 46.1 Ichthyosis vulgaris. Fine white scales on the lower extremities. Courtesy, Julie V. Schaffer, MD.

• Associated findings include hyperlinear palms (Fig. 46.2), keratosis pilaris, and atopic dermatitis (25–50% of patients, ± other atopic disorders such as asthma and allergic rhinitis).

Fig. 46.2 Hyperlinear palms in ichthyosis vulgaris. Courtesy, S. J. Bale, PhD, and J. J. DiGiovanna, MD.

• DDx: xerosis, acquired ichthyosis, X-linked ichthyosis.

• Rx: emollients (especially those containing ceramides + other lipids), humectants, and keratolytic agents (e.g. urea, lactic and salicylic acids); the latter group may be irritating in patients with coexistent atopic dermatitis.

X-Linked Recessive Ichthyosis (XLRI; Steroid Sulfatase Deficiency)

• Incidence of ~1 in 5000 male births; almost exclusively affects boys and men, with transmission by asymptomatic female carriers.

• The underlying steroid sulfatase deficiency is caused by deletion of the entire STS gene on chromosome Xp22 in ~90% of patients; XLRI is occasionally part of a contiguous Xp microdeletion syndrome that also includes Kallman syndrome (hypogonadotropic hypogonadism with anosmia) and X-linked recessive chondrodysplasia punctata.

• Affected neonates may have generalized exfoliation of translucent scales, followed during infancy by the development of characteristic dark brown, polygonal, adherent scales favoring the neck, preauricular area, scalp (especially in young children), extremities, and trunk; the palms, soles, and flexural sites tend to be spared (Fig. 46.3).

Fig. 46.3 X-linked recessive ichthyosis. Large light brown (A) and more prominent dark brown (B) scales on the lower leg. C Smaller dark brown scales on the trunk, with sparing of the skin folds. D Dark scales on the neck, sometimes referred to as a ‘dirty neck.’ A–C, Courtesy, Julie V. Schaffer, MD; D, Courtesy, Gabriele Richard, MD, and Franziska Ringpfeil, MD.

• Often improves substantially in the summer.

• Associated findings include a perinatal history of prolonged labor due to low placental estrogen production (frequently resulting in birth via cesarean section), cryptorchidism, and asymptomatic corneal opacities.

• Dx: fluorescence in situ hybridization (FISH) detects the underlying deletion in most patients; other methods include measurement of leukocyte STS activity, array comparative genomic hybridization (CGH), and molecular genetic testing.

• Prenatal findings include decreased unconjugated estriol levels in maternal serum and the presence of nonhydrolyzed sulfated steroids in maternal urine.

• Rx: topical humectants, keratolytics, and retinoids.

Epidermolytic Ichthyosis (EI; Bullous Congenital Ichthyosiform Erythroderma, Epidermolytic Hyperkeratosis [EHK])

• Uncommon autosomal dominant disorder due to mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) gene; occasionally occurs in the offspring of an individual with an epidermolytic epidermal nevus due to a mosaic KRT1/10 mutation that involves the gonads as well as the skin.

• Presents at birth with erythroderma, peeling skin, and erosions (Fig. 46.4A); sepsis, dehydration, and electrolyte imbalances may occur.

Fig. 46.4 Epidermolytic ichthyosis (bullous congenital ichthyosiform erythroderma). A Erythroderma with widespread peeling and erosions during the neonatal period. B Later development of hyperkeratosis with focal erosions. C Hyperkeratosis with a cobblestone pattern on the dorsal hand. D Corrugated hyperkeratosis in the antecubital fossa. A, B, Courtesy, Eugene Mirrer, MD; C, Courtesy, S. J. Bale, PhD, and J. J. DiGiovanna, MD; D, Courtesy, Julie V. Schaffer, MD.

• Skin fragility decreases over time, with development of widespread hyperkeratosis that forms corrugated ridges in flexures and a cobblestone pattern on extensor surfaces of joints (Fig. 46.4B–D); palmoplantar keratoderma (PPK) is seen in patients with KRT1 mutations.

• Other manifestations include episodic blistering, secondary skin infections, and a pungent body odor.

• Characteristic histologic changes of epidermolytic hyperkeratosis (e.g. keratinocyte vacuolization and clumped keratin filaments) help to establish the diagnosis.

• DDx: in neonates – epidermolysis bullosa, staphylococcal scalded skin syndrome, other erosive disorders (see Chapter 28); in children/adults – superficial EI, ichthyosis hystrix of Curth–Macklin, other ichthyoses with nonscaling hyperkeratosis (e.g. Sjögren–Larsson and KID syndromes).

• Rx in neonates: protective isolation, emollients, and monitoring.

• Rx in children and adults: emollients/humectants, mechanical exfoliation of hyperkeratotic areas, antiseptic washes (e.g. dilute sodium hypochlorite baths), antimicrobial therapy for superinfections; keratolytics and retinoids (topical or oral) can improve hyperkeratosis but may lead to irritation and exacerbate skin fragility; widespread application of concentrated salicylic acid preparations should be avoided due to risk of salicylism.

• Superficial epidermolytic ichthyosis (ichthyosis bullosa of Siemens) is a related autosomal dominant condition due to mutations in the keratin 2 gene (KRT2), which is expressed only in the upper epidermis; affected individuals have milder, more superficial skin shedding (‘molting’; Fig. 46.5), minimal erythema, and no PPK.

Fig. 46.5 Superficial epidermolytic ichthyosis. Increased skin markings and ‘collarettes’ where the skin has been superficially shed (‘Mauserung’). Courtesy, Anthony Mancini, MD.

• Ichthyosis hystrix of Curth–Macklin, which is caused by specific KRT1 mutations, features hyperkeratosis (sometimes severe and spiky) and PPK similar to epidermolytic ichthyosis, but no skin fragility or histologic evidence of epidermolysis.

Nonsyndromic Autosomal Recessive Congenital Ichthyosis (ARCI): Lamellar Ichthyosis and Congenital Ichthyosiform Erythroderma (CIE)

• Lamellar ichthyosis and CIE exist on a phenotypic spectrum, and nonsyndromic ARCI with these clinical findings can be caused by mutations in at least seven different genes, including those encoding transglutaminase 1 (TGM1; most common), two lipoxygenases (ALOX12B, ALOXE3), and an ABC lipid transporter (ABCA12).

Collodion Baby

• Infants with ARCI (and occasionally other ichthyoses; see Table 46.1) are often born covered by a taut, shiny, transparent membrane resembling plastic wrap, which leads to ectropion, eclabium, and distortion of the nose and ears (Fig. 46.6).

Fig. 46.6 Collodion baby. A Day 1 with ectropion and eclabium. B Day 8 with erythema and diffuse mild scaling and misshapen ears.

• Neonatal complications can include impaired sucking, restricted ventilation, fluid and electrolyte imbalances, skin infections, and sepsis.

• Rx: humidified incubator, emollients, and monitoring for complications; keratolytic agents and manual debridement of the membrane are not advised due to risk of systemic absorption and infection, respectively.

• Within 2 weeks, the membrane peels off in sheets and a transition to the underlying disease phenotype takes place; a subset of collodion babies with underlying mutations in TGM1, ALOX12B, or ALOXE3 have a ‘self-healing’ phenotype where the skin is fairly normal in appearance when the membrane resolves.

Lamellar Ichthyosis

• Characterized by large, brown, plate-like scales with little or no associated erythema (Fig. 46.7).

Fig. 46.7 Lamellar ichthyosis. A Large, plate-like scales on the lower extremities forming a mosaic pattern. B Obvious ectropion as well as plate-like scales. A, Courtesy, Gabriele Richard, MD, and Franziska Ringpfeil, MD.

• Usually generalized, although involvement is limited to the trunk and scalp in the South African ‘bathing suit ichthyosis’ variant (due to a particular TGM1 mutation).

• Associated findings can include ectropion (which may result in conjunctivitis or keratitis), eclabium, scarring alopecia (especially of the peripheral scalp), PPK, nail dystrophy, and heat intolerance due to disruption of sweat ducts.

• Rx: oral retinoids (e.g. acitretin) for severe disease; use of topical retinoids (e.g. tazarotene) and keratolytics is limited by irritation and (for the latter agents) potential systemic absorption if applied to an extensive area; longitudinal ophthalmologic care can help to prevent complications of ectropion.

Congenital Ichthyosiform Erythroderma

• Characterized by erythroderma and small white scales, often with a powdery consistency, in a generalized distribution (Fig. 46.8).

Fig. 46.8 Congenital ichthyosiform erythroderma. The differential diagnosis may include other causes of erythroderma (see Chapter 8). A Intense redness and fine, flaky, white scale on the trunk and arms. Close-up of fine white (B) and coarser yellowish (C) scale in a background of prominent erythema. A, B, Courtesy, S. J. Bale, PhD, and J. J. DiGiovanna, MD.

• The degree of erythema and type of scale varies, and phenotypic overlap with lamellar ichthyosis is often observed; for example, larger, darker scales may be evident, especially on the lower extremities, and some patients have relatively small scales but little associated erythema.

• PPK and nail dystrophy are frequently present, but ectropion and scarring alopecia are less common than in lamellar ichthyosis; severe exfoliative erythroderma represents a substantial metabolic stress that can result in poor growth and failure to thrive in children.

Other Ichthyoses and Erythrokeratodermas

• Major features of several additional ichthyoses and erythrokeratodermas are summarized in Table 46.2 (Figs. 46.9–46.15); many other rare disorders of cornification with diverse cutaneous and extracutaneous manifestations also exist.

Table 46.2

Major features of other selected ichthyoses and erythrokeratodermas.

ABCA12, ATP-binding cassette, subfamily A, member 12; ABHD5, abhydrolase domain-containing 5; AD, autosomal dominant; ALDH3A2, aldehyde dehydrogenase 3A2; AR, autosomal recessive; CHILD, congenital hemidysplasia with ichthyosiform nevus and limb defects; CIE, congenital ichthyosiform erythroderma, EBP, emopamil binding protein (sterol isomerase); ERCC2/3, excision repair cross-complementing 2/3; FTT, failure to thrive; GJB2/3/4, gap junction β2/3/4 (encoding connexins 26/31/30.3); GTF2H5, general transcription factor IIH, polypeptide 5; KRT10, keratin 10; NSDHL, NAD(P)-dependent steroid dehydrogenase-like; PEX7, peroxisome biogenesis factor 7; PHYH, phytanoyl-CoA hydroxylase; PPK, palmoplantar keratoderma; SCC, squamous cell carcinoma; SPINK5, serine protease inhibitor Kazal type 5; X-D, X-linked dominant.