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Ichthyoses and Erythrokeratodermas


  • Ichthyoses and erythrokeratodermas represent a diverse group of disorders of cornification, which are characterized by a defective epidermal barrier due to abnormal differentiation and/or desquamation of keratinocytes.

  • Ichthyoses feature diffuse scaling of the skin, often in a widespread distribution, whereas erythrokeratodermas present with circumscribed areas of hyperkeratosis without prominent scaling.

  • These conditions usually have a genetic basis, with the occasional exception of acquired ichthyosis associated with disorders such as malnutrition, hypothyroidism, sarcoidosis, lymphoma, leprosy, or HIV infection.

  • A thorough family history helps in recognizing the inheritance pattern; an affected parent suggests dominant inheritance, whereas inheritance in patients with unaffected parents may be autosomal recessive (especially with affected siblings or parental consanguinity), X-linked recessive (especially for a male patient with affected maternal male relatives), or dominant (e.g. due to a “new” mutation or with incomplete penetrance).

  • Clinical features that are useful in determining the type of ichthyosis include the time of presentation (e.g. at birth, ± a collodion membrane, vs later in life), the quality and distribution of the scaling, other cutaneous manifestations (e.g. erythroderma, blistering, abnormal hair), and extracutaneous or laboratory findings ( Table 46.1 ).

    Table 46.1
    Clues to the diagnosis of ichthyoses and erythrokeratodermas.
    The disorders in this table are discussed in greater detail in the text or Table 46.2 . Other rare ichthyoses and related disorders can also present with these findings. 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.
    Cutaneous findings in neonates

    • Collodion membrane: lamellar ichthyosis, CIE, “self-healing” form >> SLS, TTD, NLSD, others (e.g. infantile Gaucher disease, ectodermal dysplasias)

    • Blisters/erosions/peeling: EI, superficial EI, Netherton syndrome, peeling skin syndromes

    • Erythroderma: EI, CIE, Netherton syndrome, ichthyosis en confetti > SLS, TTD, NLSD, KID, CHH (along lines of Blaschko)

    Other findings

    • Hair shaft abnormalities or hypotrichosis : Netherton, TTD, KID, IFAP

    • Ocular findings : X-linked recessive ichthyosis, SLS, NLSD, TTD, KID § , IFAP § , CHH(unilateral), Refsum

    • Sensorineural hearing impairment : KID, NLSD > Refsum, CHH, CHILD

    • Neurologic abnormalities/developmental delay : SLS, NLSD, TTD, IFAP, Refsum

    • Severe pruritus : ichthyosis vulgaris (with atopic dermatitis), Netherton, SLS, inflammatory peeling skin syndrome

    • Also evaluate for microcephaly, facial dysmorphism, asymmetry, contractures, and hepatosplenomegaly.

    Initial evaluation of a neonate/infant with a collodion membrane or other signs of ichthyosis
    History

    • Prenatal diagnoses, prolonged labor (suggestive of steroid sulfatase deficiency), prematurity

    • Consanguinity makes autosomal recessive ichthyosis more likely

    • Family history of epidermal nevi, ichthyosis, or erythrokeratoderma

    Laboratory evaluation and additional assessment

    • Complete blood count, electrolytes ∗ , hepatic panel ∗∗ , IgE level † ; peripheral blood smear to evaluate for leukocyte vacuoles if suspect NLSD

    • Trichoscopy and light microscopic evaluation of clipped hairs (scalp and eyebrows)

    • ± Skin biopsy – e.g. if bullae (to assess for EI), to assess for diminished granular layer if suspect ichthyosis vulgaris, to detect dystrophic calcification if suspect CHH, or after resolution of collodion membrane for TGM-1 immunostaining

    • Ophthalmologic examination, hearing screen, ± X-rays of epiphyses (if mosaic distribution, for stippling of CHH > CHILD)

    • Consider genetic testing, especially a multigene panel if the diagnosis is not evident based on clinical and laboratory findings

    § Keratitis has variable onset.

    ∗ Hypernatremic dehydration occurs primarily in collodion babies and neonates with Netherton syndrome, EI, or Harlequin ichthyosis.

    ∗∗ Elevated transaminases are common in NLSD.

    † Increased in Netherton and inflammatory peeling skin syndromes.

  • A few ichthyoses such as epidermolytic ichthyosis have characteristic histologic features (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 ∼1 in 100 to 1 in 250.

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

  • Filaggrin deficiency results in impaired cornification, increased transepidermal water loss, enhanced penetration of irritants or allergens, and a propensity for inflammatory responses to the latter; this explains the association of FLG mutations with atopic dermatitis and increased risk of contact dermatitis (irritant and allergic) as well as IV.

  • 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.

  • Associated findings include hyperlinear palms ( Fig. 46.2 ), keratosis pilaris, and atopic dermatitis (25–50% of patients).

    Fig. 46.2, Hyperlinear palms in ichthyosis vulgaris.

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

  • Rx: emollients, humectants (e.g. urea), and keratolytic agents (e.g. lactic, salicylic, and glycolic 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; ∼5% of patients have a larger contiguous gene deletion with manifestations that may also include Kallmann syndrome (hypogonadotropic hypogonadism with anosmia), X-linked recessive chondrodysplasia punctata, ocular albinism, and/or intellectual disability/autism. A higher prevalence of attention deficit hyperactivity disorder has also been reported in children with XLRI.

  • 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.

  • 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) or microarrays (targeted or whole-genome) can detect the underlying deletion in most patients; other methods include genetic testing, detection of increased (hydroxy)cholesterol sulfate (e.g. via increased migration of the β-fraction in serum lipoprotein electrophoresis), and measurement of leukocyte STS activity.

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

  • Rx: topical humectants, keratolytics, and retinoids.

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