Etiology
All inherited ichthyoses have a genetic basis. There are a number of complex interactions of intracellular and extracellular proteins, lipids, nuclear filaments, and enzymes involved in the formation of the epidermis. Defects in any one of these components can lead to altered epidermal function.
Ichthyosis vulgaris (the most common ichthyosis) and epidermolytic ichthyosis are inherited in a dominant fashion. A positive family history is a strong risk factor for the occurrence of these conditions.
Many of the more severe types of ichthyoses are inherited in a recessive pattern. As such, there is a higher frequency of these disorders in consanguineous populations.[5]
Acquired ichthyosis can be caused by medications, including clofazimine, lipid-lowering agents, and butyrophenone.[6][7][8] Several systemic diseases have been reported in association with acquired ichthyosis, including lymphoma, diabetes mellitus, and systemic lupus erythematosus (SLE).[9][10][11][12]
Pathophysiology
The clinical manifestations of the different ichthyoses are the result of a defect in one of the many processes involved in keratinization. The clinical feature common to many of the different ichthyoses is the presence of scales. The size and thickness of these scales vary depending on the particular subtype of ichthyosis, and the degree of scaling can lead to other manifestations of disease, including erythema, pruritus, bacterial colonization, ectropion, and hair loss. Because some of the ichthyoses are caused by a defect in a protein or enzyme that plays a role in the function of other organ systems, systemic manifestations may occur.
Classification
Types of inherited ichthyosis[1]
Common ichthyoses
Ichthyosis vulgaris (autosomal semidominant; mutations in FLG):
Onset in infancy or early childhood of adherent scales; most prominent over lower legs and hyperlinear palms and soles
May have atopic dermatitis, keratosis pilaris.
Recessive X-linked ichthyosis (X-linked recessive; mutations in STS):
Variable scaling, often most prominent on the lateral neck
Associated features include asymptomatic corneal opacities and cryptorchidism.
Nonsyndromic congenital ichthyoses
Autosomal recessive congenital ichthyosis ([ARCI] mutations in ABCA12, TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22, CERS3, PNPLA1):
Umbrella term, including the spectrum of lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE), and harlequin ichthyosis (HI)
Neonatal phenotype is collodion membrane or generalized scaling and erythema, which evolves into mature phenotype of variable scale and redness
Harlequin ichthyosis presents with characteristic thick, yellow scale associated with ectropion and eclabium
Minor variants include self-healing collodion baby and bathing suit ichthyosis.
Keratinopathic ichthyosis:
Epidermolytic ichthyosis (autosomal dominant; mutations in KRT1, KRT10)
Superficial epidermolytic ichthyosis (autosomal dominant; mutations in KRT2). Present at birth with erythema, bullae, and erosions, over time variable hyperkeratosis, often most prominent over flexural sites
Palmoplantar keratoderma classically associated with KRT1 mutations.
Syndromic ichthyosis[1]
Sjogren-Larsson syndrome (autosomal recessive; mutations in ALDH3A2):
Rare neurocutaneous disorder due to deficient activity of fatty aldehyde dehydrogenase (FALDH), an enzyme required to oxidize fatty alcohol to fatty acid
Scaling over the trunk, neck, and flexural sites
Often associated with intense pruritus
Spastic diplegia or tetraplegia and intellectual disability.
Netherton syndrome (autosomal recessive; mutations in SPINK5):
Erythema and scaling at birth that evolves into one of two phenotypes: generalized erythema and scale or ichthyosis linearis circumflexa; many patients also have dermatitis
Associated features include hair shaft abnormalities (trichorrhexis invaginata), elevated serum IgE, allergies, and failure to thrive.
Refsum disease (autosomal recessive; mutations in PHYH, PEX7):
Also known as hereditary motor and sensory neuropathy type 4 (HMSN4)
About 50% of patients have skin findings with fine white scaling that often resembles ichthyosis vulgaris
Associated features include atypical retinitis pigmentosa, anosmia, progressive deafness, peripheral neuropathy, and cerebellar ataxia.
Neutral lipid storage disease with ichthyosis (autosomal recessive; mutations in ABHD5):
Generalized scaling and erythema
Associated features may include myopathy, faltering growth, sensorineural deafness, and cataracts
Lipid-containing vacuoles seen in leukocytes on peripheral blood smear.
Trichothiodystrophy (autosomal recessive; mutations in ERCC2, ERCC3, GTF2H5):
Generalized fine white scaling, brittle hair and nails
Associated features include short stature, intellectual disability, recurrent infections, skeletal anomalies, and photosensitivity.
Keratitis-ichthyosis-deafness syndrome (autosomal dominant; mutations in GJB2):
Presents at birth or early infancy with hyperkeratotic plaques favoring the face and extremities
Associated features include sensorineural hearing impairment and progressive keratitis
Recurrent infections are common, particularly with Candida albicans.
Ichthyosis prematurity syndrome (autosomal recessive; mutations in FATP4):
Triad of premature birth, thick vernix caseosa-like scale, and neonatal asphyxia
Polyhydramnios on prenatal ultrasound.
Conradi-Hunermann-Happle syndrome (X-linked dominant; mutations in EBP):
Redness and scaling along Blaschko lines at birth, evolving into follicular atrophoderma
Associated features include chondrodysplasia punctata, unilateral cataracts, skeletal anomalies, and scarring alopecia.
CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects; X-linked dominant; mutations in NSDHL):
Unilateral redness and adherent yellow scale at birth, which over time becomes hyperkeratotic or verrucous.
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