Keratinopathic ichthyoses

INTRODUCTION — The keratinopathic ichthyoses (KPI) are a group of rare cornification disorders caused by mutations in one of the keratin genes, resulting in abnormalities of the keratin intermediate filaments, a component of the keratinocyte cell cytoskeleton. KPI encompass a spectrum of clinical phenotypes of varying severity. Disorders in the KPI group include epidermolytic ichthyosis, superficial epidermolytic ichthyosis, annular epidermolytic ichthyosis, ichthyosis Curth-Macklin, and ichthyosis with confetti [1].

This topic will review the pathogenesis, clinical manifestations, diagnosis, and management of KPI. A general overview of the ichthyoses is presented separately. Recessive X-linked ichthyosis, Netherton syndrome, Sjögren-Larsson syndrome, and peeling skin syndrome are also discussed separately.

●(See "Overview and classification of the inherited ichthyoses".)

●(See "X-linked ichthyosis".)

●(See "Netherton syndrome".)

●(See "Sjögren-Larsson syndrome".)

●(See "Peeling skin syndromes".)

EPIDEMIOLOGY — In a French study, the prevalence of keratinopathic ichthyoses was estimated at approximately 1.1 per million, inclusive of epidermolytic ichthyosis, superficial epidermolytic ichthyosis, and annular epidermolytic ichthyosis, although others have estimated a frequency of nearly 3.3 per million worldwide [2]. Annular epidermolytic ichthyosis, ichthyosis Curth-Macklin, and ichthyosis with confetti are exceedingly rare, with no reliable estimates of population incidence.

PATHOGENESIS — Most cases of keratinopathic ichthyoses (KPI) result from either mutation arising de novo in the affected individual or via dominant inheritance from an affected parent, though there are rare reports of recessive mutations in KRT10 causing epidermolytic ichthyosis. Linear epidermolytic ichthyosis appearing in patterns representing the dorsoventral migration patterns of keratinocyte precursors has also been described and results from somatic mutation in KRT10 or KRT1 [3]. Generalized epidermolytic hyperkeratosis has been reported in the offspring of parents with linear epidermolytic epidermal nevus [4-7]. (See "Epidermal nevus and epidermal nevus syndrome", section on 'Pathogenesis'.)

Keratin intermediate filaments, a component of the keratinocyte cell cytoskeleton, are expressed in epithelia throughout the body, including in the skin, hair, and nails, and are central to structural integrity and skin barrier function [8]. Keratin expression is both tissue and cell-type specific. In normal skin, keratin 5 and 14 are most abundant in the basal layer but are replaced by keratin 10 and 1 in the suprabasal layers of the epidermis during differentiation [9]. KRT2 expression is further restricted to the upper spinous and granular layers of the skin [10].

Keratins have amino and carboxy-terminal nonhelical domains and two highly conserved rod domains, which permit formation of heterodimers between coexpressed type 1 and type 2 keratins. Heterodimers oligomerize and further associate to form intermediate filaments [11]. In K10, nonhelical domains have repeats of glycine and serine residues giving rise to a globular omega loop structure also present in other intermediate filaments and epidermal proteins, including corneodesmosin and loricrin [12]. These globular domains array on the outside of the keratin fibril and are thought to stabilize filament organization and to direct interaction with other proteins containing similar globular domain structure. Keratin intermediate filaments provide mechanical strength to cells but also function in regulation of cell proliferation, growth, and differentiation [13].

CLINICAL PHENOTYPES

Epidermolytic ichthyosis — Epidermolytic ichthyosis, also called epidermolytic hyperkeratosis or bullous congenital ichthyosiform erythroderma (MIM #113800), is an autosomal dominant disorder of keratinization caused by mutations in the keratin 1 or 10 genes (KRT1 and KRT10). Epidermolytic ichthyosis is characterized by marked skin fragility with blistering and erythroderma at birth (picture 1). Because of blistering and widespread erosions, epidermolytic ichthyosis can initially be mistaken for epidermolysis bullosa. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features".)

During childhood, blistering becomes less frequent, except at sites of trauma, and there is significant clinical heterogeneity in severity. Some individuals develop thick, corrugated scale most prominent at flexures (picture 2A-B), while others develop palmoplantar keratoderma. The spectrum of epidermolytic ichthyosis presentations is correlated with the type of mutated keratin. Palmoplantar keratoderma is most commonly seen in patients with KRT1 mutation, whereas a more generalized disease is more typically associated with KRT10 mutation [14].

Skin infection is a frequent complication in infants and children, though symptoms tend to improve over time.

Minor variants — Minor variants of keratinopathic ichthyoses include superficial epidermolytic ichthyosis, ichthyosis Curth-Macklin, ichthyosis with confetti, and annular epidermolytic ichthyosis (AEI).

Superficial epidermolytic ichthyosis — Superficial epidermolytic ichthyosis (MIM #146800), previously called ichthyosis bullosa of Siemens, is caused by mutations in the KRT2 gene [10]. The clinical phenotypes of superficial epidermolytic ichthyosis tend to be less severe, due to the predominant expression of keratin 2 in the uppermost layers of the epidermis (upper stratum spinosum and stratum granulosum) [15].

Superficial epidermolytic ichthyosis presents at birth with generalized erythema and skin fragility similar to epidermolytic ichthyosis. In infancy and childhood, blistering can occur in response to trauma, particularly on the hands and feet, but tends to be less severe than that seen in epidermolytic ichthyosis. Hyperkeratosis is most prominent on the extremities, with corrugated scale evident at flexures. Erosions tend to be more superficial than in epidermolytic ichthyosis and can manifest as regions of peeling skin. Corrugated hyperkeratosis with dark brown skin develops mainly on the extremities.

Ichthyosis hystrix Curth-Macklin and ichthyosis Lambert type — Ichthyosis Curth-Macklin (MIM #146590) is a rare autosomal dominant disorder caused by mutation in KRT10. It presents with verrucous plaques involving the extensor aspects of arms and legs and palmoplantar keratoderma. A related disorder, ichthyosis hystrix Lambert type (MIM #146600), caused by mutations in KRT10, is characterized by more generalized verrucous plaques involving the entire body, with accentuation at extensor surfaces and less prominent palmoplantar keratoderma (picture 3) [16-18].

Ichthyosis with confetti — Ichthyosis with confetti (IWC; MIM #609165), also called congenital reticular ichthyosiform erythroderma or ichthyosis variegata, is a rare autosomal dominant disorder caused by frameshift mutations in KRT1 or KRT10 genes [19,20].

IWC presents at birth with generalized ichthyosiform erythroderma or a collodion baby and palmoplantar keratoderma. During childhood or adolescence, patients develop hundreds of confetti-like white spots of normal skin on a background of scaling erythroderma. These spots, which increase in number and size over time, result from revertant mosaicism, due to local spontaneous replacement of mutated KRT1 or KRT10 genes by wild-type alleles via mitotic recombination [19,21-23].

Additional clinical features of IWC include ear deformities, severe palmoplantar keratoderma, hypertrichosis, eclabium (outward lip eversion), and ectropion.

Annular epidermolytic ichthyosis — AEI is characterized by blistering and scaling at birth and in the perinatal period with subsequent development of annular or polycyclic hyperkeratotic lesions that can appear and resolve. Specific mutations in KRT1 and KRT10 have been identified that cause AEI [24-26].

PATHOLOGY — On histopathologic examination, epidermolytic ichthyosis shows a thickened, acanthotic epidermis with hyperkeratosis, hypergranulosis, vacuolar degeneration of the stratum spinosum (epidermolysis), and coarse keratohyalin granules in the granular layer. Superficial epidermolytic ichthyosis shows similar features with epidermolysis in the granular layer [27]. Electron microscopy shows clumping of intermediate filament fibrils, which leads to cellular fragility via disruption of intermediate filaments, apoptosis, and cell proliferation [28].

Ichthyosis hystrix Curth-Macklin and Lambert type both feature acanthosis, hyperkeratosis, an absent granular layer, and perinuclear vacuolization due to tonofilament collapse without evidence of epidermolysis [18]. Milder epidermolytic ichthyosis phenotypes also appear to result from filament network collapse rather than filament clumping, leading to lower rates of apoptosis and markedly less severe cell fragility [28].

Ichthyosis with confetti due to KRT10 mutation features acanthosis, perinuclear vacuolization, hyperkeratosis, and parakeratosis [10], while ichthyosis with confetti due to KRT1 mutation features acanthosis, hyperkeratosis, and hypergranulosis [19]. Ichthyosis with confetti due to mutations affecting the nonhelical end domains of K1 and K10 shows on electron microscopy poor investment of desmosomes with keratin intermediate filaments and filament network collapse, with intranuclear accumulation of both proteins [19,21].

DIAGNOSIS — Early consultation with a dermatologist can aid in the diagnosis of keratinopathic ichthyosis in the neonatal period. Newborns with epidermolytic ichthyosis presenting with widespread skin erosions are sometimes misdiagnosed as having epidermolysis bullosa, particularly in cases with a negative family history. Although both disorders can present with areas of denuded skin, a skin biopsy suggests the correct diagnosis. In contrast with epidermolysis bullosa, which shows a subepidermal or intraepidermal cleft, epidermolytic ichthyosis is characterized by hypergranulosis and lysis of the epidermis above the basal layer. Genetic testing for KRT1, KRT2, and KRT10 mutations can confirm the diagnosis.

In adults, the diagnosis of superficial epidermolytic ichthyosis, epidermolytic ichthyosis, or ichthyosis with confetti is suspected based upon the clinical findings and disease history. Examination of a skin biopsy and genetic testing can be performed to confirm the diagnosis. It is important to note that a large fraction of cases are due to de novo mutations present in the affected individual but not in other family members. Such individuals are at risk, however, of transmitting the mutated allele to future generations.

DIFFERENTIAL DIAGNOSIS — In neonates and young infants, congenital or acquired disorders that should be considered in the differential diagnosis of keratinopathic ichthyosis include:

●Epidermolysis bullosa (picture 4) (see "Diagnosis of epidermolysis bullosa")

●Staphylococcal scalded skin syndrome (picture 5) (see "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Staphylococcal scalded skin syndrome')

●Aplasia cutis congenita (picture 6) (see "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Aplasia cutis congenita')

●Congenital herpes simplex virus infection (picture 7) (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis")

●Sucking blisters (picture 8)

In adults, conditions that may mimic keratinopathic ichthyosis include:

●Erythrokeratodermia variabilis et progressiva (EKVP) – The erythrokeratodermias are a heterogeneous group of inherited keratinization disorders characterized by fixed or migratory erythematous plaques and fixed hyperkeratotic plaques, often in association with palmoplantar keratoderma [29,30]. Lesions appear during infancy, progress during childhood, and then become stable. EKVP is caused by mutations in the connexin genes GJB3, GJB4, and GJA1 [30-32].

●Palmoplantar keratodermas (Vohwinkel syndrome, Papillon-Lefèvre syndrome, Unna-Thost keratoderma). (See "The genodermatoses: An overview", section on 'Palmoplantar keratodermas'.)

●Erythrokeratodermia-cardiomyopathy syndrome – Erythrokeratodermia-cardiomyopathy syndrome is a condition associated with mutations in the desmoplakin gene (DSP) and characterized by erythrokeratodermia, progressive cardiomyopathy, and dental enamel and nail abnormalities [33].

MANAGEMENT — The management of patients with keratinopathic ichthyoses involves a close collaboration between dermatologists and pediatricians or primary care providers and specialists as needed. Given the rarity of keratinopathic ichthyoses, the approach to treatment is mainly based upon clinical experience and very limited evidence from small case series and single case reports. (See "Inherited ichthyosis: Overview of management".)

General measures — In the newborn period, if blistering is prominent, treatment is focused on wound healing and prevention of infection and dehydration [34]. Liberal application of petrolatum-based emollients with nonstick dressings favors the re-epithelialization. Beyond the neonatal period, blistering tends to be restricted to pressure and friction-bearing areas, and efforts to reduce friction can ameliorate the disease. When blisters are present, monitoring for signs of infection such as fever or tenderness or redness near sites of blistering is advised.

Over time, most patients will develop hyperkeratosis of the skin and/or palms and soles. Hyperkeratosis can lead to accumulation of scale on the body with formation of thick, corrugated hyperkeratosis and to painful fissuring on the palms and soles. Odor due to bacterial colonization of hyperkeratotic areas is common and is a source of considerable distress for patients. Long bathtub soaks can aid in removing scale, and intermittent diluted bleach baths can decrease colonization with pathogenic microbes and odor associated with hyperkeratosis. A diluted bleach bath is prepared by adding 0.5 cup or 120 mL of 6% bleach in a full bathtub (40 gallons or 150 L) of lukewarm water.

Petrolatum and other bland emollients, humectants, and keratolytics can soften and remove scale and make palms and soles more pliable. In the setting of thick hyperkeratosis on the palms and soles, affected individuals and their caregivers may choose to pare or sand callouses.

Topical and systemic retinoids — Topical and systemic retinoids can be effective in reducing hyperkeratosis and palmoplantar keratoderma. Topical retinoids such as tazarotene or tretinoin can be applied to focal areas once daily in small amounts. The primary side effect of such therapy is local irritation, which may require a reduction in frequency (to once or twice weekly, for example) or amount of application.

When hyperkeratosis is severe, time spent grooming is excessive, or when more widespread improvement in skin appearance is sought, systemic retinoids including isotretinoin and acitretin may be a therapeutic option. Both are oral medications administered at doses ranging from 0.2 to 1.5 mg/kg/day. Given the tendency of these medications to worsen skin fragility, it is advisable to start with a low dose and titrate gradually to efficacy, with a goal of using the lowest dose possible to achieve efficacy.

Dryness of the skin, lips, and eyes is a common adverse effect of systemic retinoids. Other adverse effects include hypertriglyceridemia, mood changes, and ectopic calcification of tendons and ligaments. While adverse effects can be concerning to patients and their families/caregivers, systemic retinoids can lead to significant improvement of skin appearance, quality of life, and ability to conduct activities of daily living.

Monitoring for hypertriglyceridemia and hepatotoxicity are required with retinoid therapy. Systemic retinoids are teratogenic and must not be used during pregnancy. Pregnancy is contraindicated for three years after discontinuing acitretin. In women of child-bearing potential, isotretinoin is preferred to acitretin because of its shorter half-life; pregnancy is contraindicated for one month after discontinuing isotretinoin.

PROGNOSIS — Given the rarity of keratinopathic ichthyoses, long-term studies of disease natural history have not been performed. Improvements in neonatal intensive care have reduced complications in the perinatal period, and early demise is very rare. Affected individuals have normal intelligence, and there is no evidence of reduced lifespan. The skin may require lifelong care. Initiation of social services to help the patient seek resources and providing contact with a patient support group, such as the Foundation for Ichthyosis and Related Skin Types (FIRST), may be beneficial.

Since most keratinopathic ichthyoses are inherited in an autosomal dominant manner, there is significant risk of an affected individual having affected offspring. Genetic counseling can be useful to discuss genetic diagnosis and family planning options, including preimplantation genetic testing. (See "Preimplantation genetic testing".)

SUMMARY AND RECOMMENDATIONS

●Definition – The keratinopathic ichthyoses (KPI) are a group of rare cornification disorders caused by autosomal dominant mutations in the keratin genes KRT1, KRT10, and KRT2. (See 'Introduction' above and 'Pathogenesis' above.)

●Clinical phenotypes – KPI encompass a spectrum of clinical phenotypes of varying severity, including epidermolytic ichthyosis, superficial epidermolytic ichthyosis, ichthyosis hystrix Curth-Macklin (picture 3), ichthyosis with confetti, and annular epidermolytic ichthyosis. Epidermolytic ichthyosis presents at birth with marked skin fragility with blistering and erythroderma. Older children and adults may develop thick, corrugated scale most prominent at flexures (picture 2A-B). (See 'Clinical phenotypes' above.)

●Diagnosis – The diagnosis of KPI is based upon the clinical appearance and the examination of a skin biopsy. Histology typically shows epidermolytic hyperkeratosis (a thickened epidermis with hyperkeratosis, hypergranulosis, vacuolar degeneration of the stratum spinosum, and coarse keratohyalin granules in the granular layer). (See 'Diagnosis' above and 'Pathology' above.)

●Management – In the newborn, treatment is focused on wound healing and prevention of infection and dehydration. Liberal application of petrolatum-based emollients with nonstick dressings favors the re-epithelialization. In older children and adults, treatment is directed at reducing the scale and softening the skin. Topical retinoids (eg, tazarotene, tretinoin) can be applied daily to focal areas. In patients with severe and extensive hyperkeratosis, systemic retinoids (eg, acitretin, isotretinoin) are a therapeutic option. (See 'Management' above.)