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Autosomal recessive congenital ichthyoses

Autosomal recessive congenital ichthyoses
Literature review current through: Jan 2024.
This topic last updated: Jul 06, 2023.

INTRODUCTION — The inherited ichthyoses are skin disorders characterized by scaling and erythema with or without associated systemic abnormalities. Autosomal recessive congenital ichthyoses (ARCI) encompass several rare phenotypes of varying severity, from severe/life-threatening (eg, harlequin ichthyosis, lamellar ichthyosis, and congenital ichthyosiform erythroderma) to intermediate, milder forms with moderate degrees of erythema and scaling (eg, self-improving collodion ichthyosis) [1]. Other phenotypes inherited in an autosomal recessive manner include syndromic forms, such as Sjögren-Larsson syndrome, Netherton syndrome, neutral lipid storage disease, and trichothiodystrophy.

This topic will review the major types of ichthyoses inherited in an autosomal recessive fashion and will utilize the consensus nomenclature adopted by the 2009 Ichthyosis Consensus Conference [2].

An overview of the inherited ichthyoses, including rare types of ARCI, and other types of ichthyoses are discussed separately.

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

(See "Ichthyosis vulgaris".)

(See "X-linked ichthyosis".)

(See "Keratinopathic ichthyoses".)

EPIDEMIOLOGY — ARCI are rare, and individual subtypes have an average population frequency of 1:200,000 individuals (except in areas where consanguinity is more common) [3].

PATHOGENESIS

Skin barrier abnormalities — The epidermis is a stratified, squamous, keratinizing epithelium, and its primary cellular component, the keratinocyte, undergoes a patterned program of gene expression tied to function. In the proliferating basal layer, genes relevant to cell adhesion are highly expressed, while suprabasal layers express structural proteins and components central to the barrier function of the skin. In the top layers of the epidermis, the end product cell is the anucleate corneocyte, which is central both to the structural integrity of the skin and to water retention and is shed via a process known as desquamation [4].

The primary physiologic defect underlying the scaling and redness of ARCI is a compromised barrier function of the skin. Pathogenic variants in genes relevant to lipid biosynthesis, intercellular adhesion, shedding of differentiated cells, and vitamin A biosynthesis (among others) all result in barrier dysfunction. (See 'Genetics' below.)

The skin barrier disruption is associated with alteration of the skin microbiome, with significant loss of skin commensals (such as the lipophilic microorganisms Cutibacterium acnes and Malassezia globosa) and concurrent increase of Staphylococcus and Corynebacterium species [5].

Genetics — The increased accessibility and decreased cost of whole exome sequencing has enabled the discovery of many new genetic causes of ARCI. Variants in specific genes involved in the maintenance of the skin barrier may be predictive of both disease severity and risk of extracutaneous findings, though the wide phenotypic variation makes it difficult to establish genotype-phenotype correlations. Many genetic and epigenetic factors are likely to impact the outcome for any one particular patient [6].

The primary disease phenotypes of nonsyndromic ARCI are caused by variants in at least 13 genes [6,7]:

ABCA12, encoding an ATP-binding cassette (ABC) transporter that transports lipids into lamellar bodies

ALOX12B and ALOXE3, encoding lipoxygenases that oxygenate ceramides necessary for the corneocyte lipid envelop

CERS3, encoding ceramide synthase 3

CYP4F22, encoding a fatty acid omega-hydroxylase involved in the biosynthesis of acylceramides

NIPAL4, encoding the protein ichthyin in the NIPA-like domain that functions as a Mg2+ transporter involved in lipid processing and lamellar body formation

PNPLA1, encoding patatin-like phospholipase domain-containing 1, which is involved in acylceramide biosynthesis

SDR9C7, encoding a protein with similarity to the short-chain dehydrogenase/reductase (SDR) family

SULT2B1, encoding sulfotransferase family 2B member 1

TGM1, encoding transglutaminase 1, an enzyme that cross-links proteins to form the cornified cell envelope

LIPN, encoding lipase family member N, a lipase that is highly expressed in granular keratinocytes in the epidermis and is involved in keratinocyte differentiation

CASP14, encoding a member of the caspase family involved in cell apoptosis

SLC27A4, encoding a member of a family of fatty acid transport proteins

Approximately 15 percent of patients with ARCI do not have pathogenic variants in any of the genes listed above [6,8].

Emerging evidence suggests that genetic variants underlying ARCI contribute to inflammation and shifts in the microbiome, though much research is needed to understand how mutations affecting many distinct cellular functions result in common phenotypic features [9].

CLINICAL PHENOTYPES — ARCI encompass cutaneous phenotypes of varying severity (table 1). Although most are characterized by the accumulation of abnormal scale, some disorders feature excessive desquamation that results in a red, denuded, and scaly skin appearance. Congenital ichthyosis may also be part of a number of autosomal recessive syndromic disorders with manifestations involving every organ system (table 2).

Collodion infant — The majority of patients with ARCI present at birth with red, scaly skin, and many will present as collodion infants [10]. In collodion presentations, infants are born with a clear, shiny, and taut membrane covering the entire skin. Associated skin tightness often causes out-turning of the eyelids (ectropion) and lips (eclabium) (picture 1). With supportive care, this membrane spontaneously sheds over days to weeks to reveal red, scaly, tight, or thickened skin.

Nonsyndromic autosomal recessive congenital ichthyoses — In nonsyndromic ARCI, the phenotypic expression of the disorder is seen only in the skin (table 1).

Lamellar ichthyosis phenotype — While variants in many genes can present with a lamellar ichthyosis phenotype, most patients have variants in TGM1 (which encodes transglutaminase 1) [11]. TGM1 is an enzyme necessary for cross-linking proteins that comprise the cornified envelope of differentiated keratinocytes and provides a scaffold for the elaboration of lipid. Recessive, loss-of-function variants cause the lamellar ichthyosis phenotype.

Lamellar ichthyosis most commonly presents at birth with a collodion membrane, which is shed to reveal red, scaly skin that develops large, plate-like scales that are most prominent on the trunk and lower extremities (picture 2A-C). Persistent ectropion and eclabium are common. The palms and soles can be variably affected, with some cases manifesting marked thickening (palmoplantar keratoderma) (picture 3). (See "Palmoplantar keratoderma".)

Thick scaling of the scalp can lead to peripheral scarring alopecia, as scale surrounds and pulls upon hair. Scaling occludes sweat glands, leading to anhidrosis or hypohidrosis, and many patients suffer from heat intolerance and are at risk for overheating.

Congenital ichthyosiform erythroderma phenotype — Autosomal recessive biallelic pathogenic variants in ALOXE3 or ALOX12B commonly cause congenital ichthyosiform erythroderma [12]. These genes encode lipoxygenases, which are necessary for the formation of fatty acid precursors of the cutaneous lipid barrier.

Congenital ichthyosiform erythroderma typically presents with a collodion membrane at birth that sheds to reveal red skin and fine, white, generalized scaling. Ectropion, if present, tends to be mild, and eclabium is rarely seen. There is variability in the ability to sweat, and many patients have anhidrosis. Palmoplantar keratoderma may be present but tends to be milder than that seen in lamellar ichthyosis.

Harlequin ichthyosis phenotype — Harlequin ichthyosis is caused by autosomal recessive biallelic variants in ABCA12, which encodes a transporter involved in epidermal lipid transport and secretion. Loss-of-function variants cause the severe harlequin ichthyosis phenotype, while less damaging missense mutations have been found in patients with less severe phenotypes [13,14].

Harlequin ichthyosis has a dramatic, sometimes fatal, neonatal presentation. Infants are born with thick plates of scale separated with deep, red fissures that appear in geometric patterns, and they are frequently born prematurely. There is marked ectropion and eclabium and malformation or absence of the ear (picture 4). Fingertips are tapered with loss of distal digital pulp and hyperconvexity of the nail.

Harlequin scale sheds in the first months of life to reveal deep red and scaly skin, resembling a severe congenital ichthyosiform erythroderma. While prior reports suggested that the mortality rate in the neonatal period was approximately 50 percent (with many infants with harlequin ichthyosis dying shortly after birth), improved neonatal intensive care and early treatment with oral retinoids improve the prognosis [15,16]. Neonatal demise primarily occurs from infection and respiratory compromise.

Ichthyosis prematurity syndrome — Ichthyosis prematurity syndrome (MIM #608649), associated with pathogenic variants in SLC27A4 [17], is a rare subtype of ARCI associated with erythrodermic skin at birth covered with a striking vernix caseosa-like material. Prenatal ultrasound findings include polyhydramnios, separation of the chorionic and amniotic membranes, sediment in the amniotic fluid (which parents may recall in retrospect), and clear chorionic fluid [18]. Most have neonatal asphyxia or some respiratory distress at birth and reduced Apgar score. Rapid improvement during infancy results in a mild, chronic, pruritic ichthyosis with a characteristic pebbled surface.

Less severe phenotypes — Milder forms of ARCI are more comprehensively described in the literature and are presumed to result from milder variants in well-known genes [6]. As an example, bathing suit or temperature-sensitive ichthyosis varies in phenotype because certain TGM1 variants encode a transglutaminase 1 protein that is less effective at higher temperatures near the core of the body [19,20].

Moreover, milder forms of ARCI can be associated with certain gene loci in general. For example, mutations in CASP14, which encodes a filaggrin degradation protein, is associated with finer scaling of the skin and seems to be in a phenotypic gray zone between ichthyosis vulgaris and the more severe types of ARCI [21].

Syndromic autosomal recessive congenital ichthyoses — ARCI may present as syndromic diseases with involvement of the skin and other organs or systems (table 2).

Netherton syndrome — Netherton syndrome is caused by autosomal biallelic pathogenic variants in SPINK5, which encodes a protease inhibitor necessary for the regulation of desquamation [22]. Netherton syndrome is characterized by scaly skin, abnormal hair, and increased risk of atopy. Scale can assume a characteristic pattern called "ichthyosis linearis circumflexa," which manifests as migratory, erythematous plaques with double-edged scale at the periphery (picture 5). Examination of the hair frequently reveals trichorrhexis invaginata, which is visible using light microscopy as a bamboo-like configuration in which the distal hair shaft invaginates into the proximal one (picture 6) [23]. Patients experience manifestations of the atopic triad including atopic dermatitis, food allergy, and asthma and often have marked elevation of serum immunoglobulin E (IgE). Itching can be severe.

Netherton syndrome is discussed in detail separately. (See "Netherton syndrome".)

Neutral lipid storage disease — Neutral lipid storage disease, also called Chanarin-Dorfman disease (MIM #275630), is caused by biallelic pathogenic variants in ABHD5, which encodes a protein necessary for lipolysis of triglycerides. Loss of ABHD5 function leads to triglyceride accumulation within cells and alterations in the content of the cutaneous lipid barrier, disrupting its function.

The disease is characterized by generalized, plate-like scale of varying severity and can be associated with hepatosplenomegaly with transaminitis, fatty liver, myopathy, psychomotor delay, cataracts, and decreased hearing [24]. The disease presents at birth, often with a collodion membrane. Elevated liver function tests may be the first indication in milder ichthyosis cases. Oral retinoids must be used with care or avoided in these patients. The accumulation of lipid droplets within granulocytes on peripheral blood smear is a diagnostic finding. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism", section on 'Neutral lipid storage diseases'.)

Sjögren-Larsson syndrome — Sjögren-Larsson syndrome is caused by biallelic pathogenic variants in FALDH, which encodes an enzyme necessary for metabolism of fatty alcohols and other substrates. Accumulation of toxic metabolites results in skin and systemic disease.

Clinical features of Sjögren-Larsson syndrome include congenital ichthyosis, intellectual disability, and spastic di- or tetraplegic paralysis. Patients present at birth with scaling, which can be mild to moderate, and severe pruritus, which persists throughout life. The skin can become thickened and brown, particularly at sites of excoriation, including flexures, the neck, and abdomen. During early development, signs of developmental delay and spastic paralysis become evident. A diagnostic finding in many patients includes the presence of macular, white dots upon ophthalmologic examination of the retina [25].

Sjögren-Larsson syndrome is discussed in greater detail separately. (See "Sjögren-Larsson syndrome".)

Trichothiodystrophy — Trichothiodystrophy (MIM #601675) is caused by a defect of deoxyribonucleic acid (DNA) repair and transcription. Most patients with trichothiodystrophy have biallelic pathogenic variants in ERCC2/XPD, encoding the transcription factor TFIIH. Less frequently, trichothiodystrophy is associated with autosomal recessive mutations in ERCC3/XPB, GTF2E2, and GTF2H5. In contrast with patients with xeroderma pigmentosum, patients with trichothiodystrophy do not appear to be at increased risk for skin cancer. (See "Xeroderma pigmentosum".)

Trichothiodystrophy has a highly variable presentation, characterized by scaly skin in 65 percent of cases [26]. Brittle hair that shows alternating birefringence when viewed with polarized light microscopy is considered a defining feature (picture 7A-B) [26]. This "tiger tail" appearance in the majority of hairs under polarized light is considered diagnostic. (See "Hair shaft disorders", section on 'Trichothiodystrophy'.)

Some patients present with a collodion membrane at birth. One-half of patients have dystrophic nails with findings including ridging, splitting, hypoplasia, and koilonychia (picture 8). Some patients experience thickening of the palms and soles.

Short stature and characteristic facial features, including microcephaly, protruding ears, and micrognathia, are seen in many patients. Other clinical findings, including intellectual impairment, hearing loss, photosensitivity, and cataracts, may be found with a broad spectrum of severity. Ectropion is rare.

EVALUATION AND DIAGNOSIS — Consultation with pediatric dermatology is essential to reveal clinical features central to diagnosis. This, combined with genetic testing, if available, can lead to a precise diagnosis.

History and clinical examination — The clinical diagnosis of ARCI is based on the evaluation of the following [1]:

History of collodion baby presentation, severe erythroderma, or generalized scaling at birth (see 'Collodion infant' above)

Family history and apparent inheritance mode

Assessment of skin phenotype, including scale pattern, quality, and color; presence of a collodion membrane at birth; presence of erythroderma; presence or absence of erosions or blistering; presence of palmoplantar keratoderma; facial features (eg, ectropion, eclabium) (see 'Clinical phenotypes' above)

Time of onset and evolution over time

Presence of associated cutaneous manifestations (eg, photosensitivity, hair abnormalities)

Presence of associated extracutaneous manifestations (table 2) (see 'Syndromic autosomal recessive congenital ichthyoses' above)

Genetic testing — Genetic testing is helpful for obtaining and/or confirming diagnosis and for genetic counseling. (See 'Genetic counseling' below.)

A panel type test that includes multiple well-known disease variants causative of ichthyosis is typically used. Whole exome sequencing may be indicated for infants with ARCI and other organ involvement who are suspected to have a syndromic form of ARCI.

In the United States, Clinical Laboratory Improvement Amendments (CLIA)-certified genetic testing is available from multiple providers. Information on CLIA-certified and research-based laboratories performing disease-specific genetic testing worldwide is available through the Genetic Testing Registry.

GENETIC COUNSELING — All families having a child diagnosed with ARCI should be offered genetic consultation to better understand the inheritance pattern, to assess reproductive risk for parents and close family members, and for information about their reproductive options, including prenatal and preimplantation diagnosis. Parents of a child with ARCI are almost always unaffected carriers, so each has a 50 percent likelihood of transmitting their pathogenetic variant to a future child, resulting in a 25 percent probability that any future offspring will be affected (figure 1). (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)".)

PRINCIPLES OF MANAGEMENT — There is no definitive treatment for ARCI. Therapy is largely symptomatic and focuses on improving skin hydration, reducing scale, and improving the comfort and appearance of the skin [27]. (See "Inherited ichthyosis: Overview of management".)

Good-quality studies on the management of ARCI are limited. Treatments are mainly based on evidence from small case series and clinical experience.

Care of the neonate with autosomal recessive congenital ichthyoses

General principles — Most neonates with ARCI present with red, scaly skin, and many will present with a collodion membrane, which appears as a glistening, translucent, cellophane-like membrane covering the entire body (see 'Collodion infant' above). They have a compromised barrier function, which is associated with increased transepidermal water loss, hypernatremic dehydration, increased heat loss, and increased risk of infection [28].

Early consultation with a multidisciplinary team is required in the most severe cases. The team should include a dermatologist, clinical geneticist, nutritionist, physical/occupational therapist, and social worker.

Neonates with ARCI are often managed in neonatal intensive care units. Advances in neonatal care have led the survival rate for collodion presentation to approach near 100 percent. While no randomized trials for interventions have been enacted, there are a series of considerations to address in the neonatal period, including:

Water loss – ARCI leads to increased insensible losses, and there is a risk of hypernatremic dehydration with abnormalities in electrolytes ensuing. Newborns with ARCI should be placed in isolettes with increased humidity (in the range of 50 to 70 percent) and closely monitored for body temperature, vital signs, and electrolytes. (See "Fluid and electrolyte therapy in newborns", section on 'Hypernatremia'.)

Nutrition – Increased metabolic demand due to more rapid epidermal turnover in hyperproliferative conditions requires caloric supplementation.

Infection – Collodion and harlequin presentations can lead to fissures, which increase risk of infection. Close monitoring for signs of infection is mandatory.

Skin care – Liberal application of bland, petrolatum-based emollients can decrease water loss, improve pliability of the skin, permit shedding of accumulated scale, and provide a proper environment for healing of fissures or erosions.

Parent/caregiver education – The unexpected appearance of an affected infant often results in fear and a tendency to isolate the infant from their parents/caregivers. Interaction with family, including skin-to-skin contact, should be encouraged. Additional information for the family, caregivers, and medical team is available at the Foundation for Ichthyosis and Related Skin Types (FIRST) website. Printed material near the bedside, readily available for rotating caregivers, may be helpful. (See 'Patient support resources' below.)

Neonates with harlequin ichthyosis — Neonates with harlequin ichthyosis should be admitted to a neonatal intensive care unit. Management includes supportive care and treatment of hyperkeratosis and skin barrier dysfunction.

Intubation is often required until nares are patent and armor-like plates of scale are shed from the thorax. Nutritional support with tube feeds is essential until eclabium resolves and infants can begin nursing. Ophthalmology consultation can be helpful in the early management of ectropion, which is initially pronounced and improves as scale is shed. To avoid digital ischemia, careful debridement of constrictive bands of hyperkeratosis should be performed.

Systemic retinoids have a central role in the neonatal period for some patients, particularly in cases with scale preventing full respiratory effort, but are less commonly used in childhood and adulthood [15,16].

As many infants and children suffer from failure to thrive, particular attention must be paid to growth and development with focus on nutrition and caloric supplementation.

Bathing — Daily, long tub soaks of at least 30 minutes are beneficial to clean the skin and soften scale. The addition of sodium bicarbonate (baking soda) in bathwater to achieve a pH of approximately 7.8 (two handfuls of baking soda in a tub of water) activates cutaneous proteases, facilitating desquamation and scale removal [29]. Scale can be removed mechanically by the gentle use of a sponge or a microfiber cloth. Application of petrolatum-based emollients directly after soaking prolongs water retention and softens the skin.

Topical therapies — Topical therapies, including emollients, keratolytics, and topical retinoids, are the first-line treatments for patients with ichthyosis, though keratolytics and retinoids are not typically introduced in the immediate newborn period.

Emollients and keratolytics — Emollients and keratolytics are the mainstay of treatment for all types of ichthyoses (see "Inherited ichthyosis: Overview of management"):

Emollients – Emollients are available in many formulations, depending on the water-to-oil ratio. Generally, water-in-oil preparations are preferred. Glycerin can be added to commercial moisturizers, if needed. Emollients can be liberally used multiple times per day and should always be applied immediately after bathing.

Keratolytics – Keratolytic preparations containing varying concentrations of urea, salicylic acid, propylene glycol, or alpha-hydroxy acids (eg, lactic acid, glycolic acid) alone or in combination help remove scale by enhancing desquamation. The use of all keratolytics is contraindicated in infants and small children due to irritation and systemic absorption. Topical salicylic acid can be used in older children and adults for the treatment of limited, stubborn body areas. Its use is contraindicated for the treatment of large body areas due to the risk of systemic absorption and toxicity [30].

In older patients, keratolytics should be introduced gradually, with a trial to a small area first (eg, 3 cm2) since some may sting if applied too often or too liberally. They can initially be applied once weekly and titrated up as tolerated.

Topical retinoids — Due to their antiproliferative and antikeratinizing effects, topical retinoids, such as tazarotene or tretinoin, can be used for the treatment of focal areas of hyperkeratosis. They are applied in small amounts three times weekly and up to daily until therapeutic benefit is seen [31]. Some patients prefer an even less frequent interval of once weekly. The primary side effect of such therapy is local irritation, which may require a reduction in frequency or amount of application. Unlike emollients, applying retinoids to wet skin may make them more irritating. Topical retinoids have also been shown to improve ectropion.

Systemic retinoids — Systemic retinoids, including isotretinoin and acitretin, can dramatically reduce scaling in many patients with ARCI. They modulate keratinocyte proliferation and differentiation and reduce tissue infiltration by inflammatory cells.

Considerations for initiating treatment with systemic retinoids include severity of ichthyosis; patient/family/caregiver concern regarding scaling severity; and the presence of keratoderma-related hand contractures that impair the ability to work or hold a pencil or constricting bands of the digits, which may improve with retinoid use [32]. Patients report that retinoids reduce scaling and the time needed for daily skin care, improve ectropion, and confer some capacity for sweating. If therapeutic response is achieved, long-term therapy is necessary, though many patients elect to take retinoid holidays at periods of lesser severity (eg, summer).

Retinoids can be used at any age, but a conversation regarding risks and potential benefits is necessary in the individual patient. 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 [33].

Administration – Both isotretinoin and acitretin are oral medications administered at doses ranging from 0.2 to 1.5 mg/kg/day. It is advisable to start with a low dose and titrate gradually to efficacy, with the goal of using the lowest dose possible to achieve efficacy [34]. Continued administration is necessary to maintain therapeutic benefit.

Dosing and tips for administration in children are reviewed in detail separately. (See "Inherited ichthyosis: Overview of management", section on 'Retinoids'.)

Adverse effects – Dryness of the skin, lips, and eyes is a common adverse effect of systemic retinoids. Other adverse effects include myalgias, visual changes, idiopathic intracranial hypertension, hepatotoxicity, hyperlipidemia, ectopic calcification of tendons and ligaments, and premature epiphyseal closure. Clinical, laboratory, and imaging monitoring for adverse effects of systemic retinoids are summarized in the table (table 3).

Systemic retinoids are teratogenic and must not be used during pregnancy. Pregnancy is contraindicated for three years after discontinuing acitretin. In females of childbearing potential, isotretinoin is preferred to acitretin because of its shorter half-life; pregnancy is contraindicated for one month after discontinuing isotretinoin. Serial photographs to monitor progress and establish ideal dosing are helpful.

Special situations

Eye and ear complications — In patients with lamellar ichthyosis, management of ectropion is of primary importance to prevent lagophthalmos and corneal damage and scarring. Frequent use of ocular lubricants, such as lipid-containing eye drops, is helpful in improving signs and symptoms of eye dryness [35]. Ectropion improvement with topical tazarotene has been reported in both adult and pediatric patients with lamellar ichthyosis [31,36].

Ear complications are mainly due to scale build-up in the external ear canal. Excessive scale accumulation in the auditory canal, if left untreated, can lead to hearing impairment and speech delay in children. Regular hearing evaluation and cleaning by an ear, nose, and throat (ENT) specialist is recommended. The surface of the ears can be included during regular gentle shampooing to help remove excess scale accumulation of the external ear.

Hypohidrosis and heat intolerance — Patients with ARCI may have hypohidrosis and reduced heat tolerance due to mechanical plugging of sweat gland ducts by hyperkeratosis. Topical therapy with emollients and keratolytics may be helpful in improving the thermoregulation in these patients. There is an isolated report of hypohidrosis improvement in a patient with lamellar ichthyosis treated with oral retinoids [37].

Children with hypohidrosis may have a tendency to become overheated, which can be worsened in direct sunlight and can occur regardless of ambient temperature. In general, individuals with ichthyosis learn over time what can and cannot be tolerated. In school and all activities, it is important for children with hypohidrosis to have ready access to water and a cool environment when needed. One of the first signs of overheating is increased redness of the skin. Some children have used a "buddy system" at school so that all students in the class can be aware that an affected child is becoming overheated and can help by suggesting water or a cool environment if they notice signs of overheating, such as increased redness.

Fungal infection — Ichthyosis increases the risk of dermatophyte infection of the skin and scalp, and fungal infections may account for acute episodes of localized or generalized scaling. Itch and loss of hair can be associated. Scraping of the scale for microscopic examination with potassium hydroxide (KOH), chlorazol black stain, or culture can confirm the diagnosis. (See "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation' and "Office-based dermatologic diagnostic procedures", section on 'Fungal culture'.)

Topical antifungal therapy can be sufficient, but follow-up examination to confirm response is needed. Oral medication for treatment may be necessary to ensure complete resolution. (See "Dermatophyte (tinea) infections".)

EXPERIMENTAL THERAPIES — There is evidence that inflammation is present in ichthyoses and may contribute to the redness and scaling observed in these disorders [9]. Biologic therapies targeting inflammatory pathways have been used in specific (primarily autosomal dominant) subtypes of ichthyosis with good effect, though there is neither a US Food and Drug Administration (FDA)-approved therapy nor consistent response in ARCI. There are several case reports of response to individual biologic therapies, though a larger study across ARCI genotypes employing interleukin (IL) 17 inhibition failed to demonstrate efficacy [38]. Off-label utilization of biologic therapies must take into consideration the need for lifelong therapy, the potential risks of these medications, and the degree of response obtained. Several clinical trials investigating the role of biologics in the treatment of ARCI genotypes, including Netherton syndrome, are underway.

PROGNOSIS — While ARCI can have a significant impact on quality of life, most individuals with nonsyndromic forms have normal lifespan and intelligence. Skin symptoms require lifelong management, and advances in neonatal intensive care unit care have improved neonatal outcomes.

PATIENT SUPPORT RESOURCES — Patient support organizations, such as the Foundation for Ichthyosis and Related Skin Types (FIRST), can provide resources for affected individuals and their families/caregivers. FIRST provides patient information resources, opportunities to interact with other affected individuals and their caregivers, and an expert physician-led telemedicine platform to assist clinicians in the care of patients with ichthyosis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ichthyosis".)

SUMMARY AND RECOMMENDATIONS

Definition and clinical phenotypes – Autosomal recessive congenital ichthyoses (ARCI) represent a group of rare, recessive disorders that can present with skin scaling with or without erythema. ARCI encompass cutaneous phenotypes of varying severity, including (table 1) (see 'Nonsyndromic autosomal recessive congenital ichthyoses' above):

Lamellar ichthyosis

Congenital ichthyosiform erythroderma

Harlequin ichthyosis

Congenital ichthyosis may also be part of a number of autosomal recessive syndromic disorders with manifestations involving every organ system (table 2). (See 'Syndromic autosomal recessive congenital ichthyoses' above.)

Management – There is no definitive treatment for ARCI. Therapy is largely symptomatic and focuses on improving skin hydration, reducing scale, and improving the comfort and appearance of the skin (see 'Principles of management' above and "Inherited ichthyosis: Overview of management"):

Newborns – Neonates with ARCI presenting with red, scaly skin; with a collodion membrane; and who have a compromised barrier function resulting in increased transepidermal water loss, hypernatremic dehydration, and increased heat loss are often managed in neonatal intensive care units. (See 'Care of the neonate with autosomal recessive congenital ichthyoses' above.)

Adults and older children – Emollients and keratolytic preparations containing varying concentrations of urea, salicylic acid, or propylene glycol alone or in combination are the mainstay of treatment in adults and older children. The use of all keratolytics is contraindicated in infants and small children due to irritation and systemic absorption. (See 'Principles of management' above and 'Emollients and keratolytics' above.)

Systemic retinoids, including isotretinoin and acitretin, can dramatically reduce scaling in many patients with ARCI, but continued administration is necessary to maintain therapeutic benefit. Due to their multiple adverse effects (eg, mucocutaneous disorders, myalgias, idiopathic intracranial hypertension, hyperlipidemia, hepatotoxicity, teratogenicity), the risk-benefit ratio of systemic retinoid therapy should be weighed in the individual patient. (See 'Systemic retinoids' above and "Inherited ichthyosis: Overview of management", section on 'Systemic retinoids'.)

Prognosis – While ARCI can have a significant impact on quality of life, most individuals with nonsyndromic forms have normal lifespan and intelligence. Patient support organizations, such as the Foundation for Ichthyosis and Related Skin Types (FIRST), can provide resources for affected individuals and their families/caregivers. (See 'Prognosis' above and 'Patient support resources' above.)

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Topic 112583 Version 9.0

References

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