Autosomal Recessive Congenital Ichthyosis

Clinical characteristics.

Autosomal recessive congenital ichthyosis (ARCI) encompasses several forms of nonsyndromic ichthyosis. Although most neonates with ARCI are collodion babies, the clinical presentation and severity of ARCI may vary significantly, ranging from harlequin ichthyosis, the most severe and often fatal form, to lamellar ichthyosis (LI) and (nonbullous) congenital ichthyosiform erythroderma (CIE). These phenotypes are now recognized to fall on a continuum; however, the phenotypic descriptions are clinically useful for clarification of prognosis and management.

• Infants with harlequin ichthyosis are usually born prematurely and are encased in thick, hard, armor-like plates of cornified skin that severely restrict movement. Life-threatening complications in the immediate postnatal period include respiratory distress, feeding problems, and systemic infection.
• Collodion babies are born with a taut, shiny, translucent or opaque membrane that encases the entire body and lasts for days to weeks.
• LI and CIE are seemingly distinct phenotypes: classic, severe LI with dark brown, plate-like scale with no erythroderma and CIE with finer whiter scale and underlying generalized redness of the skin. Affected individuals with severe involvement can have ectropion, eclabium, scarring alopecia involving the scalp and eyebrows, and palmar and plantar keratoderma.

Besides these major forms of nonsyndromic ichthyosis, a few rare subtypes have been recognized, such as bathing suit ichthyosis, self-improving collodion ichthyosis, or ichthyosis-prematurity syndrome.

Diagnosis/testing.

The diagnosis of nonsyndromic ARCI is established by skin findings at birth and in infancy. Skin biopsy is not necessary to establish the diagnosis of ARCI. The twelve genes known to be associated with ARCI are ABCA12, ALOX12B, ALOXE3, CASP14, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, and TGM1; at least 15% of affected families do not have pathogenic variants in any of the known genes. A multigene panel that includes these genes is the diagnostic test of choice. If such testing is not available, single-gene testing can be considered starting with ABCA12 in individuals with harlequin ichthyosis, TGM1 in individuals with ARCI without harlequin presentation at birth and SLC27A4 in those presenting with ichthyosis-prematurity syndrome.

Management.

Treatment of manifestations: For neonates, a moist environment in an isolette, hygienic handling to prevent infection, and treatment of infections; petrolatum-based creams/ointments to keep the skin soft, supple, and hydrated; for older children, humidification with long baths, lubrication, and keratolytic agents such as alpha-hydroxy acid or urea preparations to promote peeling and thinning of the stratum corneum; for those with ectropion, lubrication of the cornea; for those with severe skin involvement, cautious use of oral retinoids.

Prevention of secondary complications: Prevention of infection, dehydration and overheating, corneal drying; high caloric diet; when necessary, release of collodion membrane on digits to maintain circulation and on the thorax for adequate respiration.

Surveillance: Regular physical examination for evidence of infection, management of skin involvement, as well as for the increased (but still low) risk for skin malignancy (squamous cell carcinoma, basal cell carcinoma, atypical melanocytic nevi, or malignant melanoma).

Agents/circumstances to avoid: Skin irritants; overheating.

Genetic counseling.

ARCI is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both ARCI-related pathogenic variants have been identified in a family.

Suggestive Findings

Autosomal recessive congenital ichthyosis (ARCI) should be suspected in newborns who have either harlequin ichthyosis, a collodion membrane, or thick, hyperkeratotic skin with desquamation.

• Harlequin ichthyosis is characterized by a thick, taut body armor-like covering that severely restricts movement and results in deformities of the face, head, and extremities.
• Collodion babies have a taut, shiny, translucent or opaque membrane that encases the entire body and lasts for days to weeks. Most infants with ARCI are born as collodion babies.
• Babies with ichthyosis-prematurity syndrome are born with erythematous, thick, hyperkeratotic skin with desquamation resembling vernix caseosa.

Establishing the Diagnosis

The diagnosis of ARCI is established in a proband (typically an infant):

• With scaly skin with or without a history of harlequin ichthyosis, collodion membrane, or thick, hyperkeratotic skin AND the later development of ONE of the following:
  • Classic lamellar ichthyosis (LI). Brown, plate-like scale over the entire body, associated with ectropion (eversion of eyelids), eclabium (eversion of lips), scarring alopecia, and palmar and plantar hyperkeratosis
  • (Nonbullous) congenital ichthyosiform erythroderma (CIE). Erythroderma (red skin) with fine, white scale and often with palmoplantar hyperkeratosis
  • Intermediate forms with some features of both LI and CIE, or nonLI/nonCIE form with mild hyperkatosis;
  AND/OR
• By identification of biallelic pathogenic variants in one of the genes listed in Table 1.

Molecular testing approaches can include use of a multigene panel, serial single-gene testing and more comprehensive genomic testing:

• A multigene panel that includes the genes in Table 1a and Table 1b and other genes of interest (see Differential Diagnosis) is the diagnostic test of choice, as it offers the possibility to evaluate concurrently for syndromic forms of congenital ichthyosis, which may not be distinguishable based on clinical grounds prior to onset of specific symptoms. Note: (1) The genes included and the sensitivity of multigene panels varies by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Serial single-gene testing can be considered if multigene panel testing is not available; the order of testing is determined by the genes in which pathogenic variants most commonly occur for a given phenotype. Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • In individuals with harlequin ichthyosis, analysis of ABCA12 should be performed first.
  • In individuals with ARCI and without harlequin presentation at birth, analysis of TGM1 should be performed first.
  • In individuals with ichthyosis-prematurity syndrome, molecular genetic testing should start with SLC27A4.
  • For individuals with ARCI in whom analysis of ABCA12, TGM1, and SLC27A4 has not identified pathogenic variants, use of a multigene panel containing ALOX12B, ALOXE3, CASP14, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, and SDR9C7 is recommended.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered especially in individuals with ARCI who also have other organ manifestations (syndromic presentation). Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Although most neonates with autosomal recessive congenital ichthyosis (ARCI) are collodion babies, the clinical presentation and severity of ARCI may vary significantly, ranging from harlequin ichthyosis, the most severe and often fatal form, to lamellar ichthyosis (LI) and (nonbullous) congenital ichthyosiform erythroderma (CIE) in older individuals. While these phenotypes are now recognized to fall on a continuum, the phenotypic descriptions are clinically useful for clarifying prognosis and management for affected individuals. Ichthyosis-prematurity syndrome (IPS) also manifests at birth with extensive hyperkeratosis, erythema, and edema of the skin with serious secondary complications, but improves quickly and regresses to a mild ichthyosis phenotype, which later in childhood can be difficult to distinguish from other forms of ARCI.

Children with ARCI are often born prematurely. They can experience high levels of transepidermal water loss with resultant hypernatremia. They are at increased risk for infection/sepsis during the neonatal period.

Harlequin ichthyosis. Babies with harlequin ichthyosis are born prematurely covered in thick, hard, armor-like plates of cornified skin separated by deep fissures. The taut skin results in deformation of facial features and microcephaly. Babies are at risk for life-threatening complications in the postnatal period including respiratory distress, dehydration, electrolyte imbalance, temperature instability, feeding problems, and bacterial infections, often with fatal consequences. A survival rate of 56% has been reported, and is expected to further increase with improved neonatal intensive care and treatment options, such as early topical and/or systemic retinoids [Rajpopat et al 2011].

Surviving children eventually shed this armor and develop generalized scaling and intense redness of the skin (erythroderma, severe CIE-like phenotype). Harlequin ichthyosis remains a serious and chronic skin disorder, and severe ectropion, eclabium, alopecia, palmoplantar keratoderma with painful fissures and digital contractures, and growth delay are common.

Lamellar ichthyosis (LI). Neonates with LI typically present with a collodion membrane. The membrane subsequently dries and peels away to be replaced by a whitish, later brown, plate-like scale over the entire body. Ectropion, eclabium, scarring alopecia involving the scalp and eyebrows, and palmar and plantar hyperkeratosis can be seen in severely affected infants. The nails may be curved and beaked and the ears are often crumpled and adherent to the scalp. Erythroderma may be present, but is usually mild and never the predominant feature.

Congenital ichthyosiform erythroderma (CIE). As many as 90% of infants with CIE present with collodion membrane as neonates. They subsequently develop erythroderma (generalized redness of the skin) and fine, white semi-adherent scales. They also have palmoplantar keratoderma, often with painful fissures and digital contractures [Fischer et al 2000]. Ectropion, eclabium, scalp involvement, and loss of eyebrows can occur in severely affected newborns.

Intermediate phenotypes. Many affected individuals lie either somewhere along the LI-CIE spectrum and may be classified as having mild LI or mild CIE, or have non-LI/non-CIE features of fine/mild scaling, referred to as congenital ichthyosis with fine/mild scaling (CIFS).

Other rare subtypes

• "Bathing suit ichthyosis," a rare presentation of ARCI predominantly observed in individuals from South Africa and caused by pathogenic variants in TGM1, shows brown or dark-gray scaling on the trunk (bathing suit area), while the extremities and central face are almost completely spared. It is hypothesized that pathogenic variants exert an effect on temperature-dependent activity of the transglutaminase 1 enzyme, with marked decrease in enzyme function at higher temperatures [Oji et al 2006].
• Collodion babies who have nearly complete resolution of their ichthyosis in infancy with only xerosis, residual mild or focal scaling, hyperlinear palms, red cheeks, or anhidrosis are classified as "self-healing collodion baby" or more correctly "self-improving collodion ichthyosis" [Raghunath et al 2003, Vahlquist et al 2010]. This minor subtype of ARCI has been observed in about 10% of individuals with ARCI [Ahmed & O'Toole 2014].
• Babies with ichthyosis-prematurity syndrome (IPS) are born prematurely between 29-35 weeks' gestation. There is typically a pregnancy history of polyhydramnios and fetal ultrasound may reveal echogenic sediment in the amniotic fluid. The skin at birth is erythrodermic, swollen, and massively thickened with a vernix-like appearance. Most severely affected is the scalp, often with verruciform hyperkeratosis. Neonates suffer from severe, sometimes fatal asphyxia due to reduced lung function from intrauterine amniotic fluid aspiration. They have poor Apgar scores and require intensive care and prolonged hospitalization. Nevertheless, the prognosis of IPS is generally excellent. After a few days the skin sheds and improves significantly, revealing an underlying erythema, which eventually resolves. Later in life individuals have dry, rough skin with cobblestone-like hyperkeratosis, keratosis pilaris, and pruritus [Khnykin et al 2012].
• Individuals with ARCI born with erythroderma but mostly without collodion membrane who later develop generalized LI and hyperlinear palms and soles have been reported as having LI type 3 [Lefèvre et al 2006].

Skin biopsy

• Histologic findings in ARCI are mostly nonspecific. ARCI is characterized by hyperkeratosis (thickened stratum corneum, the uppermost layer of the epidermis) with or without parakeratosis with an underlying acanthosis.
• Harlequin ichthyosis is characterized by extreme hyperkeratosis, follicular plugging, and the absence of lamellar bodies and lipid bi-layers in a skin biopsy by electron microscopy.

Genotype-Phenotype Correlations

ABCA12. Pathogenic variants in ABCA12 have been found in virtually all children with harlequin ichthyosis of diverse ethnic backgrounds [Akiyama et al 2005, Kelsell et al 2005, Thomas et al 2006, Akiyama 2010, Pigg et al 2016].

• Most are nonsense changes and small insertions/deletions resulting in premature termination of protein translation; splice site defects and missense changes are less common.
• Partial-gene deletions spanning from one to 35 exons have been observed.
• Based on a comprehensive study analyzing molecular genetic findings in 45 individuals with harlequin ichthyosis [Akiyama 2010]:
  • All individuals homozygous for a detrimental loss-of-function allele had the most severe and fatal course of harlequin ichthyosis.
  • Those who were compound heterozygous for two different disease alleles (loss-of-function or missense) were less severely affected.
  • The mildest outcome (with features of CIE or LI) was observed in individuals with harlequin ichthyosis who had at least one pathogenic missense variant.

Most surviving individuals with pathogenic variants in ABCA12 have a severe CIE phenotype [Sakai et al 2009], while a few individuals showed a severe LI phenotype [Parmentier et al 1996, Parmentier et al 1999, Lefèvre et al 2003].

Note: While pathogenic variants in ABCA12 account for most cases of harlequin ichthyosis, ABCA12 pathogenic variants have also been reported in ten families with LI (most from northern Africa) [Lefèvre et al 2003] and in eight families with CIE [Akiyama 2010].

ALOX12B, ALOXE3. Individuals typically have the CIE or intermediate phenotypes [Jobard et al 2002] although self-improving collodion ichthyosis has been reported in others [Raghunath et al 2003, Harting et al 2008, Mazereeuw-Hautier et al 2009, Hackett et al 2010, Vahlquist et al 2010].

CERS3. Consistent skin findings in individuals with biallelic pathogenic variants in CERS3 include collodion membrane presentation at birth, erythema and fine scales on the face and trunk, larger, brown scales on the lower limbs, and hyperlinear and hyperkeratotic palms and soles. A distinct feature of CERS3-related ichthyosis is keratotic lichenification with a prematurely aged appearance of the skin [Eckl et al 2013, Radner et al 2013].

CYP4F22. Pathogenic variants have been reported in consanguineous families with LI associated with hyperlinear palms and soles but without collodion presentation at birth [Lefèvre et al 2006] and also in individuals with self-improving collodion ichthyosis [Noguera-Morel et al 2016].

LIPN. In contrast to all other forms of ARCI, those with pathogenic variants in LIPN appear to manifest not in infancy but later during childhood with generalized fine, white scaling and minimal erythema [Israeli et al 2011].

NIPAL4. Individuals with pathogenic variants present with CIE or intermediate phenotypes [Lefèvre et al 2004, Dahlqvist et al 2007]. There is a higher prevalence of NIPAL4 pathogenic variants in Scandinavia (Sweden, Denmark, and Norway), where they account for approximately 89% of TGM1-negative cases with erythrodermic ARCI without collodion presentation [Dahlqvist et al 2007, Pigg et al 2016].

PNPLA1. Individuals with pathogenic variants in PNPLA1 typically present at birth with collodion membrane and then transition to a CIE phenotype with scalp involvement and hyperlinear palms and soles [Grall et al 2012, Fachal et al 2014]. However, generalized, dark brown scaling with hypohidrosis or mild disease with generalized fine exfoliation and hyperkeratotic plaques over knees have also been observed, while ectropion, eclabium, and alopecia are lacking.

SLC27A4. Individuals with biallelic pathogenic variants present with the ichthyosis-prematurity syndrome (IPS) phenotype.

TGM1. The vast majority of individuals with the classic LI phenotype have TGM1 pathogenic variants; many persons with much milder non-erythrodermic phenotypes also have TGM1 pathogenic variants.

In addition, TGM1 pathogenic variants have been reported in a few individuals with "bathing suit ichthyosis" [Hackett et al 2010] as well as in individuals with self-improving collodion ichthyosis [Raghunath et al 2003, Mazereeuw-Hautier et al 2009, Hackett et al 2010, Vahlquist et al 2010].

Locus heterogeneity of unknown cause

• Finnish individuals with a form of ARCI linked to a locus on chromosome 19 reportedly have a very mild, non-erythrodermic, non-LI phenotype [Fischer et al 2000].
• Individuals from two families with a form of ARCI linked to a locus on chromosome 12 (ARCI-7 locus) had no collodion membrane and typical CIE features [Mizrachi-Koren et al 2005].

Nomenclature

Historically, the term "lamellar ichthyosis" was used to describe any individual with ARCI, and even rare cases of autosomal dominant ichthyosis, regardless of whether erythroderma was present. At the international Ichthyosis Consensus Conference in 2009, the term "autosomal recessive congenital ichthyosis" (ARCI) was designated the umbrella term for three major types of congenital ichthyosis [Oji et al 2010]:

• "Harlequin ichthyosis"
• "Lamellar ichthyosis" for collodion baby resolving to non-erythrodermic skin with large, plate-like brown or whitish scale
• "(Nonbullous) congenital ichthyosiform erythroderma" (CIE) to distinguish the erythrodermic form of ARCI with fine white scale from the lamellar, non-erythrodermic form

Note: "Bullous congenital ichthyosiform erythroderma" refers to an autosomal dominant ichthyosis, also called "epidermolytic ichthyosis" (EI) or "epidermolytic hyperkeratosis" (EHK), which does not present as collodion baby, and is a result of pathogenic variants in genes encoding epidermal keratins.

Prevalence

According to the Foundation for Ichthyosis and Related Skin Types, ARCI affects approximately 1:200,000 individuals in the US.

The disease affects all ethnic and racial groups and is seen in higher frequency in populations in which consanguineous marriage is common. The frequency of LI is estimated at 1:91,000 in Norway [Pigg et al 1998] and 1:122,000 in Galicia (northern Spain) [Rodríguez-Pazos et al 2011] ‒ in both cases as a result of a founder effect. A population-based study in Spain reported a higher prevalence of ARCI – 1:62,000 – with approximately two thirds of individuals having LI and one third having CIE [Hernández-Martín et al 2012].

The harlequin ichthyosis phenotype is very rare.

IPS is most prevalent in Scandinavia, with an estimated local heterozygote carrier frequency of one in 50 [Klar et al 2004, Klar et al 2009, Sobol et al 2011, Pigg et al 2016], but isolated cases or families with IPS have been reported worldwide.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with autosomal recessive congenital ichthyosis (ARCI), the following are recommended:

• Examination for evidence of infection
• Evaluation for problems relating to prematurity
• Evaluation by a dermatologist familiar with congenital ichthyosis
• Assessment of transepidermal water loss and hydration status
• Assessment of corneal hydration in babies with ectropion
• Assessment of feeding and nutrition status
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

For neonates, providing a moist environment in an isolette, preventing infection by hygienic handling, and treating infection are paramount.

Petrolatum-based creams and ointments are used to keep the skin soft, supple, and hydrated.

As the child becomes older, humidification with long baths, lubrication, and keratolytic agents such as alpha-hydroxy acid or urea preparations may be used to promote peeling and thinning of the stratum corneum. Topical salicylic acid preparations should be used very cautiously because of absorption.

For individuals with ectropion, lubrication of the cornea with artificial tears or prescription ophthalmic ointments, especially at night, is helpful in preventing dessication of the cornea.

Topical or oral retinoid therapy is recommended for those with severe skin involvement; however, side effects include bone toxicity and ligamentous calcifications from long-term use. Oral retinoid therapy should be used with great caution in women of child-bearing age because of concerns about teratogenicity. A detailed review of choice of retinoid, dosage, treatment duration, toxicity, monitoring, and disease-specific considerations for ARCI are provided by Digiovanna et al [2013].

Prevention of Secondary Complications

The following measures are appropriate:

• Prevention of infection in the newborn