Clinical Characteristics
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]:
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
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]:
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.
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Autosomal Recessive Congenital Ichthyosis: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Table B.
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|
190195 | TRANSGLUTAMINASE 1; TGM1 |
|
242100 | ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 2; ARCI2 |
|
242300 | ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 1; ARCI1 |
|
242500 | ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 4B; ARCI4B |
|
601277 | ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 4A; ARCI4A |
|
603741 | ARACHIDONATE 12-LIPOXYGENASE, R TYPE; ALOX12B |
|
604194 | SOLUTE CARRIER FAMILY 27 (FATTY ACID TRANSPORTER), MEMBER 4; SLC27A4 |
|
605848 | CASPASE 14, APOPTOSIS-RELATED CYSTEINE PROTEASE; CASP14 |
|
607206 | ARACHIDONATE LIPOXYGENASE 3; ALOXE3 |
|
607800 | ATP-BINDING CASSETTE, SUBFAMILY A, MEMBER 12; ABCA12 |
|
608649 | ICHTHYOSIS PREMATURITY SYNDROME; IPS |
|
609383 | NIPA-LIKE DOMAIN-CONTAINING 4; NIPAL4 |
|
609769 | SHORT CHAIN DEHYDROGENASE/REDUCTASE FAMILY 9C, MEMBER 7; SDR9C7 |
|
612121 | PATATIN-LIKE PHOSPHOLIPASE DOMAIN-CONTAINING PROTEIN 1; PNPLA1 |
|
612281 | ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 6; ARCI6 |
|
613924 | LIPASE FAMILY, MEMBER N; LIPN |
|
613943 | ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 8; ARCI8 |
|
615023 | ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 9; ARCI9 |
|
615276 | CERAMIDE SYNTHASE 3; CERS3 |
|
617320 | ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 12; ARCI12 |
For a detailed summary of gene and protein information for the genes associated with this disorder, see Table A, Gene.
ABCA12
Gene structure.
ABCA12 is large (206 kb) and contains 53 coding exons [Annilo et al 2002].
Pathogenic variants. More than 100 different ABCA12 pathogenic variants have been identified in individuals with harlequin ichthyosis; five different ABCA12 pathogenic variants have been identified in individuals with lamellar ichthyosis (LI). All pathogenic variants causing the severe harlequin phenotype are predicted to have a deleterious effect because they completely destroy the production or function of the transporter protein encoded for by ABCA12. Many but not all affected individuals with a pathogenic variant in ABCA12 are homozygous. The pathogenic variant spectrum also includes partial-gene deletion, spanning from one to more than 30 exons. LI-causing variants in ABCA12 cluster in five neighboring exons that form the first nuclear binding fold and exclusively represent missense variants predicted to interfere with specific functions of this protein domain.
Normal gene product. The ABCA12 cDNA encodes a protein of 2,595 amino acids that belongs to a subfamily of ATP-binding cassette (ABC) transporters. The protein is responsible for the energy-dependent transport of epidermal lipids and their processing enzymes (called lamellar bodies or lamellar granules) in and out of specialized organelles in the upper layers of the epidermis. Therefore, the protein is necessary for formation and function of lamellar granules and the subsequent development of lipid bi-layers in the outermost horn layer of the skin, an essential component of the skin barrier.
Abnormal gene product. Pathogenic variants in ABCA12 result in a deficiency of this epidermal lipid transporter. As a consequence, lamellar bodies are not properly formed and essential epidermal lipids (e.g., glucosylceramide) are abnormally processed and incompletely (or not) secreted in the intercellular spaces. These changes prevent the formation of lipid bi-layers in the stratum corneum and result in hyperkeratosis and abnormal barrier function [Akiyama et al 2005]. Moreover, ABCA12 deficiency impairs the transport of proteolytic enzymes (e.g., kallikrein proteases) that are required for normal desquamation of the epidermis, thus leading to the massive build-up of stratum corneum in harlequin ichthyosis [Zhang et al 2016].
ALOX12B
Gene structure.
ALOX12B is 15 kb in size and contains 15 coding exons [Sun et al 1998]. Its cDNA is 2.5 kb in length.
Pathogenic variants. Three studies reported pathogenic variants in ALOXE3 or ALOX12B in affected individuals from 29 unrelated families of different origins. Most affected individuals were born with a collodion membrane and later showed mild-to-moderate (nonbullous) congenital ichthyosiform erythroderma (CIE). Pathogenic variants are predominantly private missense variants scattered across the two genes [Jobard et al 2002, Eckl et al 2005, Lesueur et al 2007]. Overall, ALOX12B pathogenic variants were identified in 6.8% and 12% of individuals in two independent studies of 250 and 520 patients with ARCI, respectively [Eckl et al 2009, Fischer 2009]; actual numbers could be even lower [Authors, unpublished observations].
Normal gene product. The protein product of ALOX12B, the enzyme arachidonate 12-lipoxygenase, 12R-type (12R-LOX), has 701 amino acid residues and catalyzes the conversion of arachidonic acid to 12R-hydroxyeicosatetraenoic acid (12R-HETE). 12R-LOX is responsible for generating fatty acid hydroperoxide and functions in sequence with eLOX-3 to generate epoxy alcohol metabolites, which are crucial for formation of the epidermal lipid barrier [Eckl et al 2005].
Abnormal gene product. Pathogenic variants in the epidermal ALOX genes are predicted to interfere with the normal structure and/or function of these lipid-processing enzymes, resulting in disturbed skin barrier function. Specifically, two pathogenic variants were demonstrated to partially disturb the secretion of lamellar granule contents in the epidermis [Akiyama 2010].
ALOXE3
Gene structure.
ALOXE3 is 22.6 kb, distributed in 15 exons [Sun et al 1998]. The cDNA is 3.3 kb in length.
Pathogenic variants. See ALOX12B, Pathogenic variants. ALOXE3 pathogenic variants were identified in 5% and 7% of individuals in two independent studies of 250 and 520 patients with ARCI, respectively [Eckl et al 2009, Fischer 2009].
Normal gene product. The protein product of ALOXE3, hydroperoxide isomerase ALOXE3 (eLOX-3), has 711 amino acid residues. Both enzymes, 12R-LOX and eLOX-3, are preferentially synthesized in the epidermis and function in sequence to generate epoxy alcohol metabolites, which are crucial for formation of the epidermal lipid barrier. The enzyme eLOX-3 functions as hydroperoxide isomerase to generate epoxy alcohols [Eckl et al 2005].
Abnormal gene product. See ALOX12B, Abnormal gene product.
CYP4F22 (formerly FLJ39501)
Gene structure.
CYP4F22 is a member of the cytochrome P450 family 4, subfamily F. The gene includes 12 coding exons and the cDNA spans 2.6 kb in length.
Pathogenic variants. Individuals with ARCI from 12 consanguineous families from Mediterranean countries (Algeria, France, Lebanon, and Italy) were found to harbor homozygous pathogenic variants in CYP4F22. The variant spectrum included five missense variants, one single-base deletion, and a partial-gene deletion including exons 3-12. Affected individuals were mostly born with erythroderma but without collodion membrane and later in life presented with LI with larger, white-gray scale and hyperlinear palms and soles. Additional CYP4F22 pathogenic variants have been reported from different geographic regions including northern Europe, Czech Republic, and Israel [Pigg et al 2016, Israeli et al 2013, Bučková et al 2016]. Pathogenic variants include both loss-of-function and missense variants.
Normal gene product.
CYP4F22 encodes a protein of 531 amino acids that is predicted to include a signal peptide of 48 or 49 residues and a large CYP domain (residues 60-524). The protein is a member of the CYP superfamily of heme-thiolate enzymes, which is thought to play a role in the 12(R) lipoxygenase (hepoxilin) pathway involved in arachidonic acid metabolism and eicosanoid synthesis. Further work revealed that CYP224 is the gene encoding ultra-long-chain fatty acid ω-hydroxylase, a crucial enzyme required for acylceramide production in the skin [Ohno et al 2015].
Abnormal gene product. All CYP4F22 pathogenic variants reported to date are predicted to abolish the function of the encoded type I membrane protein in the endoplasmic reticulum. Initially, pathogenic variants in CYP4F22 were thought to compromise the 12(R) lipoxygenase (hepoxilin) pathway, as was also hypothesized for other known ARCI-causing genes (e.g., ALOXE3, ALOX12B). However, recent studies demonstrated that CYP4F22 encodes a very long-chain fatty acid ω-hydroxylase crucial for acylceramide (ω-O-acylceramide) synthesis. Enzyme deficiency due to pathogenic variants in this gene results in decreased production of epidermal acylceramide, which is a specialized lipid essential for skin barrier formation and function [Ohno et al 2015]. Therefore, CYP4F22-, PNPLA1-, and CERS3-associated ARCI share a very similar pathogenesis.
NIPAL4
(formerly ICHTHYIN; ICHYN)
Gene structure.
NIPAL4 spans 3.3 kb and contains six coding exons.
Pathogenic variants.
Lefèvre et al [2004] identified six homozygous NIPAL4 pathogenic variants in 14 consanguineous families with congenital recessive ichthyosis. Dahlqvist et al [2007] reported recessive NIPAL4 pathogenic variants in 16 of 18 families with ARCI from northern Europe, suggesting that pathogenic variants in this gene are responsible for a large portion of those individuals with generalized congenital ichthyosis and mild-to-moderate erythroderma who mostly lack a collodion presentation at birth. The two missense variants p.Ala176Asp and p.Gly230Arg accounted for approximately 90% of disease alleles in this cohort, whereas p.Ala176Asp also accounted for half of disease alleles in the Lefèvre cohort, comprising mostly Mediterranean families. See also Fischer [2009]. Wajid et al [2010] also reported the missense variant p.Ala176Asp in two consanguineous Pakistani families with ARCI. ARCI cohort studies from Scandinavia, Czech Republic, the UK, and Israel identified numerous additional disease-causing variants in 5%-16% of affected unrelated individuals, including missense, nonsense, splice site, and frameshift variants [Israeli et al 2013, Scott et al 2013, Bučková et al 2016, Pigg et al 2016].
Table 2.
NIPAL4 Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
NIPAL4 encodes a putative magnesium transporter protein; isoform 1 [NP_001092757.1] has 466 amino acids. The protein is highly expressed in brain, lung, stomach, leukocytes, and keratinocytes. Wajid et al [2010] demonstrated that the magnesium transporter NIPA4 (formerly ichthyin) protein is highly expressed in the granular layer of the epidermis. The function of the magnesium transporter NIPA4 protein is unknown.
Abnormal gene product. All pathogenic variants reported to date are predicted to abolish the function of the ichthyin protein.
PNPLA1
Gene structure.
PNPLA1 belongs to the family of human patatin-like phospholipases. The gene has three isoforms; transcript 1 (NM_173676.2) includes eight coding exons and the cDNA is 2.36 kb in length.
Pathogenic variants. One missense and one nonsense variant in the conserved catalytic domain were found in six homozygous individuals from two consanguineous families from Algeria and Morocco, who were born with a collodion membrane and later developed features of CIE. No PNPLA1 pathogenic variants were identified in eight other families with ARCI who also mapped to this locus on chromosome 6p21 [Grall et al 2012]. A few additional PNPLA1 variants were subsequently reported in patients from Iran, Pakistan, Spain, and northern Europe [Fachal et al 2014, Ahmad et al 2016, Pigg et al 2016, Vahidnezhad et al 2017]. In another study of about 700 individuals with ARCI, PNPLA1 pathogenic variants were identified in 17 families, and the contribution of pathogenic variants in PNPLA1 to ARCI was estimated at 3% [Zimmer et al 2017]. Most pathogenic variants were unique; no common recurrent variants were observed except for c.387C>A (NM_001145717.1); p.Asp129Glu (NP_001139189.2) in four consanguineous, unrelated Pakistani families [Ahmad et al 2016, Lee et al 2016]. The majority of pathogenic variants cluster at the patatin-like subdomain of PNPLA1 containing the catalytic site of the encoded enzyme [Vahidnezhad et al 2017].
Normal gene product. PNPLA1 is expressed in the upper layers of the epidermis, especially in the granular layer, and was localized to regions of keratin intermediate filament bundles. Findings suggest that PNPLA1 (437 amino acid residues; NP_775947.2) activity is localized to the cytoplasm and associated with the cytoskeleton.
PNPLA1 is responsible for the final step of synthesis of the epidermis-specific sphingolipid acylceramide (ω-O-acylceramide), functioning as transacylase. It catalyzes the ω-O-esterification with linoleic acid to form acylceramides. Acylceramides form the corneocyte-bound lipid envelope, which is essential for establishing a skin barrier as demonstrated in Pnpla1-deficient mice, which die prematurely after birth due to a severe skin barrier defect [Grond et al 2017, Hirabayashi et al 2017, Ohno et al 2017].
Abnormal gene product.
PNPLA1 pathogenic variants reported to date are predicted to abolish the function of this transacylase, reduce production of omega-O-acylceramides, lead to an accumulation of nonesterified omega-hydroxy-ceramides and compromise the lipid barrier of the epidermis.
Abnormal forms of PNPLA1 enzyme found in patients with ARCI showed reduced or no enzyme activity in either cell-based or in vitro assays [Grond et al 2017, Ohno et al 2017]. Topical acylceramide application on skin of Pnpla1-deficient mice partially rescued the phenotype by rebuilding the lipid envelope, suggesting that supplementing ichthyotic skin with omega-O-acylceramides could be a successful therapeutic approach for individuals with ARCI caused by omega-O-acylceramide deficiency (CERS3, CYP4F22, PNPLA1-related ARCI) [Grond et al 2017, Hirabayashi et al 2017].
SLC27A4 (formerly FATP4)
Gene structure.
SLC27A4 encodes a long-chain fatty acid transporter protein (FATP4) and is classified as member 4 of the solute carrier family 27. The gene is located at 9q34.11 and is 20,910 bp in size. The cDNA (NM_005094.3) includes 13 exons, 12 of which are coding [Watkins et al 2007].
Pathogenic variants.To date, 22 distinct sequence variants in SLC27A4 have been reported as pathogenic in individuals with ichthyosis-prematurity syndrome (IPS). About two thirds of variants are missense changes, while the remainder are loss-of-function variants (nonsense, frameshift, splice site variants) (see Table A, HGMD). One nonsense variant, c.504C>A (NM_005094.3); p.Cys168Ter (NP_005085.2), was found to segregate with ARCI in all unrelated ARCI families from Scandinavia tested, due to a founder effect [Klar et al 2009, Sobol et al 2011, Pigg et al 2016]. IPS caused by other pathogenic variants has been observed worldwide [Morice-Picard et al 2010, Inhoff et al 2011, George et al 2015, Tsuge et al 2015, Lwin et al 2016, Bueno et al 2017]. No whole- or partial-gene deletions or duplications were reported thus far.
Table 3.
SLC27A4 Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. FATP4 (NP_005085; 643 amino acids) is a transmembrane protein expressed in the epidermis that is important for the uptake of exogenous fatty acids; it also has enzymatic acyl-CoA synthetase activity. FATP4 is an essential protein for epidermal barrier formation during embryogenesis and in the neonatal period, while other members of the FATP protein family may compensate for defective FATP4 later in life [Klar et al 2009].
Abnormal gene product. Pathogenic SLC27A4 variants are expected to compromise the normal functions of the lipid transporter protein, thus leading to defective epidermal lipid metabolism. FATP4 deficiency in a mouse model and in patient-derived keratinocytes was shown to impair fatty acid transport, leading to accumulation of abnormal lipid masses in the upper epidermis, reduced activity of very long chain fatty acids (VLCFA)-CoA synthetase, and impaired incorporation of VLCFA into cellular lipids, thus resulting in a severe skin barrier defect [Klar et al 2009]. FATP4 null mice have a greatly thickened skin, impaired skin barrier properties, and breathing problems secondary to their tight, restrictive skin. They usually die either in utero or in the neonatal period [Klar et al 2009]. Similarly, patients with IPS are born prematurely and have a severe neonatal phenotype, while ichthyosis improves with age and may almost resolve by adulthood, possibly due to compensation by other FATP proteins [Klar et al 2009].
TGM1
Gene structure.
TGM1 has 14,133 bp distributed in 15 exons [Kim et al 1992, Yamanishi et al 1992]. The TGM1 cDNA is approximately 2.5 kb in length (NM_000359.2).
Pathogenic variants. To date, more than 130 different pathogenic variants in TGM1 have been identified in individuals with autosomal recessive congenital ichthyosis (ARCI). The majority are single-base changes; rarely, insertions or deletions are found. TGM1 pathogenic variants include missense, nonsense, and splice site variants. To date, all reported pathogenic variants have either (1) resulted in a truncated protein product, (2) altered residues that are conserved among the family of transglutaminases both within and across species, or (3) been absent in a large series of control samples, thus confirming that all reported variants are pathogenic variants and not polymorphisms. Most pathogenic variants are distributed in the first two thirds of the gene. One of the common pathogenic variants in TGM1 affects the intron 5 splice acceptor site (NM_000359.2:c.877-2A>G; alias IVS5-2A>G), and has been found in approximately 39% of persons with known pathogenic variants and in most affected Norwegian individuals because of a founder effect [Pigg et al 1998, Shevchenko et al 2000, Farasat et al 2009]; 41% of all TGM1 pathogenic variants occur in arginine residues (including especially amino acids 142 and 143) that contain CpG islands [Farasat et al 2009]. Other missense variants affect protein residues critical to transglutaminase K function and/or reduce mRNA stability.
Normal gene product. The protein product of TGM1, protein-glutamine gamma-glutamyltransferase K (transglutaminase K), has 813 amino acid residues with a molecular weight of 89.3 kd and a poiseuille of 5.7 [Kim et al 1991] (NP_000350.1). It is an enzyme that catalyzes formation of an isodipeptide bond between the epsilon-amide group of lysine to the carboxyl group of a glutamyl residue of a protein. Transglutaminase K shows approximately 50% sequence homology with the other human transglutaminase proteins of known sequence [Kim et al 1991] and greater than 90% homology with transglutaminase K proteins of other species. Transglutaminase K is primarily found in the upper layers of the epidermis, where its function is to cross-link proteins in the formation of the cornified envelopes composing the uppermost layer of the epidermis. One of the primary functions of these cornified envelopes is to provide the barrier function of the skin.
Abnormal gene product. The mutated alleles of TGM1 are predicted to code for truncated mRNA that is subject to degradation prior to translation, or to code for abnormal residues in critical portions of the protein that are thought to interfere with the enzymatic function of transglutaminase K.
Additional Genetic Causes of ARCI
For further information on genes listed in click here (pdf).
