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Autosomal Recessive Congenital Ichthyosis


Author Information and Affiliations

Initial Posting: ; Last Update: May 18, 2017.

Estimated reading time: 43 minutes


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.


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.


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 a pregnancy at increased risk are possible if both ARCI-related pathogenic variants have been identified in a family.

GeneReview Scope

Autosomal Recessive Congenital Ichthyosis: Included Phenotypes
  • Harlequin ichthyosis
  • Classic lamellar ichthyosis (LI)
  • (Nonbullous) congenital ichthyosiform erythroderma (CIE)

For synonyms and outdated names see Nomenclature.


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;
  • 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 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.

Table 1a.

Molecular Genetics of Autosomal Recessive Congenital Ichthyosis: Most Common Genetic Causes

Gene 1Proportion of ARCI Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Detectable by Method
analysis 3
Gene-targeted deletion/duplication analysis 4
ABCA12 5%-7% (>93% of harlequin ichthyosis) 5>95% 6At least 4% 7
ALOX12B 7%-13% 8>95% 8Unknown 9
ALOXE3 4%-8% 8>95% 8Unknown 9, 10
CYP4F22 3%-8% 1124/25 12Unknown 9, 12
NIPAL4 5%-16% 1334/34 13Unknown 9
PNPLA1 Up to 3% 1430/30 14Unknown 9
SLC27A4 4% 1530/30 16Unknown 9
TGM1 32%-68% (~70%-90% of LI) 17>95% 17Unknown 9, 17
Unknown 18NA

Pathogenic variants of any one of the genes listed in this table account for >1% of ARCI; genes are listed in alphabetic order.


See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Akiyama [2010]; Author, personal experience


No data on detection rate of gene-targeted deletion/duplication analysis are available.


A single homozygous intragenic deletion involving exons 1-6 in ALOXE3 has been reported in a consanguineous Pakistani family with ARCI [Ullah et al 2016].


Further heterogeneity is suggested by the fact that at least 15% of affected families do not have pathogenic variants in any of the 12 known genes [Pigg et al 2016] and their phenotype does not map to the other known genes [Krebsová et al 2001]. Pathogenic variants have not been identified in any of the following situations: (1) linkage to two other loci on the same chromosome (chromosome 19) has been suggested [Fischer et al 2000, Virolainen et al 2000]; (2) homozygosity mapping in two consanguineous families identified a region on chromosome 12 (ARCI7) [Mizrachi-Koren et al 2005]; and (3) linkage to a locus on 15q26.3 ‒ possibly identical to the location of CERS3 ‒ has been suggested in an aboriginal family from Taiwan [Wu & Lee 2011].

Table 1b.

Molecular Genetics of Autosomal Recessive Congenital Ichthyosis: Less Common Genetic Causes

Gene 1, 2Comment
CASP14 A 2-bp deletion was reported in 3 patients from 2 (unrelated) Algerian families [Kirchmeier et al 2017].
CERS3 3 consanguineous Tunisian families w/congenital ichthyosis & eye, heart, & skeletal anomalies due to a contiguous gene deletion encompassing ADAMTS17, CERS3, & FLJ42289 were reported. Weill-Marchesani syndrome-like extracutaneous features were attributed to deletion of ADAMTS17, while deletion of CERS3 was assoc w/congenital ichthyosis [Radner et al 2013]. This causal relationship was confirmed when a homozygous splice donor site & missense variant in CERS3 were identified in 2 addl families w/ARCI w/o extracutaneous findings [Eckl et al 2013, Radner et al 2013].
LIPN Only 1 study reports a homozygous 2-bp deletion in LIPN in a large consanguineous family w/childhood-onset ARCI in 7 affected family members [Israeli et al 2011, Israeli et al 2013]. Pigg et al [2016] did not identify pathogenic variants in LIPN among 132 persons w/nonsyndromic congenital ichthyosis from Scandinavia.
SDR9C7 3 consanguineous Lebanese families were reported w/a homozygous missense variant in this gene in all affected probands [Shigehara et al 2016]. A Japanese person w/ARCI was found to be homozygous for a deletion involving SDR9C7 [Takeichi et al 2017].

Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <1% of ARCI); genes are listed in alphabetic order.


Click here (pdf) for further information on some of the genes included in the table.

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]:

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


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.


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.

Differential Diagnosis

Birth. The differential diagnosis of autosomal recessive congenital ichthyosis (ARCI) includes the following:

  • Sjögren-Larsson syndrome (OMIM 270200), an autosomal recessive disorder, is characterized by spastic paraplegia, intellectual disability, and retinopathy in addition to ichthyosis. Pathogenic variants in ALDH3A2 and abnormal levels of fatty aldehyde dehydrogenase (FALDH) activity in cultured fibroblasts identify children who have Sjögren-Larsson syndrome.
  • Netherton syndrome (OMIM 256500) is an autosomal recessive congenital ichthyosis featuring chronic inflammation of the skin, hair shaft anomalies, epidermal hyperplasia with an impaired epidermal barrier function, failure to thrive, and atopic manifestations. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and sepsis. The disease is caused by pathogenic variants in SPINK5, encoding serine protease inhibitor Kazal-type 5 [Raghunath et al 2004].
  • Gaucher disease, an autosomal recessive inborn error in glucosylceramidase, has a wide spectrum of clinical presentation. The perinatal lethal form may present as collodion skin abnormality and developmental and neurologic problems (pyramidal signs). Gaucher disease is caused by pathogenic variants in GBA.
  • Keratitis-ichthyosis-deafness (KID) syndrome (OMIM 148210), an autosomal dominant disorder, is characterized by vascularizing keratitis, congenital ichthyosis, palmoplantar keratoderma, and sensorineural hearing loss. Pathogenic variants in GJB2 or (rarely) GJB6 underlie the disorder [Richard et al 2002, Jan et al 2004].
  • Trichothiodystrophy (OMIM 601675) ("sulfur-deficient hair") is characterized by one or more of the following: photosensitivity, ichthyosis, brittle hair, infertility, developmental delay, and/or short stature. This disorder can be diagnosed by identifying reduced sulfur content of hair or by demonstrating UV sensitivityin cultured fibroblasts, although there also exists a non-photosensitive form of trichothiodystrophy. Most affected individuals have pathogenic variants in ERCC2; less commonly this disorder is associated with pathogenic variants in ERCC3, GTF2H5, MPLKIP, RNF113A, or GTF2E2.
  • Chanarin-Dorfman syndrome (OMIM 275630) (neutral lipid storage disease) is an autosomal recessive neuroichthyotic disorder in the differential diagnosis of the CIE phenotype that is caused by pathogenic variants in abhydrolase-5 (ABHD5) on chromosome 3. Screening involves examination of a peripheral blood smear for lipid storage vacuoles in neutrophils, eosinophils, and monocytes. Skin biopsy shows lipid droplets in the basal layer of the dermis.
  • Conradi-Hünermann-Happle syndrome (X-linked chondrodysplasia punctata with early gestational male lethality) is caused by a defect in cholesterol biosynthesis. It is characterized in affected females by cicatricial scarring, alopecia, patchy or diffuse ichthyosis that may resolve into atrophoderma and hyperpigmentation, punctuate calcification in epiphyseal cartilage, asymmetric rhizomelic limb shortening, cataracts, and deafness. This disorder is caused by pathogenic variants in EBP on Xp11.23.
  • Hypohidrotic ectodermal dysplasia is characterized by sparseness of scalp and body hair, reduced ability to sweat, and congenital absence of teeth. Inheritance can be autosomal recessive, autosomal dominant, or X-linked. Pathogenic variants in three genes have been identified as causing hypohidrotic ectodermal dysplasia: EDA (X-linked form), EDAR, and EDARADD (autosomal forms). In addition, pathogenic variants in WNT10A are associated with onycho-odontodermal dysplasia (OMIM 257980) and Schöpf-Schultz-Passarge syndrome (OMIM 257980), disorders in which hypohidrotic ectodermal dysplasia is a finding [Adaimy et al 2007, Bohring et al 2009, Cluzeau et al 2011].
  • Epidermolytic and superficial epidermolytic ichthyosis, formerly known as epidermolytic hyperkeratosis (OMIM 113800) and ichthyosis bullosa of Siemens (OMIM 146800), respectively, are autosomal dominant disorders that can be distinguished from ARCI by family history and histologic examination of the skin. Individuals with autosomal dominant epidermolytic ichthyosis virtually never present with a collodion membrane at birth. Nonbullous forms of palmoplantar keratodermas can present at birth or soon after, although the findings are mostly limited to the palms and soles with only a mild generalized ichthyosis in some.
  • Autosomal recessive ichthyosis with hypotrichosis (ARIH) syndrome (OMIM 602400) is characterized by vernix-like scaling at birth, transitioning to generalized white, fine scale with scalp involvement and possibly sparing of flexures. Another feature is generalized, diffuse, non-scarring hypotrichosis. The scalp hair is light colored, sparse, and curly. Eye involvement includes photophobia and/or inflammation of the eyelids (blepharitis). This disorder was reported in two consanguineous Israeli-Arab and Turkish families as a result of pathogenic loss-of-function variants in ST14, which encodes a serine protease matriptase [Avrahami et al 2008]. Pathogenic variants in the same gene have also been reported in two consanguineous families with congenital ichthyosis, follicular atrophoderma, hypotrichosis, and hypohidrosis (IFAH). This suggests a broad clinical phenotype in individuals with pathogenic variants in ST14 which overlaps with the ectodermal dysplasias [Basel-Vanagaite et al 2007].

Infancy. Other ichthyoses that may not be evident at birth but appear soon after include the following:

  • Ichthyosis vulgaris (OMIM 146700) usually presents within the first year of life; it is characterized by mild ichthyosis/xerosis, keratosis pilaris, and hyperlinear palms and soles, and is often associated with atopy. Individuals with typical features are heterozygous for a loss-of-function pathogenic variant in FLG, the gene encoding filaggrin, while homozygous or compound-heterozygous individuals show a more severe phenotype reminiscent of classic LI [Smith et al 2006].
  • X-linked ichthyosis (steroid sulfatase deficiency; OMIM 308100) is characterized in infancy by white, adherent scale, which darkens over time (especially affecting the flexures), asymptomatic corneal opacities, and occasionally cryptorchidism. High plasma cholesterol sulfate concentration identifies affected males. X-linked ichthyosis is caused by recurrent genomic deletions including STS on Xp22.3 in more than 90% of affected males. Larger deletions may result in a more complex phenotype that additionally includes intellectual disabilities, autism spectrum disorder, loss of smell (Kallmann syndrome), or other features [Cañueto et al 2010]. Pathogenic variants detected by sequence analysis have been rarely reported as well.


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 (pivotal to outcome)
  • Prevention of dehydration
  • Maintenance of body temperature; prevention of overheating
  • Prevention of corneal drying
  • High caloric diet
  • Release of collodion membrane on digits, when necessary, to prevent reduced circulation leading to loss of digits
  • Prevention of chest constriction resulting from tautness of membrane to assure adequate respiration


Regular physical examination for evidence of infection and control of skin involvement is appropriate; frequency depends on the severity. In adults, regular surveillance for skin cancer is appropriate (cases with atypical melanocytic nevi, malignant melanoma, squamous cell carcinoma, and basal cell carcinoma have been reported) [Fernandes et al 2010, Natsuga et al 2011].

Agents/Circumstances to Avoid

Skin irritants and overheating should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Affected mothers are at no specific disease-related risks during pregnancy. Anecdotal improvement of the ichthyosis with return to baseline after delivery has been reported.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Autosomal recessive congenital ichthyosis (ARCI) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one ARCI-related pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • The offspring of an individual with ARCI are obligate heterozygotes (carriers) for an ARCI-related pathogenic variant.
  • In the rare instance that an unrelated reproductive partner is a carrier of a pathogenic variant in the same gene associated with ARCI, the offspring are at a 50% risk of being affected and a 50% risk of being carriers.

Other family members. Each sib of a proband's parents is at a 50% risk of being a carrier of an ARCI-related pathogenic variant.

Carrier Detection

Carrier testing is possible for at-risk family members once both ARCI-related pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the ABCA12, ALOX12B, ALOXE3, CASP14, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, or TGM1 pathogenic variants have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic testing are possible.

3D or 4D ultrasound examination may be helpful in identifying fetuses with harlequin ichthyosis as early as the second trimester in families with a known history of harlequin ichthyosis [Holden et al 2007, Kudla & Timmerman 2010]. Echogenic sediment in the amniotic fluid has been described on fetal ultrasound in pregnancies with IPS.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

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 B.

OMIM Entries for Autosomal Recessive Congenital Ichthyosis (View All in OMIM)


For a detailed summary of gene and protein information for the genes associated with this disorder, see Table A, Gene.


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].


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].


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.


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

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.527C>Ap.Ala176Asp NM_001099287​.1

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.


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

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.504C>Ap.Cys168Tyr NM_005094​.3

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].


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 Table 1b click here (pdf).


Literature Cited

  • Adaimy L, Chouery E, Megarbane H, Mroueh S, Delague V, Nicolas E, Belguith H, de Mazancourt P, Megarbane A. Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia. Am J Hum Genet. 2007;2007;81:821–8. [PMC free article: PMC1973944] [PubMed: 17847007]
  • Ahmad F, Ansar M, Mehmood S, Izoduwa A, Lee K, Nasir A, Abrar M, Mehmood S, Ullah A, Aziz A, Smith JD, Shendure J, Bamshad MJ, Nicekrson DA, Santos-Cortez RL, Leal SM, Ahmad W, et al. A novel missense variant in the PNPLA1 gene underlies congenital ichthyosis in three consanguineous families. J Eur Acad Dermatol Venereol. 2016;30:e210–e213. [PMC free article: PMC5093081] [PubMed: 26691440]
  • Ahmed H, O'Toole EA. Recent advances in the genetics and management of harlequin ichthyosis. Pediatr Dermatol. 2014;31:539–46. [PubMed: 24920541]
  • Akiyama M. ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts. Hum Mutat. 2010;31:1090–6. [PubMed: 20672373]
  • Akiyama M, Sugiyama-Nakagiri Y, Sakai K, McMillan JR, Goto M, Arita K, Tsuji-Abe Y, Tabata N, Matsuoka K, Sasaki R, Sawamura D, Shimizu H. Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer. J Clin Invest. 2005;115:1777–84. [PMC free article: PMC1159149] [PubMed: 16007253]
  • Annilo T, Shulenin S, Chen ZQ, Arnould I, Prades C, Lemoine C, Maintoux-Larois C, Devaud C, Dean M, Denefle P, Rosier M. Identification and characterization of a novel ABCA subfamily member, ABCA12, located in the lamellar ichthyosis region on 2q34. Cytogenet Genome Res. 2002;98:169–76. [PubMed: 12697999]
  • Avrahami L, Maas S, Pasmanik-Chor M, Rainshtein L, Magal N, Smitt JHS, van Marle J, Shohat M, Basel-Vanagaite L. Autosomal recessive ichthyosis with hypotrichosis syndrome: further delineation of the phenotype. Clin Genet. 2008;2008;74:47–53. [PubMed: 18445049]
  • Basel-Vanagaite L, Attia R, Ishida-Yamamoto A, Rainshtein L, Amitai DB, Lurie R, Pasmanik-Chor M, Indelman M, Zvulunov A, Saban S, Magal N, Sprecher E, Shohat M. Autosomal Recessive Ichthyosis with Hypotrichosis Caused by a Mutation in ST14, Encoding Type II Transmembrane Serine Protease Matriptase. Am J Hum Genet. 2007;80:467–77. [PMC free article: PMC1821100] [PubMed: 17273967]
  • Bohring A, Stamm T, Spaich C, Haase C, Spree K, Hehr U, Hoffmann M, Ledig S, Sel S, Wieacker P, Röpke A. WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes. Am J Hum Genet. 2009;85:97–105. [PMC free article: PMC2706962] [PubMed: 19559398]
  • Bučková H, Nosková H, Borská R, Réblová K, Pinková B, Zapletalová E, Kopečková L, Horký O, Němečková J, Gaillyová R, Nagy Z, Veselý K, Hermanová M, Stehlíková K, Fajkusová L. Autosomal recessive congenital ichthyoses in the Czech Republic. Br J Dermatol. 2016;174:405–7. [PubMed: 25998749]
  • Bueno E, Cañueto J, García-Patos V, Vicente MA, Bodet-Castillo D, Hernández-Ruíz ME, González-Sarmiento R. Novel mutations in FATP4 gene in two families with ichthyosis prematurity syndrome. J Eur Acad Dermatol Venereol. 2017;31:e11–e13. [PubMed: 27168232]
  • Cañueto J, Ciria S, Hernández-Martín A, Unamuno P, González-Sarmiento R. Analysis of the STS gene in 40 patients with recessive X-linked ichthyosis: a high frequency of partial deletions in a Spanish population. J Eur Acad Dermatol Venereol. 2010;24:1226–9. [PubMed: 20236202]
  • Cluzeau C, Hadj-Rabia S, Jambou M, Mansour S, Guigue P, Masmoudi S, Bal E, Chassaing N, Vincent MC, Viot G, Clauss F, Manière MC, Toupenay S, Le Merrer M, Lyonnet S, Cormier-Daire V, Amiel J, Faivre L, de Prost Y, Munnich A, Bonnefont JP, Bodemer C, Smahi A. Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum Mutat. 2011;32:70–2. [PubMed: 20979233]
  • Dahlqvist J, Klar J, Hausser I, Anton-Lamprecht I, Hellström Pigg M, Gedde-Dahl T Jr, Ganemo A, Vahlquist A, Dahl N. Congenital ichthyosis: Mutations in ichthyin associated with specific structural abnormalities in the granular layer of epidermis. J Med Genet. 2007;44:615–20. [PMC free article: PMC2597970] [PubMed: 17557927]
  • Digiovanna JJ, Mauro T, Milstone LM, Schmuth M, Toro JR. Systemic retinoids in the management of ichthyoses and related skin types. Dermatol Ther. 2013;26:26–38. [PMC free article: PMC3884695] [PubMed: 23384018]
  • Diociaiuti A, El Hachem M, Pisaneschi E, Giancristoforo S, Genovese S, Sirleto P, Boldrini R, Angioni A. Role of molecular testing in the multidisciplinary diagnostic approach of ichthyosis. Orphanet J Rare Dis. 2016;11:4. [PMC free article: PMC4712481] [PubMed: 26762237]
  • Eckl KM, de Juanes S, Kurtenbach J, Nätebus M, Lugassy J, Oji V, Traupe H, Preil ML, Martínez F, Smolle J, Harel A, Krieg P, Sprecher E, Hennies HC. Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B. J Invest Dermatol. 2009;129:1421–8. [PubMed: 19131948]
  • Eckl KM, Krieg P, Kuster W, Traupe H, Andre F, Wittstruck N, Furstenberger G, Hennies HC. Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis. Hum Mutat. 2005;26:351–61. [PubMed: 16116617]
  • Eckl KM, Tidhar R, Thiele H, Oji V, Hausser I, Brodesser S, Preil ML, Onal-Akan A, Stock F, Müller D, Becker K, Casper R, Nürnberg G, Altmüller J, Nürnberg P, Traupe H, Futerman AH, Hennies HC. Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length. J Invest Dermatol. 2013;133:2202–11. [PubMed: 23549421]
  • Fachal L, Rodriguez-Pazos L, Ginarte M, Carracedo A, Toribio J, Vega A. Identification of a novel PNPLA1 mutation in a Spanish family with autosomal recessive congenital ichthyosis. Br J Dermatol. 2014;170:980–2. [PubMed: 24344921]
  • Farasat S, Wei MH, Herman M, Liewehr DJ, Steinberg SM, Bale SJ, Fleckman P, Toro JR. Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA. J Med Genet. 2009;46:103–11. [PMC free article: PMC3044481] [PubMed: 18948357]
  • Fernandes JD, Machado MC, Oliveira ZN. Increased melanocytic nevi in patients with inherited ichthyoses: report of a previously undescribed association. Pediatr Dermatol. 2010;27:453–8. [PubMed: 20561241]
  • Fischer J. Autosomal recessive congenital ichthyosis. J Invest Dermatol. 2009;129:1319–21. [PubMed: 19434086]
  • Fischer J, Faure A, Bouadjar B, Blanchet-Bardon C, Karaduman A, Thomas I, Emre S, Cure S, Ozguc M, Weissenbach J, Prud'homme JF. Two new loci for autosomal recessive ichthyosis on chromosomes 3p21 and 19p12-q12 and evidence for further genetic heterogeneity. Am J Hum Genet. 2000;66:904–13. [PMC free article: PMC1288171] [PubMed: 10712205]
  • George R, Santhanam S, Samuel R, Chapla A, Hilmarsen HT, Braathen GJ, Reinholt FP, Jahnsen F, Khnykin D. Ichthyosis prematurity syndrome caused by a novel missense mutation in FATP4 gene-a case report from India. Clin Case Rep. 2015;4:87–9. [PMC free article: PMC4706401] [PubMed: 26783444]
  • Grall A, Guaguère E, Planchais S, Grond S, Bourrat E, Hausser I, Hitte C, Le Gallo M, Derbois C, Kim GJ, Lagoutte L, Degorce-Rubiales F, Radner FP, Thomas A, Küry S, Bensignor E, Fontaine J, Pin D, Zimmermann R, Zechner R, Lathrop M, Galibert F, André C, Fischer J. PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat Genet. 2012;44:140–7. [PubMed: 22246504]
  • Grond S, Eichmann TO, Dubrac S, Kolb D, Schmuth M, Fischer J, Crumrine D, Elias PM, Haemmerle G, Zechner R, Lass A, Radner FP. PNPLA1 deficiency in mice and humans leads to a defect in the synthesis of omega-O-acylceramides. J Invest Dermatol. 2017;137:394–402. [PMC free article: PMC5298181] [PubMed: 27751867]
  • Hackett BC, Fitzgerald D, Watson RM, Hol FA, Irvine AD. Genotype-phenotype correlations with TGM1: clustering of mutations in the bathing suit ichthyosis and self-healing collodion baby variants of lamellar ichthyosis. Br J Dermatol. 2010;162:448–51. [PubMed: 19863506]
  • Harting M, Brunetti-Pierri N, Chan CS, Kirby J, Dishop MK, Richard G, Scaglia F, Yan AC, Levy ML. Self-healing collodion membrane and mild nonbullous congenital ichthyosiform erythroderma due to 2 novel mutations in the ALOX12B gene. Arch Dermatol. 2008;144:351–6. [PubMed: 18347291]
  • Hernández-Martín A, Garcia-Doval I, Aranegui B, de Unamuno P, Rodríguez-Pazos L, González-Enseñat MA, Vicente A, Martín-Santiago A, Garcia-Bravo B, Feito M, Baselga E, Círia S, de Lucas R, Ginarte M, González-Sarmiento R, Torrelo A. Prevalence of autosomal recessive congenital ichthyosis: A population-based study using the capture-recapture method in Spain. J Am Acad Dermatol. 2012;67:240–4. [PubMed: 22000705]
  • Hirabayashi T, Anjo T, Kaneko A, Senoo Y, Shibata A, Takama H, Yokoyama K, Nishito Y, Ono T, Taya C, Muramatsu K, Fukami K, Muñoz-Garcia A, Brash AR, Ikeda K, Arita M, Akiyama M, Murakami M. PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis. Nat Commun. 2017;8:14609. [PMC free article: PMC5337976] [PubMed: 28248300]
  • Holden S, Ahuja S, Ogilvy-Stuart A, Firth HV, Lees C. Prenatal diagnosis of Harlequin ichthyosis presenting as distal arthrogryposis using three-dimensional ultrasound. Prenat Diagn. 2007;27:566–7. [PubMed: 17385787]
  • Inhoff O, Hausser I, Schneider SW, Khnykin D, Jahnsen FL, Sartoris J, Goerdt S, Peitsch WK. Ichthyosis prematurity syndrome caused by a novel fatty acid transport protein 4 gene mutation in a German infant. Arch Dermatol. 2011;147:750–2. [PubMed: 21690550]
  • Israeli S, Goldberg I, Fuchs-Telem D, Bergman R, Indelman M, Bitterman-Deutsch O, Harel A, Mashiach Y, Sarig O, Sprecher E. Non-syndromic autosomal recessive congenital ichthyosis in the Israeli population. Clin Exp Dermatol. 2013;38:911–6. [PubMed: 23621129]
  • Israeli S, Khamaysi Z, Fuchs-Telem D, Nousbeck J, Bergman R, Sarig O, Sprecher E. A mutation in LIPN, encoding epidermal lipase N, causes a late-onset form of autosomal-recessive congenital ichthyosis. Am J Hum Genet. 2011;88:482–7. [PMC free article: PMC3071911] [PubMed: 21439540]
  • Jan AY, Amin S, Ratajczak P, Richard G, Sybert VP. Genetic heterogeneity of KID syndrome: identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. J Invest Dermatol. 2004;122:1108–13. [PubMed: 15140211]
  • Jobard F, Lefèvre C, Karaduman A, Blanchet-Bardon C, Emre S, Weissenbach J, Ozguc M, Lathrop M, Prud'homme JF, Fischer J. Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1. Hum Mol Genet. 2002;11:107–13. [PubMed: 11773004]
  • Kelsell DP, Norgett EE, Unsworth H, Teh MT, Cullup T, Mein CA, Dopping-Hepenstal PJ, Dale BA, Tadini G, Fleckman P, Stephens KG, Sybert VP, Mallory SB, North BV, Witt DR, Sprecher E, Taylor AE, Ilchyshyn A, Kennedy CT, Goodyear H, Moss C, Paige D, Harper JI, Young BD, Leigh IM, Eady RA, O'Toole EA. Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am J Hum Genet. 2005;76:794–803. [PMC free article: PMC1199369] [PubMed: 15756637]
  • Khnykin D, Rønnevig J, Johnsson M, Sitek JC, Blaas HG, Hausser I, Johansen FE, Jahnsen FL. Ichthyosis prematurity syndrome: clinical evaluation of 17 families with a rare disorder of lipid metabolism. J Am Acad Dermatol. 2012;66:606–16. [PubMed: 21856041]
  • Kim HC, Idler WW, Kim IG, Han JH, Chung SI, Steinert PM. The complete amino acid sequence of the human transglutaminase K enzyme deduced from the nucleic acid sequences of cDNA clones. J Biol Chem. 1991;266:536–9. [PubMed: 1670769]
  • Kim IG, McBride OW, Wang M, Kim SY, Idler WW, Steinert PM. Structure and organization of the human transglutaminase 1 gene. J Biol Chem. 1992;267:7710–7. [PubMed: 1348508]
  • Kirchmeier P, Zimmer A, Bouadjar B, Rösler B, Fischer J. Whole-exome-sequencing reveals small deletions in CASP14 in patients with autosomal recessive inherited ichthyosis. Acta Derm Venereol. 2017;97:102–4. [PubMed: 27494380]
  • Klar J, Gedde-Dahl T Jr, Larsson M, Pigg M, Carlsson B, Tentler D, Vahlquist A, Dahl N. Assignment of the locus for ichthyosis prematurity syndrome to chromosome 9q33.3-34.13. J Med Genet. 2004;41:208–12. [PMC free article: PMC1735696] [PubMed: 14985385]
  • Klar J, Schweiger M, Zimmerman R, Zechner R, Li H, Törmä H, Vahlquist A, Bouadjar B, Dahl N, Fischer J. Mutations in the fatty acid transport protein 4 gene cause the ichthyosis prematurity syndrome. Am J Hum Genet. 2009;85:248–53. [PMC free article: PMC2725242] [PubMed: 19631310]
  • Krebsová A, Küster W, Lestringant GG, Schulze B, Hinz B, Frossard PM, Reis A, Hennies HC. Identification, by homozygosity mapping, of a novel locus for autosomal recessive congenital ichthyosis on chromosome 17p, and evidence for further genetic heterogeneity. Am J Hum Genet. 2001;69:216–22. [PMC free article: PMC1226037] [PubMed: 11398099]
  • Kudla MJ, Timmerman D. Prenatal diagnosis of harlequin ichthyosis using 3- and 4-dimensional sonography. J Ultrasound Med. 2010;29:317–9. [PubMed: 20103806]
  • Lefèvre C, Audebert S, Jobard F, Bouadjar B, Lakhdar H, Boughdene-Stambouli O, Blanchet-Bardon C, Heilig R, Foglio M, Weissenbach J, Lathrop M, Prud'homme JF, Fischer J. Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum Mol Genet. 2003;12:2369–78. [PubMed: 12915478]
  • Lefèvre C, Bouadjar B, Ferrand V, Tadini G, Megarbane A, Lathrop M, Prud'homme JF, Fischer J. Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3. Hum Mol Genet. 2006;15:767–76. [PubMed: 16436457]
  • Lefèvre C, Bouadjar B, Karaduman A, Jobard F, Saker S, Ozguc M, Lathrop M, Prud'homme JF, Fischer J. Mutations in ichthyin a new gene on chromosome 5q33 in a new form of autosomal recessive congenital ichthyosis. Hum Mol Genet. 2004;13:2473–82. [PubMed: 15317751]
  • Lee E, Rahman OU, Khan MT, Wadood A, Naeem M, Kang C, Jelani M. Whole exome analysis reveals a novel missense PNPLA1 variant that causes autosomal recessive congenital ichthyosis in a Pakistani family. J Dermatol Sci. 2016;82:46–8. [PubMed: 26778108]
  • Lesueur F, Bouadjar B, Lefevre C, Jobard F, Audebert S, Lakhdar H, Martin L, Tadini G, Karaduman A, Emre S, Saker S, Lathrop M, Fischer J. Novel mutations in ALOX12B in patients with autosomal recessive congenital ichthyosis and evidence for genetic heterogeneity on chromosome 17p13. J Invest Dermatol. 2007;127:829–34. [PubMed: 17139268]
  • Lwin SM, Hsu CK, McMillan JR, Mellerio JE, McGrath JA. Ichthyosis prematurity syndrome: from fetus to adulthood. JAMA Dermatol. 2016;152:1055–8. [PubMed: 27224495]
  • Mazereeuw-Hautier J, Aufenvenne K, Deraison C, Ahvazi B, Oji V, Traupe H, Hovnanian A. Acral self-healing collodion baby: report of a new clinical phenotype caused by a novel TGM1 mutation. Br J Dermatol. 2009;161:456–63. [PubMed: 19500103]
  • Mizrachi-Koren M, Geiger D, Indelman M, Bitterman-Deutsch O, Bergman R, Sprecher E. Identification of a novel locus associated with congenital recessive ichthyosis on 12p11.2-q13. J Invest Dermatol. 2005;125:456–62. [PubMed: 16117785]
  • Morice-Picard F, Léauté-Labrèze C, Décor A, Boralevi F, Lacombe D, Taieb A, Fischer J. A novel mutation in the fatty acid transport protein 4 gene in a patient initially described as affected by self-healing congenital verruciform hyperkeratosis. Am J Med Genet A. 2010;152A:2664–5. [PubMed: 20815031]
  • Natsuga K, Akiyama M, Shimizu H. Malignant skin tumours in patients with inherited ichthyosis. Br J Dermatol. 2011;165:263–8. [PubMed: 21517795]
  • Noguera-Morel L, Feito-Rodríguez M, Maldonado-Cid P, García-Miñáur S, Kamsteeg EJ, González-Sarmiento R, De Lucas-Laguna R, Hernández-Martín A, Torrelo A. Two cases of autosomal recessive congenital ichthyosis due to CYP4F22 mutations: expanding the genotype of self-healing collodion baby. Pediatr Dermatol. 2016;33:e48–51. [PubMed: 26646773]
  • Ohno Y, Nakamichi S, Ohkuni A, Kamiyama N, Naoe A, Tsujimura H, Yokose U, Sugiura K, Ishikawa J, Akiyama M, Kihara A. Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation. Proc Natl Acad Sci U S A. 2015;112:7707–12. [PMC free article: PMC4485105] [PubMed: 26056268]
  • Ohno Y, Kamiyama N, Nakamichi S, Kihara A. PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide. Nat Commun. 2017;8:14610. [PMC free article: PMC5337975] [PubMed: 28248318]
  • Oji V, Hautier JM, Ahvazi B, Hausser I, Aufenvenne K, Walker T, Seller N, Steijlen PM, Kuster W, Hovnanian A, Hennies HC, Traupe H. Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype. Hum Mol Genet. 2006;15:3083–97. [PubMed: 16968736]
  • Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, Coudiere P, DiGiovanna JJ, Elias P, Fischer J, Fleckman P, Gina M, Harper J, Hashimoto T, Hausser I, Hennies HC, Hohl D, Hovnanian A, Ishida-Yamamoto A, Jacyk WK, Leachman S, Leigh I, Mazereeuw-Hautier J, Milstone L, Morice-Picard F, Paller AS, Richard G, Schmuth M, Shimizu H, Sprecher E, Van Steensel M, Taïeb A, Toro JR, Vabres P, Vahlquist A, Williams M, Traupe H. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63:607–41. [PubMed: 20643494]
  • Parmentier L, Clepet C, Boughdene-Stambouli O, Lakhdar H, Blanchet-Bardon C, Dubertret L, Wunderle E, Pulcini F, Fizames C, Weissenbach J. Lamellar ichthyosis: further narrowing, physical and expression mapping of the chromosome 2 candidate locus. Eur J Hum Genet. 1999;7:77–87. [PubMed: 10094194]
  • Parmentier L, Lakhdar H, Blanchet-Bardon C, Marchand S, Dubertret L, Weissenbach J. Mapping of a second locus for lamellar ichthyosis to chromosome 2q33-35. Hum Mol Genet. 1996;5:555–9. [PubMed: 8845852]
  • Pigg M, Gedde-Dahl T Jr, Cox D, Hausser I, Anton-Lamprecht I, Dahl N. Strong founder effect for a transglutaminase 1 gene mutation in lamellar ichthyosis and congenital ichthyosiform erythroderma from Norway. Eur J Hum Genet. 1998;6:589–96. [PubMed: 9887377]
  • Pigg MH, Bygum A, Gånemo A, Virtanen M, Brandrup F, Zimmer AD, Hotz A, Vahlquist A, Fischer J. Spectrum of autosomal recessive congenital ichthyosis in Scandinavia: clinical characteristics and novel and recurrent mutations in 132 patients. Acta Derm Venereol. 2016;96:932–7. [PubMed: 27025581]
  • Radner FP, Marrakchi S, Kirchmeier P, Kim G-J., Ribierre F, Kamoun B, Abid L, Leipoldt M, Turki H, Schempp W, Heilig R, Lathrop M, Fischer J. Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet. 2013;9:e1003536. [PMC free article: PMC3675029] [PubMed: 23754960]
  • Raghunath M, Hennies HC, Ahvazi B, Vogel M, Reis A, Steinert PM, Traupe H. Self-healing collodion baby: a dynamic phenotype explained by a particular transglutaminase-1 mutation. J Invest Dermatol. 2003;120:224–8. [PubMed: 12542526]
  • Raghunath M, Tontsidou L, Oji V, Aufenvenne K, Schurmeyer-Horst F, Jayakumar A, Stander H, Smolle J, Clayman GL, Traupe H. SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases. J Invest Dermatol. 2004;123:474–83. [PubMed: 15304086]
  • Rajpopat S, Moss C, Mellerio J, Vahlquist A, Gånemo A, Hellström-Pigg M, Ilchyshyn A, Burrows N, Lestringant G, Taylor A, Kennedy C, Paige D, Harper J, Glover M, Fleckman P, Everman D, Fouani M, Kayserili H, Purvis D, Hobson E, Chu C, Mein C, Kelsell D, O'Toole E. Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases. Arch Dermatol. 2011;147:681–6. [PubMed: 21339420]
  • Richard G, Rouan F, Willoughby CE, Brown N, Chung P, Ryynanen M, Jabs EW, Bale SJ, DiGiovanna JJ, Uitto J, Russell L. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am J Hum Genet. 2002;70:1341–8. [PMC free article: PMC447609] [PubMed: 11912510]
  • Rodríguez-Pazos L, Ginarte M, Fachal L, Toribio J, Carracedo A, Vega A. Analysis of TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 in autosomal recessive congenital ichthyosis from Galicia (NW Spain): evidence of founder effects. Br J Dermatol. 2011;165:906–11. [PubMed: 21668430]
  • Sakai K, Akiyama M, Yanagi T, McMillan JR, Suzuki T, Tsukamoto K, Sugiyama H, Hatano Y, Hayashitani M, Takamori K, Nakashima K, Shimizu H. ABCA12 is a major causative gene for non-bullous congenital ichthyosiform erythroderma. J Invest Dermatol. 2009;129:2306–9. [PubMed: 19262603]
  • Scott CA, Plagnol V, Nitoiu D, Bland PJ, Blaydon DC, Chronnell CM, Poon DS, Bourn D, Gárdos L, Császár A, Tihanyi M, Rustin M, Burrows NP, Bennett C, Harper JI, Conrad B, Verma IC, Taibjee SM, Moss C, O'Toole EA, Kelsell DP. Targeted sequence capture and high-throughput sequencing in the molecular diagnosis of ichthyosis and other skin diseases. J Invest Dermatol. 2013;133:573. [PubMed: 22992804]
  • Shevchenko YO, Compton JG, Toro JR, DiGiovanna JJ, Bale SJ. Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies. Hum Genet. 2000;106:492–9. [PubMed: 10914678]
  • Shibata A, Sugiura K, Suzuki A, Ichiki T, Akiyama M. Apparent homozygosity due to compound heterozygosity of one point mutation and an overlapping exon deletion mutation in ABCA12: A genetic diagnostic pitfall. J Dermatol Sci. 2015;80:196–202. [PubMed: 26475431]
  • Shigehara Y, Okuda S, Nemer G, Chedraoui A, Hayashi R, Bitar F, Nakai H, Abbas O, Daou L, Abe R, Sleiman MB, Kibbi AG, Kurban M, Shimomura Y. Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis. Hum Mol Genet. 2016;25:4484–93. [PubMed: 28173123]
  • Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, Sergeant A, O'Regan G, Bale SJ, Compton JG, DiGiovanna JJ, Presland RB, Fleckman P, McLean WH. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006;38:337–42. [PubMed: 16444271]
  • Sobol M, Dahl N, Klar J. FATP4 missense and nonsense mutations cause similar features in Ichthyosis Prematurity Syndrome. BMC Res Notes. 2011;4:90. [PMC free article: PMC3072334] [PubMed: 21450060]
  • Sun D, McDonnell M, Chen XS, Lakkis MM, Li H, Isaacs SN, Elsea SH, Patel PI, Funk CD. Human 12(R)-lipoxygenase and the mouse ortholog. Molecular cloning, expression, and gene chromosomal assignment. J Biol Chem. 1998;273:33540–7. [PubMed: 9837935]
  • Takeichi T, Nomura T, Takama H, Kono M, Sugiura K, Watanabe D, Shimizu H, Simpson MA, McGrath JA, Akiyama M. Deficient stratum corneum intercellular lipid in a Japanese patient with lamellar ichthyosis by a homozygous deletion mutation in SDR9C7. Br J Dermatol. 2017;177:e62–e64. [PubMed: 28112794]
  • Thomas AC, Cullup T, Norgett EE, Hill T, Barton S, Dale BA, Sprecher E, Sheridan E, Taylor AE, Wilroy RS, DeLozier C, Burrows N, Goodyear H, Fleckman P, Stephens KG, Mehta L, Watson RM, Graham R, Wolf R, Slavotinek A, Martin M, Bourn D, Mein CA, O'Toole EA, Kelsell DP. ABCA12 is the major harlequin ichthyosis gene. J Invest Dermatol. 2006;126:2408–13. [PubMed: 16902423]
  • Tsuge I, Morishita M, Kato T, Tsutsumi M, Inagaki H, Mori Y, Yamawaki K, Inuo C, Ieda K, Ohye T, Hayakawa A, Kurahashi H. Identification of novel FATP4 mutations in a Japanese patient with ichthyosis prematurity syndrome. Hum Genome Var. 2015;2:15003. [PMC free article: PMC4785586] [PubMed: 27081519]
  • Ullah R, Ansar M, Durrani ZU, Lee K, Santos-Cortez RL, Muhammad D, Ali M, Zia M, Ayub M, Khan S, Smith JD, Nickerson DA, Shendure J, Bamshad M, Leal SM, Ahmad W. Novel mutations in the genes TGM1 and ALOXE3 underlying autosomal recessive congenital ichthyosis. Int J Dermatol. 2016;55:524–30. [PMC free article: PMC5090260] [PubMed: 26578203]
  • Vahidnezhad H, Youssefian L, Saeidian AH, Zeinali S, Mansouri P, Sotoudeh S, Barzegar M, Mohammadi-Asl J, Karamzadeh R, Abiri M, McCormick K, Fortina P, Uitto J. Gene-targeted next generation sequencing identifies PNPLA1 mutations in patients with a phenotypic spectrum of autosomal recessive congenital ichthyosis: the impact of consanguinity. J Invest Dermatol. 2017;137:678–85. [PubMed: 27884779]
  • Vahlquist A, Bygum A, Gånemo A, Virtanen M, Hellström-Pigg M, Strauss G, Brandrup F, Fischer J. Genotypic and clinical spectrum of self-improving collodion ichthyosis: ALOX12B, ALOXE3, and TGM1 mutations in Scandinavian patients. J Invest Dermatol. 2010;130:438–43. [PubMed: 19890349]
  • Virolainen E, Wessman M, Hovatta I, Niemi KM, Ignatius J, Kere J, Peltonen L, Palotie A. Assignment of a novel locus for autosomal recessive congenital ichthyosis to chromosome 19p13.1-p13.2. Am J Hum Genet. 2000;66:1132–7. [PMC free article: PMC1288147] [PubMed: 10712223]
  • Wajid M, Kurban M, Shimomura Y, Christiano AM. NIPAL4/ichthyin is expressed in the granular layer of human epidermis and mutated in two Pakistani families with autosomal recessive ichthyosis. Dermatology. 2010;220:8–14. [PMC free article: PMC2855276] [PubMed: 20016120]
  • Watkins PA, Maiguel D, Jia Z, Pevsner J. Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome. J Lipid Res. 2007;48:2736–50. [PubMed: 17762044]
  • Wu WM, Lee YS. Autosomal recessive congenital ichthyosis maps to chromosome 15q26.3 in an isolated aboriginal population from southern Taiwan. J Dermatol Sci. 2011;61:62–4. [PubMed: 21093221]
  • Yamanishi K, Inazawa J, Liew FM, Nonomura K, Ariyama T, Yasuno H, Abe T, Doi H, Hirano J, Fukushima S. Structure of the gene for human transglutaminase 1. J Biol Chem. 1992;267:17858–63. [PubMed: 1381356]
  • Zhang L, Ferreyros M, Feng W, Hupe M, Crumrine DA, Chen J, Elias PM, Holleran WM, Niswander L, Hohl D, Williams T, Torchia EC, Roop DR. Defects in stratum corneum desquamation are the predominant effect of impaired ABCA12 function in a novel mouse model of harlequin ichthyosis. PLoS One. 2016;11:e0161465. [PMC free article: PMC4994956] [PubMed: 27551807]
  • Zimmer AD, Kim GJ, Hotz A, Bourrat E, Hausser I, Has C, Oji V, Stieler K, Vahlquist A, Kunde V, Weber B, Radner FP, Leclerc-Mercier S, Schlipf N, Demmer P, Küsel J, Fischer J. Sixteen novel mutations in PNPLA1 in patients with autosomal recessive congenital ichthyosis reveal the importance of an extended patatin domain in PNPLA1 that is essential for proper human skin barrier function. Br J Dermatol. 2017;177:445–55. [PubMed: 28093717]

Chapter Notes

Author Notes

Dr Richard, a trained dermatologist and PhD medical geneticist, has more than 20 years' experience in clinical and molecular genetic studies of ichthyoses and other disorders of cornification. Her research laboratory has elucidated the molecular basis of numerous inherited ichthyoses and other skin disorders and she has contributed to more than 100 scientific publications, review articles, and book chapters. Web: www.genedx.com

Author History

Sherri J Bale, PhD, FACMG; GeneDx (2001-2017)
Gabriele Richard, MD, FACMG (2001-present)

Revision History

  • 18 May 2017 (ha) Comprehensive update posted live
  • 28 August 2014 (me) Comprehensive update posted live
  • 13 September 2012 (cd) Revision: sequence analysis, deletion/duplication analysis and prenatal diagnosis for PNPLA1 mutations available clinically
  • 19 April 2012 (me) Comprehensive update posted live
  • 19 November 2009 (cd) Revision: gene symbol ICHTHYIN changed to NIPAL4
  • 11 December 2008 (cd) Revision: deletion/duplication analysis available for ABCA12
  • 30 June 2008 (cd) Revision: sequence analysis and prenatal testing available for NIPAL4 mutations
  • 29 October 2007 (me) Comprehensive update posted live
  • 7 September 2005 (gr) Revision: testing for ALOX12B, ALOXE3, and ABCA12 clinically available
  • 29 December 2004 (me) Comprehensive update posted live
  • 30 January 2003 (me) Comprehensive update posted live
  • 10 January 2001 (me) Review posted live
  • June 2000 (sb) Original submission
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