Autosomal Recessive Congenital Ichthyosis

[Includes: ABCA12-Related Autosomal Recessive Congenital Ichthyosis, ALOXE3-Related Autosomal Recessive Congenital Ichthyosis, ALOX12B-Related Autosomal Recessive Congenital Ichthyosis, CYP4F22-Related Autosomal Recessive Congenital Ichthyosis, NIPAL4 (ICHTHYIN)-Related Autosomal Recessive Congenital Ichthyosis, TGM1-Related Autosomal Recessive Congenital Ichthyosis]

Summary

Disease characteristics. 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 (NCIE). Although these phenotypes are now recognized to fall on a continuum, 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 NCIE are seemingly distinct phenotypes: classic, severe lamellar ichthyosis (LI) with dark brown, plate-like scale with no erythroderma and NCIE 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.

Diagnosis/testing. The diagnosis of ARCI is established by skin findings at birth and in infancy. Skin biopsy is not necessary to establish the diagnosis of ARCI. The six genes known to be associated with ARCI are TGM1, ALOXE3, ALOX12B, NIPAL4 (ICHTHYIN), ABCA12, and CYP4F22; at least one gene remains unknown. Mutations in TGM1 account for 50%-60% of all ARCI and 90% or more of severe LI. Mutations in the two ALOX genes are present in an estimated 10% of individuals with NCIE or intermediate LI/NCIE phenotypes; NIPAL4 mutations appear to be less common. The vast majority of individuals with harlequin ichthyosis and a few individuals with LI have mutations in ABCA12, including partial-gene deletions.

Management. Treatment of manifestations: for neonates, a moist environment in an isolette, hygienic handling to prevent infection, and treatment of infections; petrolatum-based creams/ointments to keep the skin soft, supple, and hydrated; for older children, 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, corneal drying; 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 and management of skin involvement. Agents/circumstances to avoid: skin irritants.

Genetic counseling. ARCI is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% risk of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both disease-causing mutations in TGM1, ALOXE3, ALOX12B, ABCA12 (or NIPAL4) have been identified in a family. Prenatal testing may be possible through laboratories offering custom prenatal testing for pregnancies at increased risk if both CYP4F22 disease-causing mutations have been identified in a family.

Diagnosis

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Genes. Six genes are known to be associated with ARCI:

• TGM1

• ALOXE3

• ALOX12B [Krebsova et al 2001, Jobard et al 2002]

• ABCA12 [Parmentier et al 1996, Parmentier et al 1999, Lefèvre et al 2003, Akiyama et al 2005, Kelsell et al 2005]

• NIPAL4 (previously known as ICHTHYIN) [Lefèvre et al 2004, Dahlqvist et al 2007]

• CYP4F22 (FLJ39501) [Lefèvre et al 2006]

Other loci. Further heterogeneity is suggested by the fact that some affected families do not have mutations in the known genes and do not map to the other known loci [Krebsova et al 2001]. In neither of the two following situations have pathogenic mutations been identified:

• Linkage to two other loci on the same chromosome (chromosome 19) has been suggested [Fischer et al 2000, Virolainen et al 2000].

• Homozygosity mapping in two consanguineous families identified a region on chromosome 12 [Mizrachi-Koren et al 2005].

Clinical testing

• Sequence analysis

  • TGM1. Of individuals with the LI phenotype, at least 90% have mutations in TGM1 [Huber et al 1995, Russell et al 1995].

  • ALOX12B and ALOXE3. Of individuals who do not have TGM1 mutations and have a NCIE or self-healing baby phenotype, approximately 10% are expected to have mutations in either ALOX12B or ALOXE3. Of that 10%, mutations in ALOX12B account for an estimated 60% and mutations in ALOXE3 for approximately 40% [Jobard et al 2002, Eckl et al 2005].

  • ABCA12. Mutations 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]. Most are nonsense changes and small insertions/deletions resulting in premature termination of protein translation; splice site defects are less common. Partial-gene deletions spanning from one to 35 exons have been observed.
    Note: While mutations in ABCA12 account for most cases of harlequin ichthyosis, ABCA12 mutations have also been reported in nine families with LI from Northern Africa [Lefèvre et al 2003].

  • NIPAL4 (previously known as ICHTHYIN). The two missense mutations p.Ala176Asp and p.Gly230Arg accounted for approximately 90% of recessive NIPAL4 mutations in one study of families with ARCI primarily from Norway and Sweden [Dahlqvist et al 2007]; p.Ala114Asn accounted for half the mutant alleles in families from Colombia, Turkey, and Algeria in another study [Lefèvre et al 2004].

• Deletion/duplication analysis

  • ABCA12. Deletion/duplication analysis is available clinically. This type of analysis will detect both novel deletions and the previously reported partial gene deletions.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Autosomal Recessive Congenital Ichthyosis

Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method	Test Availability
Sequence analysis	TGM1 sequence variants	~90% of LI 1	Clinical
	ALOX12B sequence variants	~6% 2	Clinical
	ALOXE3 sequence variants	~4% 2	Clinical
	ABCA12 sequence variants	A few percent of LI cases; >93% of harlequin ichthyosis	Clinical
	NIPAL4 (ICHTHYIN) sequence variants	A few percent of patients negative for TGM1 mutation 3	Clinical
	CYP4F22 (also known as FLJ39501) sequence variants	See footnote 4	Research only
Deletion/duplication analysis 5	ABCA12 partial- and whole-gene deletions	Unknown	Clinical

1. Also described in "bathing suit ichthyosis"

2. Individuals with ARCI who have no mutations in TGM1

3. Approximately 89% of cases with erythrodermic ARCI without collodion presentation and no TGM1 mutation from Sweden and Norway; a few percent of ARCI cases from the Mediterranean

4. Twelve consanguineous families from the Mediterranean; mutation detection frequency in other populations has not been established.

5. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including long-range PCR encompassing more exons, quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA) or high-resolution microarray analysis may be used.

Clinical Description

Differential Diagnosis

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

• Sjögren-Larsson syndrome is characterized by spastic paraplegia, mental retardation, and retinopathy in addition to ichthyosis. Abnormal levels of fatty aldehyde dehydrogenase (FALDH) activity in cultured fibroblasts identify children who have Sjögren-Larsson syndrome.

• Netherton syndrome is an autosomal recessive congenital ichthyosis featuring chronic inflammation of the skin, hair anomalies, epidermal hyperplasia with an impaired epidermal barrier function, failure to thrive, and atopic manifestations. The disease is caused by mutations in the SPINK5 gene, encoding the serine proteinase inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI) [Raghunath et al 2004].

• Gaucher disease, an inborn error in glucosylceramidase, has a wide spectrum of clinical presentation. The perinatal lethal form may present as collodion skin abnormalities and developmental and neurologic problems (pyramidal signs).

• Keratitis-ichthyosis-deafness (KID) syndrome is characterized by vascularizing keratitis, congenital ichthyosis, palmoplantar keratoderma, and sensorineural deafness. Mutations in GJB2 or (rarely) GJB6 underlie the disorder [Richard et al 2002, Jan et al 2004].

• Trichothiodystrophy ("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 sensitivity in cultured fibroblasts. Most individuals have mutations in the ERCC2/XPD gene.

• Chanarin-Dorfman syndrome (neutral lipid storage disease) is a neuroichthyotic disorder in the differential diagnosis of the CIE phenotype that is caused by mutations in the abhydrolase-5 gene (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 syndrome (X-linked dominant chondrodysplasia punctata) is caused by a defect in cholesterol biosynthesis and presumed to be lethal in males. 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.

• 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. Three genes have been identified as causing hypohidrotic ectodermal dysplasia: EDA1 (X-linked form), EDAR, and EDARADD (autosomal forms).

• Bullous autosomal dominant ichthyoses (ichthyosis bullosa of Siemens, epidermolytic hyperkeratosis, and epidermolytic palmoplantar keratoderma) is distinguishable by family history and histologic examination of the skin. Individuals with autosomal dominant ichthyosis virtually never present with a collodion membrane at birth. Other nonbullous 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.

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

• Ichthyosis vulgaris 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.

• Steroid sulfatase deficiency is an X-linked disorder characterized by dark adherent scale (especially affecting the flexures), asymptomatic corneal opacity, and occasionally cryptorchidism. High plasma cholesterol sulfate concentration identifies affected males.

Management

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.

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.

TGM1

Normal allelic variants. The normal TGM1 gene has 14,133 bp distributed in 15 exons [Kim et al 1992, Yamanishi et al 1992]. The TGM1 cDNA is 2.5 kb in length. The protein product of the TGM1 gene, protein-glutamine gamma-glutamyltransferase K (transglutaminase K), 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.

Pathologic allelic variants. To date, more than 50 different mutations 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 mutations include missense, nonsense, and splice site mutations. To date, all reported mutations 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 mutations are disease-causing mutations and not polymorphisms. Most mutations are distributed in the first two-thirds of the gene. Only a few mutations appear to alter mRNA splicing, leading to premature chain termination. One of these affects the intron 5 splice acceptor site (IVS5-2A>G), and has been found in approximately 20% of families with known mutations and in most affected Norwegian individuals because of a founder effect [Pigg et al 1998, Shevchenko et al 2000]. A pair of arginine residues (142-143) has been found mutated in 25% of families in whom mutations have been reported. Eight mutations introduce premature chain termination codons, which likely result in truncated proteins of impaired function of unknown stability. Other missense mutations affect protein residues critical to transglutaminase K function and/or reduce mRNA stability.

Normal gene product. The protein product of the TGM1 gene has 813 amino acid residues with a molecular weight of 89.3 kd and a poiseuille of 5.7 [Kim et al 1991]. 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 mutant 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.

ABCA12

Normal allelic variants. The normal ABCA12 gene is large (206 kb) and contains 53 coding exons [Annilo et al 2002].

Pathologic allelic variants. More than 30 different mutations in ABCA12 have been identified in individuals with harlequin ichthyosis and five different mutations in individuals with lamellar ichthyosis (LI). All mutations 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 mutation in ABCA12 have been found to be homozygous for such a deleterious mutation. The mutation spectrum also includes partial gene deletion, spanning from one to more than 30 exons. LI-causing mutations in ABCA12 cluster in five neighboring exons that form the first nuclear binding fold and exclusively represent missense mutations 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, which are 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. Mutations in ABCA12 result in a deficiency of this epidermal lipid transporter. As a consequence, lamellar bodies are not properly formed and essential epidermal lipids (such as 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].

ALOX12B

Normal allelic variants. The ALOX12B gene is 15 kb in size and contains 15 coding exons [Sun et al 1998]. Its cDNA is 2.5 kb in length.

Pathologic allelic variants. Three studies reported mutations 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 (NCIE). Mutations are predominantly private missense mutations scattered across the two genes [Jobard et al 2002, Eckl et al 2005, Lesueur et al 2007].

Normal gene product. The protein product of the ALOX12B gene, 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: Mutations 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.

ALOXE3

Normal allelic variants. The ALOXE3 gene is 22.6 kb, distributed in 15 exons [Sun et al 1998]. The cDNA is 3.3 kb in length.

Pathologic allelic variants. See ALOX12B, Pathologic allelic variants.

Normal gene product. The protein product of the ALOXE3 gene, epidermis-type lipoxygenase 3 (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.

NIPAL4 (ICHTHYIN)Normal allelic variants. The NIPAL4 gene spans 3.3 kb and contains six coding exons.

Pathologic allelic variants. Lefèvre et al [2004] identified six homozygous NIPAL4 mutations in 14 consanguineous families with congenital recessive ichthyosis. Dahlqvist et al [2007] reported recessive NIPAL4 mutations in 16 of 18 families with ARCI from Northern Europe, suggesting that mutations in this gene are responsible for a large portion of those individuals with generalized congenital ichthyosis with mild to moderate erythroderma who mostly lack a collodion presentation at birth. The two missense mutations p.Ala176Asp and p.Gly230Arg accounted for approximately 90% of disease alleles in this cohort, whereas p.Ala114Asn accounted for half of disease alleles in the Lefèvre cohort, who comprised mostly Mediterranean families

Normal gene product. NIPAL4 encodes a putative transmembrane protein of 404 amino acids with a predicted molecular mass of 44 kd [Lefèvre et al 2004]. The protein is highly expressed in brain, lung, stomach, leukocytes, and keratinocytes. The function of the ichthyin protein is currently unknown.

Abnormal gene product. All mutations reported to date are predicted to abolish the function of the ichthyin protein.

CYP4F22

Normal allelic variants. 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.

Pathologic allelic variants. Individuals with ARCI from 12 consanguineous families from Mediterranean countries (Algeria, France, Lebanon, and Italy) were found to harbor homozygous mutations in the CYP4F22 gene (formerly known as FLJ39501). The mutation spectrum included five missense mutations, 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.

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.

Abnormal gene product. All CYP4F22 mutations reported to date are predicted to abolish the function of the encoded CYP protein and to compromise the 12(R) lipoxygenase (hepoxilin) pathway. In fact, it has been hypothesized that mutations in all known ARCI-causing genes, except for TGM1 and ABCA12, alter this crucial epidermal pathway.

Resources

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.

References

Chapter Notes