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Autosomal Recessive Congenital Ichthyosis

[Autosomal Recessive Lamellar 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, 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, 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; ICHTHYIN mutations appear to be less common. The vast majority of individuals with harlequin ichthyosis and a few individuals with LI have mutations in ABCA12.

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, or ABCA12 have been identified in a family. Prenatal testing may be possible through laboratories offering custom prenatal testing for pregnancies at increased risk if both ICHTHYIN or CYP4F22 disease-causing mutations have been identified in a family.

Diagnosis

Clinical Diagnosis

Newborns.  The diagnosis of autosomal recessive congenital ichthyosis (ARCI) is suspected in newborns who are either collodion babies or have harlequin ichthyosis.

• 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.

• 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.

Infants.  The diagnosis of ARCI is established in infants with a history of collodion membrane 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 (NCIE).  Erythroderma (red skin) with fine white scale

• An intermediate form with some features of both LI and NCIE

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]
• 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].

Table 1. Molecular Genetic Testing Used in Autosomal Recessive Congenital Ichthyosis Test Method Mutations Detected Mutation Detection Frequency  1 Test Availability Sequence analysis TGM1 sequence variants ~90% of LI  2 Clinical ALOX12B sequence variants ~6%  3 Clinical ALOXE3 sequence variants ~4%  3 Clinical ABCA12 sequence variants A few percent of LI cases; >93% of harlequin ichthyosis Clinical ICHTHYIN sequence variants See footnote  4 Research only CYP4F22 (also known as FLJ39501) sequence variants See footnote  5

1. Proportion of affected individuals with a mutation(s) as classified by gene and test method 2. Also described in "bathing suit ichthyosis" 3. Individuals with ARCI who have no mutations in TGM1 4. 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 5. Twelve consanguineous families from the Mediterranean; mutation detection frequency in other populations has not been established.

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

• In individuals with ARCI, sequence analysis of TGM1 should be performed first.
• For individuals with erythrodermic ARCI in whom sequence analysis of TGM1 is negative, further diagnostic testing of ALOX12B and ALOXE3 is available.
• In individuals with harlequin ichthyosis, sequence analysis of ABCA12 should be performed first.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

No phenotype other than ARCI is known to be caused by mutations in TGM1, ALOXE3, ALOX12B, ABCA12, ICHTHYIN, or CYP4F22.

Clinical Description

Natural History

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) in older individuals. Although these phenotypes are now recognized to fall on a continuum, the phenotypic descriptions are clinically useful for clarifying prognosis and management for affected individuals.

Children with ARCI are often born prematurely. They can experience high levels of transepidermal water loss with resultant hypernatremia. They have increased risk of 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, such as respiratory distress, dehydration, electrolyte imbalance, temperature instability, feeding problems, and bacterial infections, often with fatal consequences.

Surviving children eventually shed this armor and develop generalized scaling and intense redness of the skin (erythroderma). Severe ectropion, eclabium, alopecia, palmoplantar keratoderma with painful fissures and digital contractures, and growth delay are common.

LI.  Neonates with LI typically present with a collodion membrane. The membrane subsequently dries and peels away to be replaced by a 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.

NCIE.  As many as 90% of infants with NCIE present with collodion membrane as neonates. They subsequently develop erythroderma (red 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 somewhere along the LI-NCIE spectrum and may be classified as having mild LI or mild NCIE.

Other related presentations

• In "bathing suit ichthyosis," a rare presentation of ichthyosis in South Africa caused by mutations in TGM1, the extremities and central face are spared. It is hypothesized that the differential cutaneous expression in bathing suit ichthyosis is a temperature-sensitive phenotype [Oji et al 2006].

• Collodion babies who have nearly complete resolution of their ichthyosis in infancy with only mild residual scaling or xerosis are said to have "self-healing collodion baby."

• 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

• ARCI is characterizd 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 and the absence of lamellar bodies and lipid bi-layers in a skin biopsy by electron microscopy.

Genotype-Phenotype Correlations

The vast majority of individuals with the classic LI phenotype have TGM1 mutations; many persons with much milder nonerythrodermic phenotypes also have TGM1 mutations. In addition, TGM1 mutations have been reported in a few individuals with self-healing collodion membrane.

Individuals with mutations in either ALOX12B, ALOXE3 [Jobard et al 2002], or ICHTHYIN [Lefèvre et al 2004 , Dahlqvist et al 2007] have the NCIE phenotype or self-healing collodion membrane.

The vast majority of individuals with harlequin ichthyosis have mutations in ABCA12 [Akiyama et al 2005 , Kelsell et al 2005]. A few individuals with mutations in ABCA12 have a typical severe LI phenotype [Parmentier et al 1996 , Parmentier et al 1999 , Lefèvre et al 2003].

Mutations in the CYP4F22 have been reported in consanguineous families with LI associated with hyperlinear palms and soles but without collodion presentation at birth [Lefèvre et al 2006].

Finnish individuals linked to another locus on chromosome 19 reportedly have a very mild, non-erythrodermic, non-LI phenotype [Fischer et al 2000].

Nomenclature

Historically, the term "lamellar ichthyosis" was used to describe any individual with ARCI, and even rare cases of autosomal dominant ichthyosis, regardless of whether erythroderma was present. More recently, the term "autosomal recessive congenital ichthyosis" (ARCI) has been used as the general term, with the following terms reserved for specific phenotypes:

• "Lamellar ichthyosis" for collodion baby resolving to non-erythrodermic skin with large, plate-like brown or whitish scale
• "Nonbullous congenital ichthyosiform erythroderma" (NCIE) 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 hyperkeratosis" (EHK), which does not present as collodion baby, and is a result of mutations in genes encoding epidermal keratins.

Prevalence

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

The disease affects all ethnic and racial groups and is seen in higher frequency in populations in which consanguineous marriage is common. As a result of a founder effect, the frequency of LI is estimated at 1:91,000 in Norway [Pigg et al 1998].

The harlequin ichthyosis phenotype is very rare.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

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

Evaluations Following Initial Diagnosis

To establish the extent of disease 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 in babies with severe eclabium

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, keratolytic agents such as alpha-hydroxy acid or urea preparations may be used to promote peeling and thinning of the stratum corneum.

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.

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.

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 corneal drying
• 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

Surveillance

Regular physical examination for evidence of infection and control of skin involvement is appropriate; frequency depends on the severity.

Agents/Circumstances to Avoid

Skin irritants should be avoided.

Testing of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• Parents of a proband with ARCI are obligate heterozygotes and therefore carry one mutant allele.
• Heterozygotes (carriers) are asymptomatic.

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.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

• The offspring of a proband with ARCI are obligate heterozygotes (carriers).
• In the rare instance that an unrelated reproductive partner is a carrier, the offspring are at a 50% risk of being affected and a 50% risk of being carriers.

Other family members of the proband.   Each sib of a proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is available to at-risk family members on a clinical basis once the mutations in TGM1, ALOXE3, ALOX12B, and ABCA12 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 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 or at risk of having a child with ARCI.

DNA banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100% or molecular genetic testing is available on a research basis only. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing.  Prenatal diagnosis for pregnancies at increased risk for ARCI caused by mutations in TGM1, ALOXE3, ALOX12B, or ABCA12 [Akiyama et al 2007] is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

3D ultrasound examination may be helpful in identifying fetuses with harlequin ichthyosis as early as in the second trimester in families with a known history of harlequin ichthyosis [Holden et al 2007].

No laboratories offering molecular genetic testing for prenatal  diagnosis of ARCI caused by ICHTHYIN or CYP4F22 mutations are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified. For laboratories offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —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