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Autosomal Recessive Congenital Ichthyosis

, MD, FACMG and , PhD, FACMG.

Author Information
, MD, FACMG
Chief Medical Officer
GeneDx
Gaithersburg, Maryland
, PhD, FACMG
Managing Director
GeneDx
Gaithersburg, Maryland

Initial Posting: ; Last Revision: September 13, 2012.

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 (CIE). 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 CIE are seemingly distinct phenotypes: classic, severe lamellar ichthyosis (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.

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 seven genes known to be associated with ARCI are TGM1, ALOXE3, ALOX12B, NIPAL4 (formerly known as ICHTHYIN), ABCA12, CYP4F22, and PNPLA1; at least one gene remains unknown. Mutations in TGM1 account for 34%-55% of all ARCI and 90% or more of severe LI. Mutations in the two ALOX genes are present in an estimated 17% of individuals with ARCI, typically associated with CIE or intermediate LI/CIE phenotypes; mutations in NIPAL4 and CYP4F22 have been reported in up to 12% and 8%, respectively, of individuals with ARCI. The vast majority of individuals with harlequin ichthyosis and a few individuals with LI have mutations in ABCA12, including partial-gene deletions. ABCA12 mutations account for about 5% of ARCI. Least common appear to be mutations in PNPLA1, so far only reported in two consanguineous families from the Middle East.

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, 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.

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 have been identified in a family.

Diagnosis

Clinical Diagnosis

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

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 (CIE). Erythroderma (red skin) with fine white scale
  • An intermediate form with some features of both LI and CIE

Molecular Genetic Testing

Genes. Mutations in seven genes are known to cause ARCI:

In an affected individual both alleles are mutated in any one of the associated genes.

Note: See Table A for chromosomal locus and protein product for these genes.

Evidence for locus heterogeneity. 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 genes [Krebsova et al 2001]. Pathogenic mutations have not been identified in any of the following situations:

Clinical testing

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

Gene 1
(Locus Name)
Proportion of AR Congenital Ichthyosis Attributed to Mutations in This GeneTest MethodMutations Detected 2
TGM138%-55% (~90% of LI) 3, 4 Sequence analysis 5Sequence variants 6
Deletion/duplication analysis 7Unknown, none reported 8
ALOX12B6.8%-12% 4, 9 Sequence analysis 5Sequence variants
Deletion/duplication analysis 7Unknown, none reported 6
ALOXE34%-6.8% 4,9Sequence analysis 5Sequence variants
Deletion/duplication analysis 7Unknown, none reported 8
ABCA125% (>93% of harlequin ichthyosis) 10Sequence analysis 5Sequence variants
Deletion/duplication analysis 7Exonic or whole-gene deletions 10
NIPAL4 (ICHTHYIN)A few percent of patients 11, 12 Sequence analysis 5Sequence variants
Deletion/duplication analysis 7Unknown, none reported 8
CYP4F228% 13Sequence analysis 5Sequence variants
PNPLA1Rare 14Sequence analysis 5Sequence variants
Deletion/duplication analysis 7Unknown, none reported 8

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Mutations have been also described in a rare clinical variant of ARCI, "bathing suit ichthyosis."

4. Eckl et al [2009], Fischer [2009]

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, heterozygous exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Of individuals with the LI phenotype, at least 90% have mutations in both TGM1 alleles [Huber et al 1995, Russell et al 1995]. The founder splice-site mutation c.877-2 A>G accounts for 34% of mutant TGM1 alleles [Herman et al 2009]; and missense mutations in arginine codons account for 41% [Farasat et al 2009].

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. No exonic or whole-gene deletions or duplications of TGM1, ALOX12B, ALOXE3, NIPAL4, or PNPLA1 have been reported to cause ARCI.

9. Mutations have been also described in a rare clinical variant of ARCI, "self-improving collodion baby/ichthyosis" [Raghunath et al 2003, Vahlquist et al 2010].

10. 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 and require deletion/duplication analysis to detect. Note: While mutations in ABCA12 account for most cases of harlequin ichthyosis, ABCA12 mutations 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]. See also Parmentier et al [1996], Parmentier et al [1999].

11. Mutations have been also described in a rare clinical variant of ARCI, “acral self-improving collodion baby" [Mazereeuw-Hautier et al 2009].

12. There is a higher prevalence of NIPAL4 mutations in Sweden and Norway, where they account for approximately 89% of TGM1-negative cases with erythrodermic ARCI without collodion presentation [Dahlqvist et al 2007]. The two common missense mutations in this cohort are p.Ala176Asp and p.Gly230Arg [Dahlqvist et al 2007], while p.Ala176Asp also accounted for half the mutant alleles in families from Colombia, Turkey, and Algeria in another study [Lefèvre et al 2004]. See also Fischer [2009].

13. One study reports homozygous CYP4F22 mutations in 12 consanguineous families from Algeria, France, Italy, and Lebanon, including a large deletion spanning 10 exons [Lefevre et al 2006]. See also Fischer [2009].

14. Two consanguineous families [Grall et al 2012]

Testing Strategy

To confirm/establish the diagnosis in a proband

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.

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 (CIE) 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 CIE-like phenotype). 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.

CIE. As many as 90% of infants with CIE 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-CIE spectrum and may be classified as having mild LI or mild CIE.

Other related presentations

  • "Bathing suit ichthyosis,” a rare presentation of ARCI predominantly observed in individuals from South Africa and caused by mutations in TGM1, shows brown or dark-gray scaling on the trunk (bathing suite area), while the extremities and central face are almost completely 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 xerosis, residual mild or focal scaling, hyperlinear palms, red checks 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 is most often caused by mutations in ALOX12B or ALOXE3, but mutations in TGM1 have also been reported [Vahlquist et al 2010].
  • 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 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 non-erythrodermic phenotypes also have TGM1 mutations. In addition, TGM1 mutations have been reported in a few individuals with “bathing suit ichthyosis” or self-healing collodion membrane [Hackett et al 2010].

Individuals with mutations in either ALOX12B, ALOXE3 [Jobard et al 2002], NIPAL4, or PNPLA1 [Lefèvre et al 2004, Dahlqvist et al 2007, Grall et al 2012] have the CIE or intermediate phenotypes.

Self-improving collodion ichthyosis has been reported in individuals with mutations in ALOX12B, ALOXE3, or TGM1 [Raghunath et al 2003, Harting et al 2008, Hackett et al 2010, Vahlquist et al 2010].

The vast majority of individuals with harlequin ichthyosis have mutations in ABCA12 [Akiyama et al 2005, Kelsell et al 2005]. Most surviving individuals with mutations 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].

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 defined as the umbrella term for three major types of congenital ichthyosis at an international Ichthyosis Consensus Conference [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 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] and 1:122,000 in Galicia (northern Spain) [Rodríguez-Pazos et al 2011]. A population-based study in Spain reported a higher prevalence of ARCI of 1 in 62,000, with approximately two thirds of individuals having LI and one third having CIE [Hernández-Martín et al 2011].

The harlequin ichthyosis phenotype is very rare.

Differential Diagnosis

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

  • Sjögren-Larsson syndrome is characterized by spastic paraplegia, intellectual disability, and retinopathy in addition to ichthyosis. Mutations in ALDH3A2 and 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 SPINK5, 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 hearing loss. 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 affected individuals have mutations in ERCC2/XPD.
  • 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 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 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. This disorder is caused by mutations 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. Mutations in three genes have been identified as causing hypohidrotic ectodermal dysplasia: EDA (X-linked form), EDAR, and EDARADD (autosomal forms). In addition, mutations in WNT10A are associated with onycho-odontodermal dysplasia and Schöpf-Schultz-Passarge syndrome, disorders in which ectodermal dysplasia is a finding [Adaimy et al 2007, Bohring et al 2009, Cluzeau et al 2011]
  • 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. Individuals with typical features are heterozygous for a loss-of-function mutation 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].
  • 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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
  • Genetics consultation

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.

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.

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. 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 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.

Babies born with Harlequin ichthyosis and, less common, collodion membrane have an increased incidence of premature birth with concomitant perinatal morbidity and mortality.

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.

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. —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 possible for at-risk family members once both mutations 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, are carriers, or are at risk of being carriers.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 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 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].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

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.

  • Foundation for Ichthyosis and Related Skin Types, Inc. (FIRST)
    2616 North Broad Street
    Colmar PA 18915
    Phone: 215-997-9400
    Fax: 215-997-9403
    Email: info@firstskinfoundation.org
  • National Library of Medicine Genetics Home Reference
  • National Registry for Ichthyosis and Related Disorders
    University of Washington Department of Dermatology
    1959 NE Pacific Street
    Room BB1353
    Box 356524
    Seattle WA 98195
    Phone: 800-595-1265 (toll-free)
    Fax: 206-543-2489
    Email: info@skinregistry.org

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)

190195TRANSGLUTAMINASE 1; TGM1
242100ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 2; ARCI2
242300ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 1; ARCI1
242500ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 4B; ARCI4B
601277ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 4A; ARCI4A
603741ARACHIDONATE 12-LIPOXYGENASE, R TYPE; ALOX12B
607206ARACHIDONATE LIPOXYGENASE 3; ALOXE3
607800ATP-BINDING CASSETTE, SUBFAMILY A, MEMBER 12; ABCA12
609383NIPA-LIKE DOMAIN-CONTAINING 4; NIPAL4
612121PATATIN-LIKE PHOSPHOLIPASE DOMAIN-CONTAINING PROTEIN 1; PNPLA1
612281ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 6; ARCI6

TGM1

Gene structure. TGM1 has 14,133 bp distributed in 15 exons [Kim et al 1992, Yamanishi et al 1992]. The TGM1 cDNA is approximately 2.5 kb in length (reference sequence NM_000359.2). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. To date, more than 130 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. One of the common mutations in TGM1 affects the intron 5 splice acceptor site (IVS5-2A>G or NM_000359.2:c.877-2A>G), and has been found in approximately 39% of patients with known mutations and in most affected Norwegian individuals because of a founder effect [Pigg et al 1998, Shevchenko et al 2000, Farasat et al 2009]. Forty-one percent of all TGM1 mutations occur in arginine residues (including especially amino acids 142 and 143) that contain CpG islands [Farasat et al 2009]. Other missense mutations 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] (reference sequence 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 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

Gene structure. ABCA12 is large (206 kb) and contains 53 coding exons [Annilo et al 2002]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. More than 55 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 (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

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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic 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]. Overall, ALOX12B mutations 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. 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. Specifically, two mutations were demonstrated to partially disturb the secretion of lamellar granule contents in the epidermis [Akiyama 2010].

ALOXE3

Gene structure. ALOXE3 is 22.6 kb, distributed in 15 exons [Sun et al 1998]. The cDNA is 3.3 kb in length. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See ALOX12B, Pathogenic allelic variants. ALOXE3 mutations 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, 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)

Gene structure. NIPAL4 spans 3.3 kb and contains six coding exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic 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.Ala176Asp also accounted for half of disease alleles in the Lefèvre cohort, comprising mostly Mediterranean families. Wajid et al [2010] also reported the missense mutation p.Ala176Asp in two consanguineous Pakistani families with ARCI.

Table 2. Selected NIPAL4 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.527C>Ap.Ala176AspNM_001099287​.1
NP_001092757​.1
c.688G>Ap.Gly230Arg

See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).

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 ichthyin protein is currently unknown.

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

CYP4F22

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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Individuals with ARCI from 12 consanguineous families from Mediterranean countries (Algeria, France, Lebanon, and Italy) were found to harbor homozygous mutations in CYP4F22 (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.

PNPLA1

Gene structure. PNPLA1 belongs to the family of human patatin-like phospholipases. The gene has three isoforms; transcript 1 (NM_173676.2) includes eight coding exons and the cDNA is 2.36 kb in length. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. One missense and one nonsense mutation 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 mutations were identified in eight other families with ARCI who also mapped to this locus on chromosome 6p21 [Grall et al 2012].

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. Although the function of PNPLA1 remains unclear, initial studies suggest that it could possess lipolytic and/or lipogenic properties, indicating a role in lipid organization and metabolism of the epidermal barrier [Grall et al 2012].

Abnormal gene product. PNPLA1 mutations reported to date are predicted to abolish the function of the encoded patatin-like phospholipase and to compromise the lipid barrier of the epidermis.

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  51. 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]
  52. 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]
  53. 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]
  54. 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]

Suggested Reading

  1. Oji V, Traupe H. Ichthyosis: clinical manifestations and practical treatment options. Am J Clin Dermatol. 2009;10:351–64. [PubMed: 19824737]
  2. Rajpopat S, Moss C, Mellerio J, Vahlquist A, Gånemo A, Hellstrom-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. 2010;147:681–6. [PubMed: 21339420]
  3. Uitto J. The gene family of ABC transporters--novel mutations, new phenotypes. Trends Mol Med. 2005;11:341–3. [PubMed: 15996518]

Chapter Notes

Author Notes

Dr. Bale, a medical geneticist, specializes in the clinical and molecular aspects of hereditary skin disorders. She has studied more than 400 patients with these disorders and published numerous research papers, book chapters, and a book. Web: www.genedx.com

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

Revision History

  • 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 to live Web site
  • 7 September 2005 (gr) Revision: testing for ALOX12B, ALOXE3, and ABCA12 clinically available
  • 29 December 2004 (me) Comprehensive update posted to live Web site
  • 30 January 2003 (me) Comprehensive update posted to live Web site
  • 10 January 2001 (me) Review posted to live Web site
  • June 2000 (sb) Original submission
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