Goal 1.

Briefly describe the clinical characteristics of ARCI.

Goal 2.

Review the genetic causes of ARCI.

Goal 3.

Review the differential diagnosis of ARCI with a focus on genetic conditions.

Goal 4.

Provide an evaluation strategy to identify the genetic cause of ARCI in a proband (when possible).

Goal 5.

Inform genetic counseling of family members of an individual with ARCI.

Goal 6.

Review management of ARCI.

Presentation at Birth

Children with ARCI are often born prematurely encased in a collodion membrane, a taut, shiny, transparent membrane formed by the thickened cornified layers of the skin, resembling plastic wrap. They can experience high levels of transepidermal water loss with resultant dehydration and hypernatremia. They are at increased risk for skin infections and sepsis during the neonatal period. Tautness of collodion membrane often leads to ectropion, eclabium, and underdeveloped nasal and auricular cartilage. Impaired sucking and pulmonary ventilation may lead to dehydration, malnutrition, hypoxia, and pneumonia. Gradually, within two to four weeks, the collodion membrane dries and peels off, transitioning to generalized scaling and erythema characteristic of the underlying form of ARCI, predominantly LI and CIE.

In the rarest form of ARCI, harlequin ichthyosis, babies 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, microcephaly, lack of eyelashes and eyebrows, and sometimes alopecia. Circular bands of hardened skin can lead to vascular constriction, ischemia, and distal edema with a mitten-like casing of hands and feet. Babies are at risk for life-threatening complications in the neonatal and postnatal period, including respiratory insufficiency, dehydration, electrolyte imbalance, temperature instability, feeding issues, bacterial infections, and sepsis, potentially with fatal consequences. A survival rate of 56% has been reported, although that is expected to further increase with improved neonatal intensive care and treatment options, such as early topical and/or systemic retinoids [Ahmed & O'Toole 2014, Glick et al 2017].

Babies with ichthyosis-prematurity syndrome (IPS) are born prematurely between 29 and 35 weeks' gestation. Polyhydramnios is common, and fetal ultrasound may reveal echogenic sediment in the amniotic fluid. The skin at birth is erythrodermic, swollen, and massively thickened with a vernix-like appearance. The most severely affected skin is the scalp, often with cobblestone-like hyperkeratosis. Neonates suffer from severe, sometimes fatal asphyxia due to reduced lung function from intrauterine amniotic fluid aspiration. They have poor Apgar scores and require intensive care and prolonged hospitalization. Nevertheless, the prognosis of IPS is generally excellent. After a few days, the skin sheds and improves significantly, regressing to a mild ichthyosis with underlying erythema that eventually resolves [Khnykin et al 2012].

Postnatal Features

Lamellar ichthyosis (LI). LI Typically presents at birth with a collodion membrane, which is replaced by large, whitish, and later brown, plate-like scales in a generalized distribution. Erythroderma (generalized redness of the skin) may be present but is usually mild and not a predominant feature. Other frequent findings are ectropion, eclabium, and scarring alopecia involving the scalp and eyebrows. Built-up scale leads to sweat duct constriction and severe heat intolerance. Accumulation of scale in the external ear canals can lead to occlusion, bacterial colonization, and recurrent infections. Thickening and fissuring of the skin on palms and soles (palmoplantar keratoderma) and curved nails are common. Whole-body scaling and other associated features persist throughout life.

Congenital ichthyosiform erythroderma (CIE). At birth, more than 90% of infants with CIE present with a collodion membrane, which gives way to prominent generalized erythroderma and fine, white, semiadherent scales. Palms and soles are often severely thickened (palmoplantar keratoderma), with painful fissures and digital contractures. Ectropion, eclabium, scalp involvement, and loss of eyebrows can occur, although less frequently than in LI. Severe exfoliative erythroderma causes significant metabolic stress through very high caloric loss from inflammation and scaling of the skin, often leading to poor weight gain and growth deficiency if the caloric needs cannot be adequately met [Moskowitz et al 2004]. Similar to LI, scaling, hypohidrosis, and heat intolerance may persist lifelong.

Intermediate and rare phenotypes. Many affected individuals with ARCI fall between the LI-CIE spectrum and may be classified as having mild LI or mild CIE, or have overlapping, variable features. In a rare form of congenital ichthyosis, skin involvement may be limited to the trunk and scalp ("bathing suit ichthyosis") due to a temperature-sensitive effect [Marukian et al 2017].

In about 10% of babies with a collodion membrane, a milder "self-healing" phenotype known as "self-improving collodion ichthyosis" occurs [Traupe et al 2014]. Residual skin findings after infancy include generalized dry skin (xerosis), mild or focal scaling, hyperlinear palms, red cheeks, or anhidrosis [Raghunath et al 2003, 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].

Harlequin ichthyosis is the most severe form of ARCI. Morbidity and mortality in neonates are high, which can be improved by intensive neonatal care and oral/topical retinoid therapy. However, harlequin ichthyosis remains a serious and chronic skin disorder throughout life. Surviving children gradually shed the armor-like skin plates and develop generalized scaling and intense redness and inflammation of the skin (erythroderma), with a very severe CIE phenotype. Significant growth delay, hypohidrosis and anhidrosis, heat intolerance, and vitamin D deficiency are common. Other features include ocular issues related to persistent severe ectropion, alopecia, palmoplantar keratoderma with painful fissures and digital contractures, chronic constipation, anemia, arthralgia or arthritis, and joint contractures [Ahmed & O'Toole 2014].

Skin cancer. Atypical melanocytic nevi, malignant melanoma, squamous cell carcinoma, and basal cell carcinoma have been reported [Fernandes et al 2010, Natsuga et al 2011]. Albeit the true incidence of skin malignancies among individuals with ARCI has not been established, several case reports indicate that adults with ARCI are at increased risk to develop multiple squamous cell carcinoma and basal cell carcinoma at an unusually young age (between age 25 and 51 years). Other skin malignancies, such as malignant melanoma, malignant fibrous histiocytoma, and cutaneous lymphoma, were rarely observed.

Skin biopsy

• Histologic findings in ARCI are mostly nonspecific, showing epidermal hyperplasia and ortho-hyperkeratosis (thickened stratum corneum, the uppermost layer of the epidermis) with an underlying acanthosis.
• Harlequin ichthyosis is characterized by extreme hyperkeratosis and follicular plugging. Electron microscopy shows absence of lamellar bodies and lipid bilayers.

Mode of Inheritance

By definition, autosomal recessive congenital ichthyosis (ARCI) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an ARCI-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an ARCI-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an ARCI-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has ARCI or is a carrier, offspring will be obligate heterozygotes (carriers) for an ARCI-related pathogenic variant (see Family planning).

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

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ARCI-related pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Gene-targeted testing for the reproductive partners of known carriers, and for the reproductive partners of individuals affected with ARCI should be considered, particularly if both partners are of the same ethnic background. ARCI-related founder variants have been identified in individuals of Scandinavian, Norwegian/German, and Galician heritage (see Table 1).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the ARCI-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

3D or 4D ultrasound examination may be helpful in identifying fetuses with harlequin ichthyosis as early as the second trimester in families with a known history of harlequin ichthyosis. Reported findings include polyhydramnios, dense floating particles in amniotic fluid ("snowflake sign"), atypical facial morphology (O-shaped mouth, eclabium, ectropion), and flexion contractures [Rathore et al 2015, Zhou et al 2021]. Echogenic sediment in the amniotic fluid has been described on fetal ultrasound in pregnancies of a fetus with ichthyosis-prematurity syndrome [Blaas et al 2012, Dereksson et al 2012].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with autosomal recessive congenital ichthyosis (ARCI), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment of ARCI is mainly symptomatic, as no curative therapies exist.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4). For a detailed review, see also Paller & Butala [2022].

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

Invasive procedures in infants with complications related to prematurity should be avoided because of increased risk of infections related to such procedures.

Skin irritants and overheating should be avoided.

Topical salicylic acid preparations in children should be avoided because of absorption through the skin leading to toxicity.

Topical use of tacrolimus or vitamin D should be considered with caution due to skin absorption.

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, but overheating should be avoided during pregnancy.

Systemic retinoids are known to be teratogenic to a developing fetus and pose a high risk for birth defects. Therefore, women who are using systemic retinoids should be appropriately counseled about pregnancy risks and the need for highly effective contraception; regular monitoring with pregnancy tests is indicated. Systemic retinoids should be administered only by physicians who are knowledgeable regarding their risks and benefits. To access isotretinoin in the US, women and their prescribing providers must be enrolled in the iPLEDGE program to minimize the potential for fetal exposure. Pregnancy avoidance is initiated before therapy, continues during therapy, and extends post treatment until the drug is cleared from the body. While both isotretinoin and acitretin may be effective in preventing skin cancers, acitretin may take longer to be eliminated from the body, requiring an extended period (3 years) of post-therapy pregnancy avoidance to minimize teratogenic risk.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Advances in understanding the genetics and pathophysiology of ichthyosis paired with new biotechnology approaches have led to the exploration and development of pathogenesis-based therapies for ichthyoses. Among those are enzyme replacement therapy (ERT) and lipid replacement therapy (LRT); repurposing of biologic therapeutics; and gene replacement and gene editing therapies. It can be expected that some of these new therapies will prove their efficacy and will be incorporated in the treatment of ichthyosis. Nevertheless, there are only a few ongoing, registered clinical trials for treatment of ARCI. Results have not been published, and no conclusions regarding the long-term safety and efficacy can be made at this time. For a detailed review, see Joosten et al [2022] and Paller & Butala [2022].

Gene replacement. Phase II dose studies are ongoing for KB105, a gel applied to the skin to correct transglutaminase-1 (TG1) deficiency (NCT04047732). This is a preclinical gene therapy trial for ARCI. The approach is based on a successful transfer of the wild type TGM1 into keratinocytes of individuals with lamellar ichthyosis (LI) using a retroviral vector, which was effective in vitro [Choate et al 1996]. The approach was then adapted for in vivo use with a modified herpes simplex virus-1 (HSV1) vector (KB105), which is non-integrating, non-replicating, and can accommodate multiple gene copies. It was formulated into a gel, and in a Phase I placebo-controlled trial, KB105 gel was tested in four individuals with LI and showed a significant increase in TGM1 expression and functional activity based on quantitative real-time PCR, immunofluorescence, and in situ enzymatic assays performed on skin biopsies [Agarwal et al 2020]. Over the 30-day dosing period, this correlated with improvement of scaling in the KB105-treated areas based on the Investigator's Global Assessment (IGA) scale compared to placebo. Treatment was well tolerated with no adverse events and with no evidence of immune response reported.

Repurposing of FDA-approved biological therapeutic drugs and related biologics for congenital ichthyoses. Several clinical trials are ongoing to repurpose biologics successfully used to treat inflammatory skin disorders such as psoriasis and atopic dermatitis for the treatment of congenital ichthyoses:

• Phase I open-label and long-term extension study using subcutaneous injection of human monoclonal antibody targeting IL-12/IL-23 (ustekinumab) (NCT04549792)
• Phase II multicenter, randomized, double-blind, placebo-controlled dosage study using subcutaneous injection of humanized monoclonal antibody ANB019 targeting IL-36 receptor (imsidolimab) (NCT04697056)
• Phase IV experimental non-randomized clinical study comparing the effect of subcutaneous injections with either secukinumab, ustekinumab, or dupilumab with symptomatic treatment in children with congenital ichthyosis (NCT04996485)

These trials are based on the pivotal finding that congenital ichthyoses demonstrate an interleukin 17-dominant immune profile with marked elevations in Th17/IL-23 pathway cytokines and chemokines reminiscent of the inflammatory pattern of psoriasis [Paller et al 2017]. Further case reports indicated that individuals with ARCI, when treated with injections of recombinant human monoclonal antibodies targeting the cytokines IL-17, IL12/IL23 (ustekinumab or secukinumab), showed improvement of the inflammatory disease components (erythema, joint arthropathy) with minor effects on hyperkeratosis and scaling [Haiges et al 2019, Poulton et al 2019]. Ustekinumab or secukinumab also led to considerable improvements for other genetic inflammatory skin disorders due to pathogenic variants in SPINK5 (Netherton syndrome), CARD14 (pityriasis rubra pilaris), and DSP (SAM syndrome), suggesting that inhibitors of the TH17/IL-23 pathway may also ameliorate the clinical manifestations of ARCI [Paller 2020].

In a subsequent double-blind placebo-controlled Phase II trial with secukinumab (NCT03041038), 20 adults with different subtypes of congenital ichthyosis (congenital ichthyosiform erythroderma, LI, Netherton syndrome, and epidermolytic ichthyosis) received subcutaneous secukinumab injections or placebo every four weeks for 16 weeks in total, followed by a 16-week open-label phase and a 20-week extension for safety [Lefferdink et al 2023]. Overall, there was no significant improvement of severity of ichthyosis or reduction of Th17-related biomarkers. While participants with LI showed no response at all time points, some other participants receiving secukinumab showed a significant decrease in erythema and transepidermal water loss after prolonged treatment (weeks 32 and 52). These findings suggest that use of biological therapies influencing the overactive Th17 pathway in ARCI could be beneficial for certain types of ichthyoses with a more prominent inflammatory component. To pursue this approach further, the ongoing clinical trials for congenital ichthyosis listed above focus on the inhibition of IL-12/IL-23 with ustekinumab (NCT04549792, NCT04996485), IL4/IL13 with dupilumab (NCT04996485), and IL36 with imsidolimab (NCT04697056) to determine which of these biologics might reduce severity and yield lasting improvement of ichthyosis. If any are proven effective, it may soon be feasible to integrate biologics into the treatment regimen for certain congenital ichthyoses, as these biologics and their safety profile have been well studied previously.

Gene editing. In a recent study, an adenine base editor (ABE) system was developed to introduce a targeted single-nucleotide variant in DNA or RNA with the help of a single guide RNA that would correct a disease-causing variant in TGM1 identified in a couple who were heterozygous for an LI-associated variant [Dang et al 2022]. First, in vitro, different ABEs were screened for efficacy in cultured cells with a biallelic pathogenic TGM1 nonsense variant (c.607C>T) and were found to be effective in correcting this nucleotide change. Then these ABEs were injected into heterozygous human embryos in vitro generated by intracytoplasmic sperm injection into matured oocytes. The ABEs were able to correct the specifically targeted pathogenic variant and restore the wild type sequence in two of seven or in five of eight embryos, respectively. From a safety perspective, there was no evidence for editing of other (off-site) DNA nucleotides by whole-genome sequencing, but RNA sequencing revealed a high rate of RNA single-nucleotide variations that were spontaneously introduced by the deaminase (ABEs). This is the first study to demonstrate the feasibility of correcting a TGM1 pathogenic variant in an embryo in vitro with the ABE gene editing system. Nevertheless, it also highlights the need for further improvements of safety and efficacy before any clinical application is considered.

ERT and LRT. ARCI is associated with biallelic variants in at least 13 epidermally expressed genes (see Table 1), which result in deficiency of enzymes and cofactors involved in epidermal lipid metabolism and transport and formation of the skin barrier. A series of preclinical in vitro studies have aimed to directly replace either the missing enzyme or the missing epidermal lipids (e.g., omega-O-acylceramides) to restore normal skin barrier function. An example is the application of thermo-responsive nanogels containing tranglutaminase-1 on cultured full-thickness skin equivalents derived from fibroblasts and keratinocytes of individuals with TGM1-related ARCI [Plank et al 2019]. While these topical ERT/LRT studies yielded some promising results, these approaches are still hampered by several challenges, foremost by the cytotoxicity of the enzymes and/or accumulation of free fatty acids or other proximal metabolites. No clinical trials are registered at present.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Author Notes

Dr Gabriele 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 prior research studies helped elucidate the molecular basis of numerous inherited ichthyoses and other skin disorders, and she is now dedicated to the rapid molecular diagnosis of these conditions in a diagnostic laboratory, using next-generation sequencing panels and exome and genome sequencing. She has contributed to more than 100 scientific publications, review articles, and book chapters.

Acknowledgments

Dr Richard thanks the Foundation for Ichthyosis and Related Skin Types.

Author History

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

Revision History

• 20 April 2023 (sw) Comprehensive update posted live; scope changed to overview
• 18 May 2017 (ha) Comprehensive update posted live
• 28 August 2014 (me) Comprehensive update posted live
• 13 September 2012 (cd) Revision: sequence analysis, deletion/duplication analysis and prenatal diagnosis for PNPLA1 mutations available clinically
• 19 April 2012 (me) Comprehensive update posted live
• 19 November 2009 (cd) Revision: gene ICHTHYIN changed to NIPAL4
• 11 December 2008 (cd) Revision: deletion/duplication analysis available for ABCA12
• 30 June 2008 (cd) Revision: sequence analysis and prenatal testing available for NIPAL4 mutations
• 29 October 2007 (me) Comprehensive update posted live
• 7 September 2005 (gr) Revision: testing for ALOX12B, ALOXE3, and ABCA12 clinically available
• 29 December 2004 (me) Comprehensive update posted live
• 30 January 2003 (me) Comprehensive update posted live
• 10 January 2001 (me) Review posted live
• June 2000 (sb) Original submission

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