Congenital ichthyosiform erythroderma (ORPHA:79394)
A rare autosomal recessive congenital ichthyosis (ARCI) characterized by generalised scaling accompanied by a more or less severe erythroderma, without blister formation.
Epidemiology
Prevalence ranges between 1/200,000 and 1/1,000,000 individuals.
Clinical description
Congenital ichthyosiform erythroderma (CIE) is a generalized skin disease in which a more or less pronounced erythroderma predominates. A collodion membrane may sometimes be present at birth and will change into ichthyosiform erythroderma after a few days. In addition to the erythroderma, there is usually a generalized, fine, white or grey scaling. The phenotypic expression is very variable and depends on the patient's affected gene and environment. Patients with CIE are particularly prone to severe itching and intolerance to heat. Additional complications (especially for patients who presented with a collodion membrane at birth), can be observed such as ectropion and associated ocular complications (keratitis, corneal scarring), eclabium, palmoplantar keratoderma, nail dystrophy and alopecia. Failure to thrive and short stature may occur, as well as hearing impairment due to the accumulation of scales in the external ear.
Etiology
CIE is a part of the autosomal recessive congenital ichthyosis (ARCI) spectrum of disorders and mostly caused by mutations in known ARCI-related genes (ABCA12, ALOX12B, ALOXE3, CYP4F22, NIPAL4, TGM1, PNPLA1). Pathophysiologically, defects in epidermal lipids and differentiation cause disturbance of the epidermal barrier, resulting in increased transepidermal water loss (TEWL). Erythema and disease severity highly correlate with IL-17 expression in patients with ichthyosis.
Diagnostic methods
The diagnosis is based on the clinical picture and confirmed by genetic testing, mainly using next-generation sequencing (NGS) such as multi-gene panel sequencing or whole-exome sequencing (WES).
Differential diagnosis
Differential diagnosis includes other forms of neonatal erythroderma, especially syndromic ichthyoses (e.g. Netherton syndrome, KID syndrome), congenital reticular ichthyosiform erythroderma (CRIE) caused by specific mutations in the KRT10 or KRT1 gene, various congenital immunodeficiencies (e.g. hyper-IgE syndrome), and atopic dermatitis.
Antenatal diagnosis
A prenatal diagnosis (after amniocentesis or chorionic villus sampling) based on molecular genetic methods is possible if the pathogenic variant in the affected gene has previously been identified in a family member.
Genetic counseling
CIE is part of the autosomal recessive congenital ichthyosis (ARCI) spectrum of disorders. At-risk couples (both individuals are carriers of a disease-causing mutation) should be offered genetic counseling informing them that there is a 25% risk of having an affected child with each pregnancy.
Management and treatment
Management is based on daily applications of emollients. Keratolytics can be used but are often not tolerated. Oral retinoids and vitamin A analogues are indicated for hyperkeratosis rather than erythroderma, and are known to exacerbate skin inflammation and pruritus. In addition, these drugs can only be used in a limited way because of their known side effects (teratogenicity, hypertriglyceridaemia, hyperostosis). Topical anti-inflammatory drugs (i.e. steroids and calcineurin inhibitors) are less effective and have the disadvantage of being systemically absorbed. Recombinant human monoclonal anti-IL-17 (secukinumab), anti-IL-12/IL-23 (ustekinumab), and anti-IL-4/IL-13 (dupilumab) antibodies are undergoing clinical trials and have shown promising results.
Prognosis
The prognosis depends on the underlying genetic defect. There is an increased risk of sepsis during the neonatal period. In some patients, the condition may improve with age. Additional diseases or systemic infections can severely worsen the skin condition. Depending on the severity of the skin phenotype, the quality of life can be severely impacted.

                            Last update: 
                            March 2023


                            - Expert reviewer(s): 
                            Pr Judith FISCHER | ERN-Skin*


                                * European Reference Network