Autosomal Recessive Congenital Ichthyoses and Approach to the Ichthyoses

Group of non-syndromic epidermal differentiation disorders with onset at birth — harlequin ichthyosis, lamellar ichthyosis, congenital ichthyosiform erythroderma and intermediate, self-improving and temperature-sensitive forms — designated since 2025 by the affected gene (nEDD); includes the general classification of the inherited ichthyoses and the diagnostic approach to an ichthyosis.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. The concept of ichthyosis and the place of the recessive congenital forms

The term "ichthyosis" designates a group of dermatological disorders, inherited or acquired, in which the skin becomes dry, thickened and scaly, sometimes with scales resembling those of fish, from which the name derives (from the Greek ichthys, fish) [3, 15]. The acquired forms are associated with infections, neoplasms, drugs, and endocrine, metabolic and autoimmune diseases, and must be distinguished from the inherited forms, which are Mendelian disorders of cornification [1, 15]. Among the inherited ichthyoses, the autosomal recessive congenital ichthyoses (ARCI) form the most genetically heterogeneous group: lifelong skin diseases with generalised scaling and variable erythema, which manifest at birth or in early infancy and range from harlequin ichthyosis (HI), the most severe and sometimes fatal form, to lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) and intermediate phenotypes with variable degrees of erythema and of scale size and quality [2]. The phenotypes form a continuum, but phenotypic descriptions remain clinically useful for prognosis and management [2].

1.2. Milestones of molecular discovery

The molecular era of ARCI began in 1995 with two independent studies of keratinocyte transglutaminase. Huber and colleagues demonstrated, in three families with lamellar ichthyosis, drastically reduced keratinocyte transglutaminase (TGK) activity, with reduced or abnormal transcripts and absent protein in two of them, and identified homozygous or compound heterozygous variants in the corresponding gene in all, concluding that intact cross-linking of the cornified envelope is necessary for normal skin [47]. In the same year, Russell and colleagues mapped the locus for severe LI to 14q11, with complete linkage to TGM1, and described in two multiplex families arginine-to-histidine substitutions at adjacent residues in exon 3, invariant across the transglutaminase family [48]. In 1997, a study of the isolated Finnish population found five different TGM1 variants in patients with LI and with CIE, the most frequent shared on a founder haplotype, and showed that allelic heterogeneity exists even in a founder population and that the same gene can produce both phenotypes [49]. A year earlier, Choate and colleagues had achieved correction of transglutaminase 1 activity in keratinocytes from patients with LI by retroviral gene transfer, the first step towards gene therapy in this disease [50].

The first decade of the 21st century identified the lipid pathways. In 2002, Jobard and colleagues showed that two contiguous lipoxygenase genes at 17p13.1, separated by 38 kb, ALOXE3 and ALOX12B, were mutated in six consanguineous families from the Mediterranean basin with chromosome 17-linked non-bullous CIE [51]. In 2003, ABCA12, at 2q33–q35, was associated with "lamellar ichthyosis type 2" in nine African families, with four of the five missense variants in the first ATP-binding domain [52]. In 2005, two groups demonstrated that harlequin ichthyosis also results from ABCA12 variants: Kelsell and colleagues, through homozygosity mapping with SNP (single nucleotide polymorphism) chips, found large intragenic deletions and frameshift deletions in 11 of 12 patients [53]; Akiyama and colleagues described five truncating variants or variants deleting conserved regions in four families, localised the protein to lamellar granules and demonstrated recovery of lipid secretion after corrective gene transfer in patients' keratinocytes [54]. Ichthyin (NIPAL4, 5q33) was identified in 2004 in 23 patients from 14 consanguineous families from Algeria, Colombia, Syria and Turkey [55], and CYP4F22 (LI3 locus, 19p) in 2006 in 21 patients from 12 consanguineous families from Algeria, France, Italy and Lebanon with lamellar ichthyosis and palmoplantar hyperlinearity [56]. There followed LIPN in 2011, in a large consanguineous family with late-onset recessive ichthyosis [40]; PNPLA1 in 2012, identified first in golden retriever dogs and then in 6 patients from two families [57]; CERS3 in 2013, in a homozygous 15q26.3 microdeletion removing ADAMTS17 and CERS3 in consanguineous Tunisian families [58]; SDR9C7 in 2016, in three Lebanese families [59]; and SULT2B1 and CASP14 in 2017 [43, 45]. In 2026 GLTP, which encodes a glycolipid transfer protein, was described in five unrelated families with nEDD and generalised scaling [16].

1.3. The Sorèze classification (2009)

The first consensus classification of the inherited ichthyoses resulted from a project launched at the 1st World Conference on Ichthyosis, in Münster, in 2007, concluded at the 1st Ichthyosis Consensus Conference, in Sorèze (France), on 23 and 24 January 2009, with more than 37 specialists, and published in 2010 [1]. The consensus adopted the term "disorder of cornification" (DOC) and defined the inherited ichthyoses as Mendelian disorders of cornification (MEDOC) affecting all or most of the integument with hyperkeratosis and/or scaling [1]. The nosology remained clinical, with a main division between non-syndromic forms, in which only the skin is affected, and syndromic forms, in which other organs are also affected [1, 19]. Among the non-syndromic forms, the common ichthyoses (ichthyosis vulgaris, 1:250–1:1,000, and recessive X-linked ichthyosis, 1:2,000–1:6,000), the ARCI and the keratinopathic ichthyoses (KPI), an umbrella term for epidermolytic ichthyosis, superficial epidermolytic ichthyosis and rare variants, were distinguished [1]. The term ARCI was proposed as an umbrella for HI and the LI/CIE spectrum, excluding syndromic forms such as Netherton syndrome [1]. HI was included in the ARCI because null variants of ABCA12 cause it whereas missense variants in the same gene give collodion phenotypes that evolve into LI or CIE, and because HI survivors develop a very scaly erythroderma [1]. The 2017 German S1 guideline retained this organisation into two categories, non-syndromic and syndromic [19].

1.4. The 2025 classification: epidermal differentiation disorders

In 2025, the international initiative Reclassifying Epidermal Differentiation Disorders published in the British Journal of Dermatology a new classification in four articles — the general proposal, the non-syndromic forms, the syndromic forms and the palmoplantar forms — also announced in the Journal of the American Academy of Dermatology and accompanied by an editorial [3, 60–64]. "Epidermal differentiation disorders" (EDD) becomes the umbrella term for the group previously called ichthyoses, palmoplantar keratodermas and other differentiation disorders, divided into nEDD (non-syndromic: skin and appendages without extracutaneous involvement), sEDD (syndromic) and pEDD (palmoplantar) [3]. The name of each entity combines the affected gene with the subgroup and, sometimes, a clinical or histological descriptor (for example, KRT10-nEDD-epidermolytic, TGM1-nEDD) [3]. The initiative eliminated terms considered pejorative or outdated, such as "ichthyosis", "vulgaris", "hystrix" and "harlequin", and replaced eponyms [3]. In total, 53 genetically distinct nEDD were recognised, among them the former ARCI, and eleven autosomal recessive nEDD typically present with generalised scaling or encasement in a collodion-like membrane at birth: SULT2B1-, ALOX12B-, ALOXE3-, CYP4F22-, CERS3-, PNPLA1-, SDR9C7-, TGM1-, CASP14-, ABCA12- and NIPAL4-nEDD; LIPN-nEDD has a late, non-congenital onset [3]. The genes for ceramide synthesis and transport and for formation of the lipid barrier give a similar neonatal phenotype and a spectrum ranging from extensive erythroderma with fine scaling (former CIE) to lamellar scaling with variable erythema (former LI), which is why the entities are functionally linked and named by gene [3].

The criterion separating nEDD from sEDD is the proportion of patients with extracutaneous symptoms: if most have them, the entity is syndromic [3]. By this criterion, the former ichthyosis prematurity syndrome becomes SLC27A4-nEDD, because prematurity and neonatal asphyxia are considered secondary to massive scaling in utero; recessive X-linked ichthyosis remains STS-sEDD because of the frequency of learning difficulties, attention deficit hyperactivity disorder and autism in boys with deletions; KDSR-nEDD stays among the non-syndromic forms because thrombocytopenia, present in about half, is generally transient [3]. The Orphanet classification keeps IPS as a syndromic congenital ichthyosis and GeneReviews includes SLC27A4 in the ARCI gene table, which illustrates the transition between systems [2, 7]. When the disorder is limited to the skin and appendages but the morphology is not conclusive and there is no genetic result, the preliminary diagnosis is "nEDD, unspecified", optionally followed by the probable clinical diagnosis in brackets; with pathogenic variants in more than one gene, the names are combined, with the more penetrant gene first [3]. The historical terms (HI, LI, CIE, collodion baby) continue to be used as phenotypic descriptors and in the literature, and are retained throughout this article alongside the gene-based designation.

1.5. Definition of the entities within scope

Harlequin ichthyosis (ABCA12-nEDD) is, according to Orphanet, the most severe form of ARCI, characterised at birth by a thick carapace of large plates over the whole body, with severe ectropion, eclabium and flattened ears, which later evolves into severe scaling erythroderma [9]. Lamellar ichthyosis is characterised by large scales over the whole body without significant erythroderma, and congenital ichthyosiform erythroderma by generalised scaling accompanied by more or less severe erythroderma, without blister formation [10, 11]. The collodion baby is the newborn encased in a taut, shiny, transparent membrane, resembling plastic film, formed by thickened cornified layers, which fissures and sheds within two to four weeks, revealing the underlying form; it is not a diagnosis but a presentation common to several diseases [2, 65]. The self-improving collodion baby (SICI or SHCB) is the minor ARCI variant in which the collodion membrane heals in the first weeks of life, with almost complete resolution of scaling in the first three months in about 10% of cases, and the self-healing acral collodion baby is the variant in which the membrane is limited to the extremities [1, 4, 5]. Bathing suit ichthyosis is a rare TGM1-related ARCI variant in which large dark scales persist in the warmer areas of the body (trunk, axillae, scalp) and the extremities heal in the first months [1, 6]. Ichthyosis prematurity syndrome (SLC27A4-nEDD) is characterised by preterm delivery, thick caseous and scaly epidermis, neonatal respiratory asphyxia and persistent eosinophilia, with spontaneous improvement after the perinatal period and evolution to mild flat follicular hyperkeratosis with atopy [7]. Ichthyosis vulgaris (FLG-nEDD), recessive X-linked ichthyosis (STS-sEDD) and Sjögren-Larsson syndrome are covered in the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The epidermal barrier and the corneocyte envelope

The barrier function of the stratum corneum depends on two interlinked components: the proteinaceous cornified envelope, which lines each corneocyte internally, and the extracellular lipid lamellae, which fill the spaces between corneocytes and prevent water loss [15, 66]. The link between the two is made through the corneocyte lipid envelope, a monolayer of ω-hydroxylated ceramides covalently bound to the envelope proteins [66, 67]. The ceramides specific to the stratum corneum contain α- or ω-hydroxylated ultra-long-chain fatty acids (ULCFA, with 26 or more carbons); acylceramides, very hydrophobic species exclusive to the epidermis, have ω-hydroxylated ULCFA of 28 to 36 carbons esterified with linoleic acid [66]. Almost all ARCI genes encode proteins of this pathway or of envelope assembly, which explains the phenotypic convergence: with a defect at any step, the skin loses water, normal desquamation fails and the epidermis responds with hyperproliferation and accumulation of scale [3, 66].

The biochemical sequence can be described step by step. Ceramide synthase 3 (CERS3), highly expressed in the skin, N-acylates sphinganine with ultra-long-chain acyl-CoA; in a patient with a CERS3 missense variant, the skin and keratinocytes showed deficiency of ceramides with non-hydroxylated and ω-hydroxylated ULCFA, disturbed differentiation and premature keratinisation [66]. FATP4 (SLC27A4) is one of the acyl-CoA synthetases that activate fatty acids [68]. Cytochrome P450 4F22 (CYP4F22), in the endoplasmic reticulum, ω-hydroxylates ULCFA of 28 or more carbons, a step necessary for the formation of ω-O-acylceramides and protein-bound ceramides; its loss markedly reduces acylceramide [68, 69]. PNPLA1, of the patatin family, is the transacylase that transfers linoleic acid from triacylglycerols to ω-hydroxyceramide, the final step in ω-O-acylceramide synthesis [42, 66]. In the 12R-lipoxygenase pathway, 12R-LOX (ALOX12B) oxidises the linoleate of EOS ceramides (esterified ω-hydroxyacyl-sphingosine) and eLOX3 (ALOXE3), a hydroperoxide isomerase, converts the 12R-hydroperoxide to an epoxy alcohol and ketone, a modification required for ω-hydroxyceramide to bind to corneocyte proteins; functional tests of missense and splicing variants in these two genes show complete loss of function [67, 70]. SDR9C7, a short-chain dehydrogenase/reductase, was initially described as an enzyme of vitamin A metabolism and is grouped by the 2025 classification among the ceramide synthesis and transport proteins [3, 59]. SULT2B1, a sulfotransferase of cholesterol metabolism, belongs to the lipid synthesis and transport group [3, 45]. Acylceramides are glucosylated and the glucosylceramides are transported into lamellar granules by the ABCA12 transporter; in 2026, the glycolipid transfer protein (GLTP) was implicated in the transport of glucosylceramides in differentiated keratinocytes [16, 66].

The ABCA12 transporter, of the ABCA subfamily, expressed throughout the epidermis and abundant in the spinous and granular layers, loads glucosylceramides into lamellar granules, which are secreted at the apical pole of granular keratinocytes; in the extracellular space glucosylceramide is hydrolysed and the hydroxyceramides bind to the cornified envelope, forming the lamellae that maintain the permeability barrier [15, 71]. ABCA12 also transports lamellar granule proteolytic enzymes that regulate desquamation [71]. In HI, loss of ABCA12 function prevents lipid transport, with absence of lamellar bodies and lipid bilayers on electron microscopy, retention of scale and defects in thermoregulation, water balance and protection against infection [2, 15]. Corrective transfer of ABCA12 restored lipid secretion in patients' keratinocytes [54].

Transglutaminase 1 (TGM1) is a calcium-dependent, membrane-anchored enzyme that cross-links the structural proteins of the cornified envelope and binds ω-hydroxyceramides to the envelope; loss of function may result from absent protein or from protein that is present but catalytically inactive [14, 47]. Ichthyin (NIPAL4, also SLC57A6) is a multipass membrane protein of the NIPA family, a magnesium transporter, proposed as the receptor for trioxilins A3/B3 of the hepoxilin pathway and required for epidermal lipid processing and lamellar body formation, with specific structural abnormalities of the granular layer in patients with variants in this gene [39, 72]. Caspase-14 participates in terminal differentiation and its deficiency gives a picture of fine scaling similar to that of filaggrin deficiency [3, 43]. Lipase N (LIPN) is expressed exclusively in the epidermis and induced during differentiation [40].

Beyond the barrier defect, the congenital ichthyoses share an immune profile dominated by interleukin 17 (IL-17), with elevation of Th17 cytokines and IL-23 similar to that of psoriasis, an observation that provided the basis for trials of biological drugs [2, 73]. Transepidermal water loss, inflammation and continuous scaling increase caloric expenditure, which explains the growth failure of the severe erythrodermic forms [2, 74].

2.2. Inheritance pattern

Inheritance is autosomal recessive: patients have biallelic pathogenic variants, in the homozygous or compound heterozygous state, and heterozygotes are asymptomatic and not at risk of disease [2]. In consanguineous populations homozygosity predominates: in an Iranian cohort of 125 consanguineous families, 96.2% of the biallelic variants identified were homozygous [75]. The apparent homozygosity of a proband is not always real: a deletion of one or more exons not detected by sequencing can simulate homozygosity, and uniparental isodisomy of the parental chromosome carrying the variant is another possible explanation [2]. If the variant is found in only one parent, with maternity and paternity confirmed, a de novo variant in the proband or a post-zygotic variant in a mosaic parent should be considered [2]. A mosaic form of CIE due to post-zygotic somatic mosaicism of ABCA12 has been described exceptionally [2].

2.3. Genetic architecture and relative frequency of the genes

The following table brings together the relative frequency of each gene among all ARCI, the distinguishing features and the population and allelic particularities compiled by GeneReviews from Israeli, Scandinavian, Iranian, Austrian, English and North American cohorts [2, 76, 77]. The percentage of large deletions and duplications refers to distinct variants recorded in HGMD (Human Gene Mutation Database) and not to the proportion of families [2].

The distribution varies with the population and the recruitment method. In the cohort of 520 families cited by the Sorèze consensus, the proportions were TGM1 32%, NIPAL4 16%, ALOX12B 12%, CYP4F22 8%, ALOXE3 5% and ABCA12 5%, with at least 22% without a variant in the genes known at the time [1]. In an English cohort of 146 patients from 13 National Health Service hospitals, 65% under 16 years of age, biallelic variants were identified in 83%: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2% and SDR9C7 1% [36]. In the national survey of Denmark and Sweden, with 132 patients, variants were found in 113 (TGM1 56, NIPAL4 15, ALOX12B 15, ALOXE3 9, ABCA12 8, SLC27A4 5, CYP4F22 3, PNPLA1 1 and ABHD5 1), with a definitive diagnosis in 85% [18]. In a single-centre Italian series of 74 consecutive patients with a genetic diagnosis, TGM1 and ALOX12B tied with 18 patients each (24.3%), followed by CYP4F22 (12; 16.2%), ABCA12 (9; 12.2%), ALOXE3 and NIPAL4 (7 each; 9.5%) and single cases of CERS3, PNPLA1 and SDR9C7, with 25 novel variants, two TGM1 microduplications and microdeletions of CYP4F22 and NIPAL4 [38]. In the Iranian cohort of 125 consanguineous families studied with a 38-gene panel, 85% received a diagnosis, with 85 variants in 10 genes, 53% of them novel [75]. In the Freiburg laboratory, 54 of 770 families with a clinical diagnosis of ARCI studied over 22 years (≈7%) had CYP4F22 variants [79].

2.4. Variant spectrum and nomenclature

ARCI variants include missense, nonsense, splicing variants, small insertions and deletions and, in a proportion that varies by gene, large deletions and duplications [2]. The TGM1 splicing variant c.877-2A>G is the most common ARCI allele, and TGM1 microduplications have been described, so the laboratory method must detect splicing alterations and small CNVs [14, 38]. The table brings together the recurrent and founder variants, and those cited in this article, normalised by VariantValidator to the MANE Select transcript on GRCh38 [78].

GeneReviews writes the NIPAL4 hotspot as "p.Asn176Asp"; conversion of NM_001099287.2:c.527C>A in VariantValidator gives p.(Ala176Asp), which is the designation used [2, 78]. Other variants cited in the sources were not normalised and retain the original notation: TGM1 c.1223_1227delACACA (Galician founder) and c.607C>T (biallelic nonsense variant used in the base-editing studies in embryos), SLC27A4 c.504C>A p.(Cys168Ter) and SULT2B1 p.Ala140Val [2, 84, 85]. For PNPLA1, CERS3, SULT2B1, LIPN and SLC27A4, GeneGuidance gives the RefSeqs NM_173676, NM_178842, NM_004605, NM_001102469 and NM_005094, without version [41, 42, 85–87]. For ALOXE3, the RefSeq listed by GeneGuidance (NM_001165960) differs from the MANE transcript returned by VariantValidator (NM_021628.3), and the latter is used in the table [70, 78]. Articles published before 2010 often use protein numbering without a prefix and sometimes other designations; for example, residues G278R and D490G of the self-improving collodion baby are in the numbering of the original article [88].

2.5. Genotype-phenotype correlations by gene

TGM1. This is the gene most associated with classic lamellar ichthyosis, with large, thick, brownish scales, alopecia, ectropion and eclabium; in the Italian series, the mean severity score was significantly higher with TGM1 than with most other genes [38]. In the analysis of 1000 families with ichthyosis, a collodion membrane at birth was significantly associated with TGM1 variants (odds ratio 6.7; 95% confidence interval [CI] 3.0–16.7), as were hearing and eye problems, skin odour and alopecia [14, 89]. In a North American study of 104 patients with ARCI excluding HI, at least one truncating TGM1 variant was associated with more severe hypohidrosis and overheating than missense variants alone [1]. LI and CIE phenotypes can coexist in the same patient or family [14]. Two TGM1 forms illustrate the influence of the physical environment on a mutated enzyme. In bathing suit ichthyosis, studied in 10 patients with 13 TGM1 variants, cryosections of unaffected skin had almost normal activity and those of affected skin reduced activity, which demonstrates a temperature-sensitive enzyme that loses activity in the warmer areas of the body [90]. In the self-improving collodion baby described in two siblings compound heterozygous for G278R and D490G, the D490G variant is locked in an inactive trans conformation under the high hydrostatic pressure of the intrauterine environment and isomerises after birth to a partially active cis form, which explains the improvement [88]. In interpreting the two cases in section 10, the authors emphasised that severity in TGM1-nEDD depends more on the functional consequences of the variants (premature termination codons, loss of function, catalytic or structural domains) than on zygosity [81].

ABCA12. Severity follows the nature of the two alleles. In the international cohort of 64 patients from the Freiburg laboratory, with 34 novel variants and 217 described in total, loss of function of both alleles generally led to HI and biallelic missense variants mainly to CIE or LI [37]. In Japan, at least one variant on each allele must be truncating or a deletion to cause the severe loss of function that produces HI [91]. In the series of 45 HI cases with ABCA12 analysis, 52% of survivors were compound heterozygotes and all deaths occurred in patients with homozygous variants [92]. In the English cohort, admission to intensive care (p=0.004) and hand deformities (p<0.001) were associated with ABCA12 [36]. The 2025 classification describes a spectrum from mild to very severe, with deformed nose, ears, hands and feet and contractures in the most severe cases, and in some patients a phenotype similar to that of GJB3-nEDD, with well-demarcated, thickened, non-congenital erythematous plaques [3].

ALOX12B and ALOXE3. In the cohort of 224 patients with variants in these two genes, most had mild erythrodermic ichthyosis and few had severe erythroderma [93]. An ear folded forwards at birth occurred in 43% of patients with ALOX12B in the English cohort, a sign that the 2025 classification incorporated [3, 36].

Genes of the self-improving collodion baby. In a Scandinavian series of 15 cases, 8 had ALOX12B variants, 3 ALOXE3 and 1 TGM1, so a TGM1 result does not exclude a self-improving course [94]. In the German prospective study of 78 patients with ARCI, among 16 SICI cases with a confirmed gene, 8 had ALOXE3 (50%), 6 ALOX12B (37.5%), 1 PNPLA1 and 1 CYP4F22 [95]. CYP4F22 has also been described in two collodion babies who improved with few or no residual abnormalities [68]. In the English cohort, the self-improving form occurred in 8% (mainly TGM1 and ALOX12B) and was not predictable from the neonatal phenotype or the genotype [36].

NIPAL4. In an international cohort of 101 families, a patient homozygous for a splicing variant with loss of NIPAL4 messenger RNA had a more severe phenotype and additional ultrastructural abnormalities, suggesting an effect dependent on the amount of residual protein [39]. In the Italian series, NIPAL4 patients had psoriasiform lesions, a reticulate pattern on the trunk and striate keratoderma [38]. Associated arthropathy has been described [39].

CYP4F22. In the Italian series it had the lowest mean severity score [38]. The founder series of 21 patients from Mediterranean countries showed erythroderma, more pronounced scaling in the flexural areas and palmoplantar hyperlinearity [56, 68]. Patients born with erythroderma, almost always without a collodion membrane, who later develop generalised LI with hyperlinear palms and soles have been described as LI type 3 [2].

Rare genes. In the series of 6 Iranian families with CERS3, there was acrogeria and palmoplantar hyperlinearity [41]. SDR9C7 has been described in 19 patients from 5 consanguineous families, with mild to moderate dry, scaly skin, with or without hyperkeratosis, PPK and erythroderma, and in a registry series of 8 individuals with fine scale, hyperlinear palms, greater severity on the lower extremities, hypohidrosis, frequent dermatophyte infections of the skin and nails and absence of ectropion and scalp involvement; the Japanese founder variant p.(Arg276Cys) was associated with recurrent generalised tinea corporis, reduced protein-bound ceramides and reduced expression of IRF4 and IL-17A/C/F [44]. SULT2B1 was established in 6 patients from 3 families, with missense, nonsense and splicing variants and loss of RNA and protein expression in keratinocytes [45]. CASP14 accounts for 3 patients from 2 Algerian families, homozygous for c.462_463del on a shared haplotype, without collodion and with fine whitish scales without PPK or nail, hair or tooth abnormalities, first diagnosed as ichthyosis vulgaris [3, 83]. LIPN has an original description in a late-onset form and modest gene-disease evidence [40, 86].

2.6. Allelic diseases, contiguous genes and gene-disease validity

The most relevant allelic diseases are those within the spectrum itself: ABCA12 causes HI, CIE and LI depending on the combination of alleles, and the same gene can give pictures similar to erythrokeratoderma [3, 37]. In CERS3, a contiguous homozygous 15q26.3 microdeletion has been described that removes ADAMTS17, CERS3 and a long non-coding RNA, with skin, eye, heart and skeletal abnormalities in 4 patients from 3 Tunisian families; Orphanet links OMIM phenotype 615023 to the entity ichthyosis–short stature–brachydactyly–microspherophakia (ORPHA:363992) [41, 58]. GeneReviews refers to this deletion as including "CERS3 and ADAMTS1"; the original article identifies ADAMTS17, a gene associated with microspherophakia, and this is the designation adopted [2, 58]. The 2025 classification also included autosomal dominant forms of lamellar ichthyosis, NKPD1-nEDD (missense variant) and ASPRV1-nEDD (OMIM 146750), which matter in the differential diagnosis of a lamellar phenotype without recessive segregation [3, 96].

ClinGen has no gene-disease validity or actionability curation for any of the ARCI genes consulted, and ABCA12 has no dosage curation either [14, 71]. In GenCC, ALOX12B and ALOXE3 are classified as "Definitive" (G2P) and "Strong" (Genomics England PanelApp, Labcorp, PanelApp Australia) and NIPAL4 as "Definitive" (Ambry, G2P) and "Strong"; LIPN is classified as "Limited" by two of four submitters, which is why a LIPN variant should be reported with caution and supported by functional or segregation evidence [39, 67, 86]. GLTP was associated in 2026 with an nEDD with generalised scaling in 5 unrelated families, with 3 biallelic variants, loss of expression and a Gltp−/− mouse model with a lethal barrier defect; the deficiency causes lysosomal retention of glucosylceramides, autophagy dysfunction and delayed terminal differentiation [16]. A second series of 5 patients broadened the variant spectrum [97].

3. Clinical Spectrum and Manifestations by System

3.1. Neonatal presentation

Collodion baby. Children with ARCI are frequently born preterm, encased in a taut, shiny, transparent collodion membrane [2]. The membrane increases transepidermal water loss, with a risk of dehydration and hypernatraemia, and exposes the infant to skin infections and sepsis; its tension produces ectropion, eclabium and underdevelopment of the nasal and auricular cartilages, and sucking and ventilation may be compromised, with dehydration, malnutrition, hypoxia and pneumonia [2]. Within two to four weeks the membrane dries and sheds, giving way to the generalised scaling and erythema of the underlying form, mainly LI and CIE [2]. More than 90% of infants with CIE and most of those with LI have a collodion membrane, whereas patients with NIPAL4 have one in fewer than 30% and those with CYP4F22 are typically born with erythroderma without collodion [2]. The neonatal complications of the collodion baby, most severe in HI, include electrolyte imbalance and dehydration, impaired thermoregulation, pain, caloric malnutrition with weight loss due to poor sucking, skin infections by bacteria (including meticillin-resistant Staphylococcus aureus [MRSA], Streptococcus pyogenes, Pseudomonas aeruginosa and Klebsiella) and fungi (Candida albicans), systemic infections such as pneumonia, toxicity from percutaneous absorption, compression by constrictive bands with distal limb ischaemia, conjunctivitis and keratitis, obstruction of the external ear canal and respiratory difficulty [98].

Harlequin ichthyosis. Newborns, usually preterm, are covered by thick, hard, "armour-like" plates of cornified skin separated by deep, erythematous fissures [2, 99]. The taut skin distorts the features, with extreme ectropion and eclabium, conjunctival oedema, rudimentary or flattened nose and ears, microcephaly, absent eyelashes and eyebrows and sometimes alopecia, hypoplastic nails and flexion deformities of the joints [1, 2, 15]. Circular bands of hardened skin compress the limbs and produce vascular constriction, ischaemia and distal oedema, with a "glove-like" encasement of the hands and feet [2]. The rigidity restricts chest expansion and can cause respiratory failure; feeding difficulties lead to hypoglycaemia, dehydration and acute kidney injury; loss of barrier favours infections, especially by S. aureus; and ectropion predisposes to conjunctivitis, exposure keratitis and strabismus [15]. The picture includes hypernatraemic dehydration, impaired thermoregulation and increased metabolic requirements [99].

Ichthyosis prematurity syndrome. Delivery occurs between 29 and 35 weeks according to GeneReviews, or generally between 30 and 32 weeks according to Orphanet, frequently after polyhydramnios; fetal ultrasound may show echogenic amniotic fluid [2, 7, 87]. The skin at birth is erythrodermic, oedematous and very thickened, resembling vernix caseosa, most severe on the scalp, where the hyperkeratosis is frequently cobblestone-like, on the forehead and on the trunk [2, 87]. The asphyxia, severe and sometimes fatal, results from intrauterine aspiration of amniotic fluid containing corneocytes: in two autopsies, keratin debris filled the bronchial tree and alveoli [2, 87]. The Apgar score is low and the newborns require intensive care and prolonged admission [2].

3.2. Postnatal course by clinical form

Lamellar ichthyosis. The collodion membrane is replaced by large, plate-like, generalised scales, whitish and later brown; erythroderma, when present, is usually mild [2]. Ectropion, eclabium and scarring alopecia of the scalp and eyebrows are frequent; the accumulated scale constricts the sweat ducts and causes severe heat intolerance, and in the external ear canals causes occlusion, bacterial colonisation and recurrent infections; thickening and fissuring of the palms and soles and curved nails are common; scaling of the whole body persists throughout life [2]. The Sorèze consensus describes LI with coarse brownish or dark scale and considers that it probably never clears completely [1]. The description in the Brazilian textbook of genetic syndromes adds mosaic-pattern scales predominating in the flexural areas, rudimentary, flattened ears, sparse, dry, curly and brittle hair, hypohidrosis and PPK with microdactyly [15].

Congenital ichthyosiform erythroderma. After the collodion membrane, prominent generalised erythroderma appears with fine, white, semi-adherent scales; the palms and soles are frequently very thickened, with painful fissures and digital contractures; ectropion, eclabium, scalp involvement and loss of eyebrows are less frequent than in LI [2]. Severe exfoliative erythroderma imposes metabolic stress through very high caloric loss, with poor weight gain and growth failure if requirements are not met [2, 74]. Scaling, hypohidrosis and heat intolerance may persist throughout life [2].

Intermediate phenotypes. Many patients fall between LI and CIE, with mild LI, mild CIE or overlapping features [2]. The phenotype changes over time and with treatment: an LI treated with oral retinoids may evolve into erythroderma with finer scale [1].

Self-improving collodion baby and acral form. In about 10% of babies with a collodion membrane, scaling resolves almost completely in the first three months [1, 2, 100]. Residual findings after infancy include generalised xerosis, mild or focal scaling, hyperlinear palms, red cheeks or anhidrosis [2]. In the German prospective study of 78 patients with ARCI (median age 15 years; 18 SICI and 60 non-SICI), hypohidrosis or anhidrosis and insufficient vitamin D (<30 ng/mL) were frequent in both groups, brachydactyly of the 4th and 5th fingers was more frequent in SICI (p=0.023), folded helix deformity occurred in half of the SICI patients, especially with ALOX12B (p=0.005), and quality of life was less affected below 16 years of age [95]. The designation "self-healing" thus underestimates a disease with persistent mild sequelae. In the acral form, the collodion membranes are limited to the extremities and then heal; it is associated with TGM1 [1, 5].

Bathing suit ichthyosis. The infant is born with a collodion membrane and progresses to LI or CIE; in the first months the extremities heal and scaling, with large greyish or dark scales, persists in the warm areas — scalp, axillae and mid-trunk — sparing the extremities and central face [1, 3, 90]. The genotypic spectrum of this variant was broadened in a North American series that confirmed the association with TGM1 [101]. Heat worsens the skin findings [98]. The prevalence is below 1 per million [6].

Ichthyosis prematurity syndrome after the neonatal period. After a few days the skin sheds and improves greatly; the scale has a median duration of 10 weeks and evolves into mild generalised flat follicular hyperkeratosis, with underlying erythema that eventually resolves [2, 46]. Atopy persists: in the Norwegian series, peripheral eosinophilia was invariable, immunoglobulin E (IgE) was raised in most, more than 70% had respiratory and/or food allergy and severe chronic pruritus was frequent, so the disease can be mistaken for hyper-IgE syndrome [68, 87].

Non-congenital forms. LIPN-nEDD presents in childhood with fine white scaling and minimal erythema, and CASP14-nEDD with fine whitish scales similar to those of FLG-nEDD [2, 3].

3.3. Comparison of the classic forms and cohort data

The table summarises the comparative features of the three classic forms according to the Sorèze consensus [1].

The national survey of Denmark and Sweden allows forms to be compared within the same population [18]. Among 132 patients aged 0.1 to 86 years — 7 HI, 70 LI, 17 CIE and 38 with pleomorphic ichthyosis (marked changes at birth and mild changes later) — a collodion membrane or severe hyperkeratosis at birth occurred in almost all HI and LI patients and in about half of the CIE and pleomorphic patients; persistent ectropion affected 85% of HI, 57% of LI, 35% of CIE and 5% of pleomorphic patients; anhidrosis was frequent in all groups (58–100%); and the mean ichthyosis and erythema scores after infancy were 3.2 and 3.1 in HI, 2.4 and 0.6 in LI, 1.8 and 1.6 in CIE and 1.1 and 0.3 in pleomorphic ichthyosis [18]. In the Italian series of 74 patients (mean age 11.0 years), the phenotypes were LI in 50 (67.5%), CIE in 18 (24.3%), HI in 2 (2.7%) and others in 4 (5.4%), and alopecia, ectropion and eclabium were associated with TGM1 and ABCA12 [38]. These data describe cohorts from reference centres and not population proportions.

3.4. Manifestations by system

Skin and appendages. Generalised scaling, PPK with painful fissures and tapering of the fingers with flexion contractures are common [2]. Alopecia, particularly in ARCI, is scarring with recession of the hairline; it has no specific treatment [3, 17]. The nails may be curved or dystrophic, and retinoids add fragility, onycholysis and paronychia [2, 98]. The skin has a characteristic odour due to an altered microbiome, with more Staphylococcus and Corynebacterium [17, 102]. An increased number of melanocytic naevi in patients with inherited ichthyoses has been described in a series published by Brazilian authors [103].

Thermoregulation. Hypohidrosis results from keratotic plugs in the sweat ducts and possibly from an additional functional defect; it leads to heat intolerance and a risk of hyperthermia, while erythroderma reduces resistance to cold [98, 102].

Eye. Eyelid ichthyosis, scales on the eyelashes and madarosis are accompanied, in the severe forms (LI and HI), by eyelid retraction and cicatricial ectropion, which lead to lagophthalmos, chronic exposure, superficial keratopathy, corneal thinning and scarring, bacterial keratitis and even perforation, with epiphora, photophobia and visual loss; keratinisation of the palpebral conjunctiva, meibomian gland dysfunction and, occasionally in LI, deep stromal opacities without visual loss may also occur [98].

Ear. Accumulation of scales in the ear canals causes conductive hearing loss, pruritus and pain, and recurrent otitis externa carries a risk of cholesteatoma; ear, nose and throat complications affect about 80% of patients with congenital ichthyosis [17, 98].

Growth, nutrition and bone. Growth failure is more frequent in HI and in Netherton syndrome [98]. Malnutrition affects 32% of children with congenital ichthyosis, with deficiencies of selenium, iron, vitamin D, calcium and zinc [17]. 25-hydroxyvitamin D deficiency is well established, especially in children, in retrospective series of 5 to 15 patients and in three prospective studies of 45 to 119 patients; ARCI and epidermolytic ichthyosis appear to carry a higher risk, and pigmented skin, severity and winter and spring are risk factors, with clinical and radiological rickets possible [102]. Hyperkeratosis limits joint range of motion in the severe forms, and PPK limits walking and fine motor skills [98].

Infections. ARCI, especially HI, is among the ichthyoses most prone to recurrent infections by S. aureus and group A streptococcus; recurrent dermatophytosis, for example due to Trichophyton rubrum, is frequent and easily overlooked on scaly skin, candidiasis also occurs, and scabies is difficult to diagnose [17, 102].

Pain and pruritus. Pain results from fissures, especially plantar, erosions, inflammation or infection, and limits mobility; it is the factor that weighs most on quality of life, followed by scaling and female sex [24, 98].

Mental health and quality of life. The impact extends from childhood to adulthood, with domestic, school (rejection, bullying), occupational, leisure and financial burden, creams being the main cost [24]. In a cross-sectional study of the ichthyoses cited by the North American retinoid consensus, depression screening was positive in 30.2% of children and 34.4% of adults, and anxiety screening in 37.7% and 27.3% [104]. In a community in the mountainous region of Veracruz (Mexico), 24 adults with LI homozygous for TGM1 NM_000359.3:c.1054C>G p.(Pro352Ala), all with severe scaling, had significantly higher anxiety, depression and suicide risk scores than 24 controls from the same community, with 17% severe anxiety, and suicide risk was higher when anxiety and depression coexisted [105]. In a survey of 49 child-caregiver dyads with congenital ichthyosis in the USA, child-reported exposure to bullying correlated with poor peer relationships (r = −0.63) and with stigma (r = 0.53), and caregiver depression and anxiety with perception of the child's bullying (r = 0.46 and 0.52) [106]. In a retrospective online survey of 222 adults, mainly from the United Kingdom and the USA, 67 of them with ARCI, the impact on quality of life was greatest in childhood and adolescence and decreased with age, which participants attributed to personal acceptance, better care and, in ARCI, late access to acitretin and etretinate; participants with ARCI described relatively low and stable mental health throughout life, permanent difficulty in maintaining body temperature and, from the age of 30, worse bone health and more joint pain [107].

Systemic comorbidities. In the English national study of 1998–2024, based on National Health Service hospital records of a population of 57.7 million, the 3758 people with a rare ichthyosis had more asthma (18.8% versus 6.5% in the reference population), inflammatory arthropathies (10.3%, including rheumatoid arthritis in 4.2%), atrial fibrillation (9.6% versus 2.2%), cerebral palsy (9.2%) and autism (2.6%), whereas recorded depression (10.8%) was lower than in the population (13.7%); in the 316 patients coded as LI, asthma affected 7.0%, and in the 541 coded as epidermolytic ichthyosis (bullous congenital ichthyosiform erythroderma) inflammatory arthropathies reached 27.9% [108]. The data depend on hospital coding, with a risk of misclassification and surveillance bias, and underestimate conditions managed in primary care, such as some mental disorders [108]. Asthma and food allergy also appear increased in a North American survey, especially in the erythrodermic forms [109].

Skin tumours. Atypical melanocytic naevi, melanoma, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) have been described; the true incidence is not established, but several case reports indicate multiple SCCs and BCCs at an unusually young age, between 25 and 51 years; melanoma, malignant fibrous histiocytoma and cutaneous lymphoma are rare [2, 110]. The French protocol emphasises that SCC has been reported in ARCI, but without a demonstrated increase in risk [17]. In 2026 three cases of cutaneous T-cell lymphoma were described in patients with NIPAL4-nEDD, a publication read only through its metadata [111].

3.5. Harlequin ichthyosis: natural history and treated disease

For decades HI was a disease without survival beyond the neonatal period; neonatal intensive care and multidisciplinary management changed this picture [99]. In the retrospective multicentre questionnaire review of 45 cases with ABCA12 analysis, overall survival was 56% and survivors were aged between 10 months and 25 years; deaths occurred mainly in the first three months — between 1 and 52 days according to the synthesis in the Brazilian textbook — and were attributed to sepsis and/or respiratory failure in 75% [15, 92]. Among those treated with oral retinoids, 83% survived, whereas 76% of those not treated died; this is an observational association, subject to confounding by indication, which the authors phrased as "may improve survival" [92]. Among survivors, recurrent skin infections in childhood affected one third, difficulty maintaining weight 44% and developmental delay 32%, and three children developed inflammatory arthritis [92]. After the neonatal period, HI is a severe chronic disease: the plates gradually shed and generalised scaling appears with intense erythroderma, with growth delay, hypohidrosis or anhidrosis, heat intolerance, vitamin D deficiency, eye problems due to persistent ectropion, alopecia, PPK with fissures, digital contractures, chronic constipation, anaemia, arthralgia or arthritis and joint contractures [2, 21]. A 2026 systematic review of 68 published cases in 56 articles found a mortality of 60.3%, with a mean age at death of 47.19 days, ectropion in 80.9%, eclabium in 79.4% and ABCA12 confirmation in only 30.9%; because it pools case reports, it is subject to publication bias and does not estimate population mortality [112].

3.6. Ichthyosis prematurity syndrome: natural history

The long-term prognosis is generally favourable [2]. The systematic review of 26 studies with 59 cases published up to September 2024 found, however, 6 fulminant cases (10.2%) and an estimated survival at 6 months of 87.6% (95% CI 78.8–97.4), with deaths from respiratory and/or cardiac causes or sepsis; the disease, previously considered mainly Norwegian and Swedish, has been described in several ethnic groups (Italy, Spain, India, Oman, United Arab Emirates, Iraq) [46]. The Norwegian series of 23 patients from 17 families documented the atopic course described above [87, 113]. Symptoms may attenuate in childhood, leaving dry, itchy skin [68].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

In a family with an affected child, ultrasound may raise suspicion of HI from the second trimester: polyhydramnios, dense floating particles in the amniotic fluid ("snowflake sign"), atypical facial morphology with a mouth fixed in an "O", eclabium, ectropion, cystic masses in the orbital region, nasal hypoplasia, rudimentary ears, fixed or claw-like hands, loose plates of skin, restricted respiratory movements and flexion contractures [2, 15, 114, 115]. In IPS, polyhydramnios, membrane separation and echogenic amniotic fluid with clear chorionic fluid are the prenatal clues [2, 87]. These signs are late and do not replace molecular diagnosis [17].

4.2. Newborn

ARCI should be suspected in any newborn, frequently preterm, with a collodion membrane (especially with ectropion or eclabium), generalised exfoliative erythroderma or a harlequin presentation [2]. The collodion baby requires immediate monitoring for emergency signs: dehydration and hypernatraemia due to transepidermal water loss, thermal instability, signs of skin infection or sepsis, respiratory compromise due to chest constriction or nasal obstruction, digital constriction bands with ischaemia and feeding difficulty due to eclabium [2, 98]. In HI and IPS there is the additional risk of aspiration of amniotic fluid containing scales [2]. The definitive form (LI, CIE, self-improving) becomes apparent only after the membrane is shed, within two to four weeks, and about 10% of collodion babies evolve to the self-improving form; the prognosis should therefore not be communicated on the basis of the neonatal appearance alone [2, 36]. Blisters and denuded areas at birth point to epidermolytic ichthyosis, and erythroderma with continuous scaling and hair abnormalities to Netherton syndrome [2, 102]. The distinction between syndromic and non-syndromic forms can be difficult at birth, because the extracutaneous signs of many syndromes appear later, which justifies a broad panel [2, 65].

4.3. Infant, child and adult

Outside the neonatal period, the starting question is whether the ichthyosis has been present since birth: the congenital forms are rare, whereas the common late-onset forms, such as ichthyosis vulgaris, are frequent [19]. A late-onset ichthyosis suggests acquired ichthyosis, Refsum disease or a mild form of ARCI, and in a child a fine white scaling beginning in childhood may correspond to LIPN-nEDD or CASP14-nEDD [3, 19]. A poorly defined auricle in a patient with ichthyosis indicates that the patient was born as a collodion baby [17]. Marked erythroderma points to a rare congenital form, blisters in the history to a keratinopathic ichthyosis, and associated symptoms (neurological, ocular, auditory, hepatic, abnormal hair) to a syndromic form [19].

Warning signs throughout life include: hyperthermia with heat or exercise (hypohidrosis), hearing loss, otorrhoea or ear pain (scale in the ear canal), red eye, photophobia or epiphora (lagophthalmos and corneal exposure), poor growth (caloric loss and malnutrition), bone pain or signs of rickets (vitamin D deficiency), extensive dermatophytosis, and any new, ulcerated or rapidly growing skin lesion in a young adult (early SCC and BCC) [2, 17, 102]. A sudden increase in pruritus or severity may reflect infection, including scabies [102]. For emergency situations there is an Orphanet Urgences sheet on the inherited ichthyoses, with an English version on the ERN-Skin website [116].

4.4. Newborn screening

There is no biochemical or genetic newborn screening for ARCI in the sources consulted; diagnosis rests on clinical recognition at birth and on molecular testing [2].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Principles and criteria

There are no formal scored diagnostic criteria for ARCI. The diagnosis of congenital ichthyosis is clinical; identification of the type requires expertise and testing, and, except for ichthyosis vulgaris and X-linked ichthyosis, only molecular analysis gives a definitive diagnosis of the type [17]. Establishing the genetic cause helps with prognosis and counselling, and is usually based on the clinical history, examination, family history and molecular testing [2]. In the 2025 nomenclature, without a genetic result and with a picture limited to the skin, the diagnosis is "nEDD, unspecified", and with a result it is the gene name followed by nEDD [3].

5.2. Structured clinical assessment

The German guideline proposes a structured history, based on the form of the German ichthyosis network (NIRK) and the Münster Centre for Rare Diseases, which includes the course and duration of pregnancy, polyhydramnios, delivery complications and findings at birth (collodion membrane, blisters, exfoliation, ectropion, eclabium, erythroderma, ear deformities, contractures, infections), the family history with pedigree and consanguinity, the course and seasonal variation, the current findings (colour and size of the scales, degree of erythema, distribution, involvement of the antecubital and popliteal fossae, palmoplantar hyperlinearity or keratoderma, blisters, exfoliation, lichenification, hypohidrosis, photosensitivity), the appendages and extracutaneous symptoms (vision, hearing, contractures, skeleton, teeth, viscera, intellectual disability, hepatomegaly, cryptorchidism, vitamin D deficiency, Jordans anomaly, type I hypersensitivity) [19]. Four questions guide the decision: whether the ichthyosis has been present since birth, whether there is marked erythroderma, whether there have been blisters and whether there are associated symptoms [19]. The family history should cover three generations, and the absence of affected relatives does not exclude the diagnosis [2].

Examination assesses the pattern, quality and colour of the scales, the collodion membrane, erythroderma, erosions or blisters, xerosis, alopecia of the scalp and eyebrows, scars, hypohidrosis, the extremities (PPK with fissures, tapering of the fingers, flexion contractures), the nails, the face and ears, the eyes (ectropion, dry eye, corneal defects), eclabium and growth [2]. The French protocol adds the flexures, digital constrictions, signs of skin carcinoma, lymphadenopathy in erythroderma, walking distance, fine motor skills, signs of rickets or osteomalacia, the teeth (periodontal disease on retinoids) and the psychological impact [17]. Severity can be recorded in a simplified way, with scales and hyperkeratosis, erythema, pruritus and pain each scored from 0 to 10, or with the VIIS (Visual Index for Ichthyosis Severity), which scores scale and erythema from 0 to 4 in four regions, with subtotals of 16 and a total of 32, used mainly in research [17]. Photographic documentation and assessment by an expert provide clues, especially in the newborn [19].

5.3. Non-molecular tests

Timing of biopsy. The skin should not be biopsied before the collodion membrane has gone, except in an unstable baby [17]. It is preferable to perform several tests on the same sample, after consulting a specialised centre, to avoid repeated biopsies [19].

Histology and electron microscopy. The histology of ARCI is generally non-specific, with epidermal hyperplasia and orthohyperkeratosis over acanthosis [2, 3]. In HI there is extreme hyperkeratosis and follicular plugs, and electron microscopy shows absence of lamellar bodies and lipid bilayers, with lamellar granules lacking normal lamellar structures and prominent lipid vacuoles; this finding is characteristic of HI but not gene-specific, and helps to distinguish HI from LI with a collodion presentation [2, 3, 71, 91]. In TGM1-nEDD there is absence or defective formation of the cornified envelope and extracellular clefts in the stratum corneum; in a series of 56 patients with ARCI studied by electron microscopy, cholesterol clefts had 100% specificity for TGM1 [3, 38]. Type III ultrastructure, with abnormal lamellar bodies and elongated perinuclear membranes in the granular layer, suggests NIPAL4, but the ultrastructural classification does not map one-to-one onto genes and is available only in specialised centres [2, 39]. In IPS, aggregates of curved trilamellar membrane structures in the granular and cornified layers are considered pathognomonic in experienced hands [87]. Abnormal lamellar bodies have been described with SDR9C7 and CERS3 [38].

Transglutaminase 1 activity. The in situ assay on cryostat sections, which measures covalent incorporation of biotinylated substrate peptides, combined with TG1 immunohistochemistry, allows rapid screening of TGM1 cases [1, 14]. The French protocol recommends this activity assay (in situ zymography) as the first screen, when available, because it always shows absent activity with TGM1 variants, except in two phenotypes: in bathing suit ichthyosis the temperature-sensitive enzyme is active at the room temperature of the assay and the test is positive, and in the self-improving collodion baby activity normalises after birth and the test is positive or weakly positive [17]. Immunohistochemistry alone has poor specificity, because some variants retain the protein [17]. A normal result does not exclude TGM1 [14]. The Sorèze consensus also lists the scale-heating test with sodium dodecyl sulfate [1].

Clinically directed investigations. The full blood count may show eosinophilia (Netherton syndrome, inflammatory peeling skin, IPS, ichthyosis vulgaris); total IgE is raised in IPS and Netherton syndrome; liver tests and creatine kinase (CK) point to Chanarin-Dorfman, NISCH or ARC syndrome; and, in an expert centre, steroid sulfatase activity (X-linked ichthyosis), lipid droplets in neutrophils (Jordans anomaly, Chanarin-Dorfman syndrome) and phytanic acid (Refsum disease) [17, 19]. Eosinophilia and raised IgE support IPS but are not specific [87]. When Sjögren-Larsson syndrome is suspected, the first-line test is long-chain fatty alcohols, followed by enzyme activity in fibroblasts or lymphocytes [68].

Other methods. Analysis of ABCA12 messenger RNA in a hair sample has been described as a minimally invasive, although costly, means of diagnosis [15, 117]. Non-invasive lipid analysis of the stratum corneum by tape-stripping, which shows reduced ω-hydroxy ceramides, acylceramide and protein-bound ceramides in CYP4F22 deficiency, is a research method [69].

5.4. Molecular testing

Choice of test. The multigene panel including the ARCI genes and those of the differential diagnoses is the test of choice, because it simultaneously assesses syndromic forms that cannot be distinguished clinically before specific signs appear [2]. The genes included and the sensitivity vary between laboratories and over time; some panels include genes unrelated to the phenotype, and the one that maximises yield while limiting VUS and findings that do not explain the picture should be chosen [2]. In France, NGS panels reach more than 100 genes, with bioinformatic CNV detection that requires confirmation, and a detection rate for causal variants of about 90%; Sanger sequencing is reserved for an obvious gene or for the familial variant [17]. In the absence of a panel, serial single-gene tests start with sequencing and proceed to targeted deletion/duplication analysis if only one or no variant is found: ABCA12 first in HI, TGM1 first in ARCI without a harlequin presentation and SLC27A4 first in IPS [2]. Exome, or genome, sequencing is considered mainly when there are manifestations in other organs and when the panel is negative [2, 17].

Yield. Molecular diagnostic rates range from 83% (English cohort) to 85% (Scandinavia and the consanguineous Iranian cohort) and about 90% (French panels), and in several panel studies 7–17% of people with congenital ichthyosis remain without a pathogenic variant in a known gene [2, 17, 18, 36, 75]. These percentages are diagnostic yields in selected cohorts, not analytical sensitivity.

Limitations. A negative result does not exclude ARCI. Causes of false negatives include deep intronic and splicing variants not covered, small or intragenic CNVs (such as TGM1 microduplications and CYP4F22 and NIPAL4 microdeletions) not detected without targeted analysis, genes not yet discovered (GLTP was described in 2026) and mapped loci without an identified gene [2, 16, 38]. Apparent homozygosity may conceal a deletion of the second allele or uniparental isodisomy [2]. Peripheral blood is the usual sample; a lesional skin biopsy is reserved for suspected post-zygotic mosaicism, more relevant in the keratinopathies [17]. VUS are frequent: in the Iranian cohort, some of the undiagnosed cases had VUS in known genes [2, 75]. A skin biopsy (enzyme activity, ultrastructure) can help to interpret a VUS [17].

Segregation and phase. Confirmation that two variants are in trans requires parental samples; in case 2 in section 10, refusal of parental segregation testing prevented the phase of two CYP4F22 variants from being established and the diagnosis remained "suggestive" [17, 81].

Report content. The report should state the gene, the reference transcript with version, the variant in HGVS nomenclature (c. and p.), the zygosity, the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) classification and the criteria applied, and the recommendation for segregation testing. As an example, the laboratory for the cases in section 10 used a 54-gene panel with mean coverage ≥60×, more than 95% of bases at ≥20× and more than 92% at ≥30×, filtered non-synonymous exonic variants and splicing variants within ±2 nucleotides with a frequency below 1% in gnomAD v4.1, consulted ClinVar, HGMD, LOVD and DECIPHER and classified the TGM1 variant p.(Thr287Ile) as likely pathogenic by the PM1, PM2, PP2, PP3 and PP4 criteria [81]. A variant in LIPN should be reported with caution, given the limited gene-disease evidence [86].

5.5. Practical algorithm

The 2025 classification proposes a schematic algorithm for each nEDD, based on skin morphology, congenital or non-congenital onset and key histopathological findings (Figure 6 of the original article) [3].

6. Differential Diagnosis

6.1. Comparative table

6.2. The collodion baby and neonatal erythroderma

The collodion membrane is not exclusive to ARCI. It also occurs in trichothiodystrophy, the perinatal form of Gaucher disease, ELOVL4 syndrome, severe KDSR-nEDD and, rarely, X-linked ichthyosis [2, 3, 102]. Erythroderma at birth, without collodion, suggests CYP4F22-related CIE, Netherton syndrome, KID syndrome or hypohidrotic ectodermal dysplasia, and blisters suggest epidermolytic ichthyosis [2, 102]. Faced with a collodion baby or neonatal CIE, the whole differential diagnosis of the congenital ichthyoses should be considered, including the early manifestation of X-linked ichthyosis [19].

The supplement to Part 2 of the 2019 European guideline lists the forms of ichthyosis and the systemic diseases that can present with a collodion membrane at birth, with the associated genes [102].

In the original table, Gaucher disease appears with the historical symbol GBA, now GBA1, and congenital hypothyroidism is listed without an associated gene [102].

6.3. Late-onset ichthyoses: ichthyosis vulgaris and X-linked ichthyosis

Ichthyosis vulgaris usually appears in the first year, with xerosis or mild ichthyosis, keratosis pilaris, hyperlinear palms and soles and frequent atopy; FLG heterozygotes have a mild picture and homozygotes or compound heterozygotes a more severe phenotype that may resemble LI [2]. CASP14-nEDD, with fine whitish scales without erythema, was initially diagnosed as ichthyosis vulgaris and occupies a grey zone between ARCI and the ichthyosis vulgaris and atopic dermatitis spectrum [83]. X-linked ichthyosis gives adherent white scales that darken, especially in the flexures, asymptomatic corneal opacities and sometimes cryptorchidism; raised plasma cholesterol sulfate identifies affected men, and recurrent deletions including STS at Xp22.31 are present in more than 90%, while larger deletions may add intellectual disability, autism spectrum disorder or anosmia [2, 122]. The frequency is 1/1,300 to 1/1,500 men, and low maternal unconjugated oestriol on prenatal screening is a clue [122]. In a comparison of four genetic ichthyoses, the Brazilian textbook of syndromes attributes to lamellar ichthyosis AR inheritance, a frequency of 1:200,000–300,000 births and onset at birth; to ichthyosis vulgaris AD inheritance, 1:250 and onset after 3 months; to the X-linked form 1:6,000 and onset at birth; and to epidermolytic hyperkeratosis AD inheritance, 1:300,000 and onset at birth [15].

6.4. Sjögren-Larsson syndrome

Sjögren-Larsson syndrome, due to deficiency of fatty aldehyde dehydrogenase (FALDH, encoded by ALDH3A2), combines pruritic ichthyosis, spasticity, ophthalmological abnormalities and intellectual disability, a tetrad that may only be complete after 3 years [68]. The newborn may appear erythrodermic, progressing in childhood to generalised ichthyosiform hyperkeratosis that spares the face; marked pruritus distinguishes it from the other disorders of cornification, and preterm birth is frequent [2, 68]. Spastic tetraparesis predominates in the lower limbs and no adolescent walks unaided; magnetic resonance imaging shows T2 hyperintensity of the periventricular white matter and spectroscopy, after one to two years, peaks at 1.3 and 0.9 ppm that are almost pathognomonic [68]. The first-line test is long-chain fatty alcohols (octadecanol), followed by enzyme activity in fibroblasts or lymphocytes [68]. As for zileuton, an open study in 5 patients described less pruritus, but in a double-blind randomised crossover trial with 10 patients only 1 improved significantly; the statement, in another section of the same treatise, that the disease responds "dramatically" to zileuton is not supported by that trial [65, 68].

6.5. Ichthyosis in inborn errors of metabolism

About 40 inherited diseases of the metabolism of complex lipids, cholesterol and fatty acids (synthesis, remodelling, catabolism and transport) present with ichthyosis; the great majority are neurocutaneous syndromes, chondrodysplasias punctata or multiple congenital anomaly syndromes, such as congenital disorders of glycosylation (CDG) or serine synthesis defects, including Neu-Laxova syndrome [65]. The list includes lysosomal diseases (X-linked ichthyosis, multiple sulfatase deficiency, Gaucher disease type II with collodion baby), complex lipid disorders (early ARCI due to PNPLA1, ABCA12, KDSR, CERS3, CYP4F22; late ARCI due to LIPN; Chanarin-Dorfman; Sjögren-Larsson; ELOVL4 and ELOVL1; sphingosine-1-phosphate lyase deficiency [SGPL1]; IPS; adult Refsum disease), cholesterol synthesis defects (Conradi-Hünermann, CHILD, sterol-C4-methyl oxidase deficiency, IFAP), dolichol defects (MPDU1-CDG, SRD5A3-CDG, DK1-CDG), trafficking defects (CEDNIK, MEDNIK due to AP1S1, SNAP29, VIPAS39), organic acidurias (holocarboxylase synthetase and biotinidase deficiencies, methylmalonic aciduria), primary immunodeficiencies (Omenn syndrome, Wiskott-Aldrich syndrome, graft-versus-host disease) and others (Netherton syndrome, GJB2-related syndrome with deafness, dyskeratosis congenita) [65]. The table in the treatise on metabolic diseases attributes harlequin ichthyosis to "ABHD12", which is a transcription error: the gene is ABCA12 [2, 65]. Some of these diseases are treatable: sterol-C4-methyl oxidase deficiency improves with a statin and cholesterol supplementation, and systemic isotretinoin markedly improved scaling and erythema in 2 patients with KDSR-nEDD [65, 66]. ELOVL4 deficiency resembles Sjögren-Larsson syndrome with more severe neurology, and the heterozygous ELOVL1 variant NM_022821.4:c.494C>T p.(Ser165Phe) caused ichthyotic keratoderma, spasticity, dysmorphism and mild hypomyelination in 2 patients [68].

7. Treatments and Risk Management Strategies

7.1. Principles and guidelines

Treatment of ARCI is symptomatic and there is no curative therapy; the aim is to remove hyperkeratosis and scales, smooth the skin, heal and prevent fissures, hydrate the stratum corneum and reduce complications, with multidisciplinary care that preserves function and quality of life [2, 19]. The evidence is mostly of low level: there are few randomised trials, and most recommendations are based on series, reports and expert opinion [19, 24]. The table summarises the guidelines that underpin this section.

The 2024 update left unchanged the sections on emollients, bathing, scalp, PPK and therapeutic education, updated keratolytics (urea in the newborn), topical and systemic retinoids (with particularities for the USA and Asia), psychosocial management (anxiety assessment) and communication of the diagnosis, and created new sections on biologics and small molecules, therapeutic perspectives, telemedicine and prenatal diagnosis [25]. In part 2, the sections on the eye (modified recommendation on topical retinoids before ectropion surgery), ENT (voice changes), pruritus and pain, infections (swabs and antibiotics), growth and nutrition, hair and nails, physical limitations (occupational therapy programme) and the neonatal period (new discussion on incubator and antibiotics) were updated, and sections on vaccination and comorbidities were created [98]. The content of the new recommendations on biologics, Janus kinase (JAK) inhibitors, vaccination, comorbidities, telemedicine, the neonatal period and prenatal diagnosis could not be read, because the main text is paywalled; on these topics, the text relies on the 2019 recommendations, the 2024 supplements and open-access studies and reviews published between 2020 and 2026, cited at each point, without attributing to them the content of the update. In the European guidelines, levels of evidence follow the SIGN 50 manual: 1++ to 1− for meta-analyses, systematic reviews and randomised trials, 2++ to 2− for case-control and cohort studies, 3 for non-analytical studies (case reports and series) and 4 for expert opinion; grade A requires at least one 1++ study or a consistent body of 1+ studies, grade B 2++ studies or extrapolation from 1++ or 1+ studies, grade C 2+ studies or extrapolation from 2++ studies, and grade D corresponds to level 3 or 4 evidence; the grade reflects the strength of the evidence and not the clinical importance of the recommendation [24]. The 2019 guideline was developed from 2015 onwards by a multidisciplinary group from 16 countries — 25 dermatologists, one paediatrician, one otorhinolaryngologist, one ophthalmologist, one clinical geneticist, one psychologist, one pharmacist, one dermato-epidemiologist and one nurse — with three representatives of patient associations, following the AGREE II instrument (Appraisal of Guidelines for Research and Evaluation), and provided for revision every 5 years [24]. The 2019 supplementary tables bring together all the recommendations with their respective level and grade, and most of those concerning complications and the neonatal period are level 3–4 and grade D [24, 102].

The 2021 French PNDS is based on a Medline search without date limit up to April 2021, with selection according to the HAS literature analysis guide and grading according to the Scottish Intercollegiate Guidelines Network grid [23]. Among treatment studies with at least six patients, it identified 32 references, the oldest from 1972: 15 on oral retinoids, 2 on keratolytics, 2 on emollients, 2 on topical retinoids, 1 on N-acetylcysteine, 1 on balneotherapy, 1 on therapeutic education and 3 on targeted treatments [23]. Only 7 were placebo-controlled randomised trials; samples were small, mixed forms of ichthyosis and used non-validated efficacy criteria, so the recommendations on complications rest mainly on expert consensus [23]. The following table brings together the points on which the 2021 text diverges from the other guidelines cited or from itself.

7.2. Assessment after diagnosis

The initial assessment should ideally take place in a reference or competence centre, with the dermatologist coordinating a network that includes general practice, paediatrics, pharmacy, nursing, psychology, social services, podiatry, occupational therapy, psychomotor therapy, physiotherapy, dietetics, orthotics and prosthetics, ENT, ophthalmology and genetics [17]. In the neonatal ichthyoses, neonatology and dermatology work together, with timely assessment by ophthalmology and ENT and, depending on the disease, orthopaedics and gastroenterology [19].

7.3. Neonatal period: collodion baby and harlequin ichthyosis

Organisation. The newborn with a collodion membrane or HI should be admitted to a neonatal intensive care unit with a multidisciplinary team — dermatology, neonatology, ophthalmology, ENT, plastic surgery, dietetics, psychology and nursing — and parental involvement, facilitating physical contact between parents and baby (level of evidence 3–4, grade D) [24, 102]. A 2023 North American clinical guide considers immediate genetic testing, as soon as the skin abnormality is detected, to be the standard of care, in order to guide the management specific to each form [124]. The evidence underpinning these recommendations comes from six descriptive retrospective series (17 to 32 collodion babies; 16 to 45 HI), from case reports and from case reviews centred on the practical management of the collodion baby [102, 126].

Environment. The 2019 European guideline recommends an incubator with an initial humidity of 60–80%, reduced every 3–4 days until normal conditions are reached, because high humidity favours Pseudomonas infections and candidiasis, with a temperature of 32–34 °C, monitoring for hypothermia and hyperthermia and transfer to an open cot when caloric intake and weight gain are adequate [102]. GeneReviews and the Brazilian textbook give a humidity of 50–70% [2, 15]. The 2024 update revised the discussion on the incubator, but its text was not read [98].

Hydration and nutrition. Weight should be recorded daily, with fluid balance, prevention of hypernatraemia and dehydration and a high-calorie diet; an oro- or nasogastric tube is often needed because of poor sucking caused by eclabium and the metabolic requirements, and parenteral nutrition may be needed in HI [2, 15, 102]. A 2022 narrative review of HI adds monitoring of urine output, serum electrolytes and renal and hepatic function, describes the transition from tube feeding to breastfeeding when sucking and swallowing allow it and records frequent vomiting attributed to gastrointestinal dysmotility in some cases [127]. In a newborn collodion baby, wrapping the body in sterile polyethylene film allowed kangaroo care and breastfeeding from the 2nd day of life, with a fall in pain scores on the EDIN and N-PASS scales during the sessions and without infections or other adverse events [128]. Vitamin D deficiency should be corrected [15].

Skin. Emollients are applied 3–8 times a day; sterile white soft paraffin is common, but may increase infections and impair sweating, so water-in-oil emollients are an alternative; the technique should avoid contamination (latex-free gloves, single-dose containers), and the daily bath precedes the emollient [102]. Urea, lactic acid and silver sulfadiazine should be avoided because of percutaneous absorption, and salicylic acid is an absolute contraindication [102]. The 2024 update maintains caution with urea in the neonatal period, except on very limited areas such as the palms and soles [25].

Infection. Bacterial swabs twice a week (flexures, eyes, catheter sites), aqueous 0.05% chlorhexidine on erosions, topical antifungal on macerated areas and prompt treatment according to the antibiogram are recommended; prophylactic antibiotic therapy is not recommended in the collodion baby and is an option in HI [2, 102]. In a newborn with HI, suspicion of sepsis should be high so as not to delay antibiotic therapy [15]. In a Turkish series of six patients with ALOX12B-related ARCI, two had neonatal sepsis, one of them with pneumonia and 51 days in intensive care, and a third had umbilical venous catheter-associated thrombosis, treated with enoxaparin and resolved [129].

Airway and access. Invasive procedures should be avoided; intubation is justified if ventilation is restricted by skin constriction or there is nasal obstruction, especially in severe HI; an umbilical venous catheter is used for a limited period if peripheral access is impossible [2, 102]. In IPS, immediate oropharyngeal suction with or without ventilation or intubation treats the aspiration of amniotic fluid containing corneocytes [102].

Constrictive bands. Massage of the bands with emollient, or with 10% urea on limited areas, is the first measure; response to topical 0.1% tazarotene has been described; oral retinoids can be very effective; and linear surgical incisions of the bands treat evident ischaemia [2, 102]. The 2022 review of HI recommends a low threshold for assessing surgical release of entrapped limbs, because ischaemia of the digital pulps is usually irreversible once it becomes evident and early discolouration and progressive hardening of the tissues indicate impending compartment syndrome; it describes incisions that release the constriction without crossing the full thickness of the dermis, multiple Z-plasties to reorient the scars and avoid new bands, topical antibiotic on surgical wounds until healing and local anaesthesia as an alternative to sedation when the latter offers no benefit, and cites reports in which acitretin impaired healing of extensive surgical wounds [127]. The 2023 North American guide includes surveillance for compartment syndrome in the collodion baby [124].

Eyes and ears. Ophthalmological and otological assessment is close; the Brazilian textbook indicates lubricating eye ointment every 6–12 hours in HI, with surgery when indicated, and debris in the ear canal is removed regularly [15, 102].

Pain. Pain is assessed with neonatal scales; analgesics are given before bathing and non-nutritive sucking and a soft or water mattress are used [102]. In the 2022 review, most newborns with HI required opioid analgesics, although some patients with a less severe phenotype had pain that was controllable without them [127]. The summary table of the 2019 European guideline for the collodion baby and HI summarises management: highly humidified incubator (>60%), nutritional support, emollients 3 to 8 times a day without other topical agents, antiseptics on erosive lesions and antifungal on macerated areas, neutral eye ointments, removal of scales from the ears, preventive massage of the bands with surgery if there is ischaemia, oral retinoids acceptable in HI but not in the collodion baby, regular analgesia and psychological support [102].

Systemic retinoids in the neonatal period. In the collodion baby the membrane sheds spontaneously within a few weeks and oral retinoids are generally unnecessary [2, 102]. In HI their value is controversial: in the review cited by the European guideline, 83% of treated patients survived and 24% of untreated patients survived long-term, but it is not known whether the difference is due to neonatal care or to the retinoid, and the diversity of ABCA12 variants influences outcome [92, 102]. When treatment is needed, the European guideline recommends acitretin, and isotretinoin has been used occasionally [102]. The German guideline recommends acitretin 0.5 mg/kg per day (maximum 1 mg/kg) in newborns with HI [19]. The 2023 North American clinical guide indicates acitretin at 1 mg/kg/day, started early in HI, to accelerate shedding of the plates and reduce respiratory restriction, a dose higher than that of the German guideline and than the maximum initial dose of 0.5 mg/kg/day generally recommended by the 2024 European update [19, 25, 124]. The PeDRA consensus considers that newborns with HI whose constrictive scales restrict breathing or threaten the viability of the extremities may benefit from a systemic retinoid and that milder phenotypes may not need one (III, C) [104]. The Brazilian textbook of genetic syndromes reports etretinate, isotretinoin or acitretin at 0.5–1 mg/kg/day orally from 7 days of life, discontinued by 6 months, with improvement of ectropion and eclabium and accelerated shedding of the plates, without citing a primary source for this regimen [15]. In all the jurisdictions consulted, the use of systemic retinoids in the newborn is outside the approved indication, either because of age or, in the USA, because of the indication [26, 27]. A 2026 report described the survival of a preterm newborn with HI in a rural hospital without modern incubators, with an improvised humidified incubator, intensive emollients, basic respiratory support, an umbilical venous catheter and oral isotretinoin started late [130].

Other neonatal presentations. CIE and Netherton syndrome present with erythroderma and scaling at birth; epidermolytic ichthyosis requires care similar to that of epidermolysis bullosa, without adhesives or heat [102].

7.4. Skin care in children and adults

Choice of topical treatment. The 2019 European guideline bases the choice on morphology (scaling, hyperkeratosis), distribution, presence of inflammation or erosions, severity and age and, for the specific agent, on availability in the country, formulation and texture, reimbursement and cost, the clinician's experience and the patient's preferences, which it considers decisive because the outcome depends on adherence to time-consuming care; unpleasant smells and very greasy consistencies should be avoided (level 4, grade D) [24]. Topical agents are first line, as monotherapy or combined with oral retinoids, and the studies assessed the effect on the body, not on the scalp or the palms and soles [24]. Increased skin permeability raises the risk of allergic contact dermatitis, and in forms with thick scale the guideline recommends adding other agents to emollients (level 1, grade B) [24].

Bathing and mechanical keratolysis. Daily bathing is beneficial in severe ichthyoses: the 2019 European guideline recommended lukewarm baths of 30 minutes or more and the 2024 update recommends at least 15 minutes, with mild soap or a soap-free wash base [24, 25]. Sodium bicarbonate is used at 3–6 g/L (2019) or 6 g/L (2024); the German guideline indicates ≈6 g/L (3–4 handfuls, ≈400 g per bathtub) in adults and from 1 year of age, and half (≈3 g/L) in infants and young children [19, 24, 25]. Saline baths (NaCl or Dead Sea salt) at 1–8% have been used without complications in adults, without exceeding 3–4% in children, and sting in the erythrodermic and erosive forms [19]. After 10–20 minutes of bathing, removal of scales with pumice stone, gloves or microfibre cloths is done from once a day to once a week, and the average time for the whole body in a controlled severe ichthyosis is 60–90 minutes [19]. In LI, pH-neutral additives have almost no effect [19]. Antiseptics are not used routinely, only with recurrent infections or odour (2–3 times a week) [17, 25]. Thermal balneotherapy was beneficial in one uncontrolled study (level 2+, grade C) [24]. The 2019 recommendations table provides for bathing once or twice a day with mild soap (level 4, grade D), and the text allows moisturising additives, colloidal preparations, bicarbonate and baths with 0.9% saline [24]. The 2023 North American guide describes baths of alkaline seawater (pH 8.1) or with bicarbonate for 30–60 minutes at least once a week, dilute bleach baths 2–3 times a week for recurrent infections, followed by a quick shower, and soaks in dilute acetic acid (vinegar) for recurrent Gram-negative bacterial and fungal infections, which sting if there are fissures [124]. The 2023 Nature Reviews Disease Primers review indicates a daily bath of 30–60 minutes, accepts showering if it allows mechanical exfoliation and mentions careful trimming of partially adherent scales with scissors and scalpel debridement of thickened palms and soles [131].

Emollients. They are recommended in all ichthyoses (level 1, grade B), at least twice a day and ideally immediately after bathing [24]. In severe forms they are applied to the whole body once or twice a day, and in infants in formulations without active ingredients about 6–8 times a day, because of greater absorption and irritability [19]. Pure occlusive ointments over large areas are not recommended (heat, maceration, infections), and occlusives are unsuitable in hot, humid climates [17, 24]. Wet wrapping — abundant emollient after bathing and plastic film under a blanket for one hour — and occlusive dressings are effective in recalcitrant areas, for example over the joints [17, 19].

Keratolytics and humectants. The table summarises the concentrations and age limits in the guidelines.

The combination of 5% urea and 5% glycerol gives good keratolysis with less irritation [19]. Keratolytics are applied once or twice a day, with reduction according to response, avoiding the face, flexures and fissures (level 1, grade B), and irritation may limit their use [2, 24]. For the face and eyelids, glycerol and low-dose keratolytics (urea ≤3%) in an oil-in-water base, 5% panthenol or 5% vitamin E are used [19]. On the scalp, an emollient or wash-off keratolytic is applied for hours or overnight, at variable weekly frequency, and scales are removed with a comb; plastic occlusion increases absorption and requires caution in children [24, 25]. Foams, solutions and shampoos are more acceptable than gels and ointments, but may be less effective; some centres use hot steam with a professional hair steamer, and in forms with fragile hair, such as Netherton syndrome and trichothiodystrophy, procedures should be gentler [24]. In moderate to severe adult PPK, salicylic acid up to 25% or urea up to 40% in ointment is used for a limited period, once or twice a day, protecting fissures with white soft paraffin, with manual removal of calluses by a podiatrist [25]. In milder forms of PPK, topical tazarotene is an option (level 4, grade D) [24].

Topical retinoids and other agents that modify differentiation. Tazarotene (0.05% and 0.1% gel or cream, once a day), tretinoin (0.025%, 0.05% and 0.1% cream, once a day, which can be compounded with 2% salicylic acid for palmoplantar use) and adapalene (0.1% and 0.3% gel, less irritating) reduce scale, improve digital contractures in the newborn and reverse ectropion (III, C), with more reports in LI and with tazarotene [104]. They cause erythema, pruritus, irritation and photosensitivity; they are used on localised and recalcitrant areas (hands, feet, legs, periarticular areas); extensive tazarotene gives measurable but low plasma levels; they are contraindicated in pregnancy and in women of childbearing potential without reliable contraception; and they do not require systemic laboratory monitoring (II, B) [2, 19, 104]. In France topical retinoids are not authorised for ichthyosis and tazarotene is no longer available [17]. Vitamin D analogues (calcipotriol, tacalcitol, calcitriol) have been effective in adults, with calcipotriol limited to 100 g per week; tacrolimus and topical vitamin D are used with caution because of absorption [2, 24, 25]. Topical N-acetylcysteine was no longer recommended in 2024 (sulfurous smell, irritation, cost) [25]. In 2019 it was considered useful (level 3, grade B), and the addition of fragrances to mask the smell carried a risk of sensitisation [24]. In ceramide synthesis deficiencies, topical application of specific ceramides has been proposed as a hypothesis, without a trial [66].

Antiseptics. Chlorhexidine (dilution of 5/1000 to 5/10,000), 0.1% octenidine, 0.1% polyhexanide, 1/10,000 potassium permanganate and 0.005–0.01% bleach baths (1–2 mL/L, not evaluated in ichthyosis) are used, usually with rinsing; iodine-based antiseptics are not recommended because of the thyroid risk [25].

Cost, reimbursement and magistral preparations in France. Topical care can take more than 2 hours a day and leaves grease on clothing and surroundings, so the PNDS makes the patient's preferences the decisive criterion in the choice of product [23]. In France, only the creams of the Dexeryl® generic group (glycerol 15%, white soft paraffin 8% and liquid paraffin 2%) and magistral preparations within the composition limits set by Social Security circular CIR-58/2008 are reimbursed; the other dermocosmetic emollients and keratolytics are not reimbursed and, applied to the whole integument, reach consumption of at least 1 kg per month [23]. As a first step, while awaiting a specialist appointment, prescribing a reimbursed emollient is justified [23]. Appendix 4 of the protocol gives examples of reimbursed magistral preparations, summarised in the table; the percentages are approximate w/w values calculated from the quantities indicated.

The PNDS adds to the bath additives starch glycerolate (a handful in the water) and 0.9% salt water, recommends rubbing thick scales with a sponge, glove or pumice stone and describes wraps after the therapeutic bath, most often with emollient and, in very hyperkeratotic areas, a keratolytic at moderate concentration because of the occlusion [23]. The FIMARAD network provides educational videos on palmoplantar debridement and wraps [23].

7.5. Systemic retinoids

Indication. Systemic treatment is considered when topical agents are insufficient or to give a break from topical agents (level 2, grade D); ciclosporin has been tried but is not recommended [24]. Moderate to severe ARCI frequently requires an oral retinoid, which reduces hyperkeratosis and scaling and is less effective on erythroderma [2]. The PeDRA consensus recommends that adults and children with moderate to severe disease and significant functional or psychological impact may undergo a benefit-risk assessment (III, C), and records improvement with retinoids in selected forms, including CIE of selected genotypes, HI and LI (II, B), with no data or no improvement in IPS, and possible worsening in disorders with fragility, such as Netherton syndrome (II, B) [104]. Genotyping did not improve the prediction of response [104]. Acitretin also improves hypohidrosis, hair regrowth, ectropion and eclabium and hearing, and reduces daily care time, being especially useful for the thick scale of LI and HI [19, 24]. Even on a systemic retinoid, most patients still need intensive topical treatment, and the skin returns to its previous state shortly after discontinuation [19, 104]. The 2025 classification considers a systemic retinoid the treatment of choice in several nEDD, especially TGM1- and ABCA12-nEDD, including in the neonatal period [3]. The 2019 European guideline differentiates by form: in ichthyoses with prominent erythroderma, no keratolytics and oral retinoids only with caution and at low dose, alitretinoin possibly reducing erythema; in ichthyoses with prominent, thick scales, keratolytics and oral retinoids [102].

Acitretin. Acitretin, a synthetic aromatic derivative of retinoic acid and the main active metabolite of etretinate, is presented as 10 mg and 25 mg capsules, taken once a day with a meal or with milk, because fat increases absorption (bioavailability ≈60%, ranging from 36–95%) [25, 26]. It is the retinoid of choice of the European guidelines (level 2, grade D) and of the French protocol, and the 2017 German guideline described it as the only drug approved for the systemic treatment of the ichthyoses [17, 19, 24]. The 2019 European guideline restricts prescription to dermatologists experienced with the drug (level 2, grade D), warns that rapid escalation increases adverse effects and refusal of treatment, and records efficacy also in severe X-linked ichthyosis; in epidermolytic ichthyosis, results are better with KRT10 variants than with KRT1 variants, which may worsen on a retinoid [24]. In Japan, etretinate is the only approved oral retinoid [131]. The table compares the doses. Retinoids act mainly as ligands of nuclear transcription factors that control gene expression; they are lipophilic and turn over slowly in the body, so a single daily dose, or even dosing on alternate days, is sufficient, the clinical effect persists for days to weeks after discontinuation and complete elimination may take months [24]. Isotretinoin is eliminated faster and does not cross-react with the aromatic retinoids (acitretin and etretinate) in the rare cases of previous allergy to these [24].

The 2023 North American clinical guide proposes doses outside this European range: in severe LI, often at least 1 mg/kg/day; in epidermolytic ichthyosis, very low doses, such as 0.25 mg/kg/day, because higher doses worsen erosions; and in HI, 1 mg/kg/day early [124]. The maximum approved dose of acitretin remains 75 mg/day [25].

To give capsules to children, the PeDRA consensus suggests piercing the capsule and adding the contents to food, or softening it for 2–3 minutes in warm water or milk and adding it to ≈30 mL of breast milk or formula in infants, with fatty food, protecting it from light and using it immediately after removal from the packaging [104]. The 2024 European guideline recommends opening the capsules away from light and using a feeding bottle protected with aluminium foil [25].

Isotretinoin and alitretinoin. Isotretinoin is effective in LI and epidermolytic ichthyosis in an open study and in case reports, including HI, but requires high doses and has a safety profile considered less favourable (intracranial hypertension, myalgia, stiffness, skeletal toxicity) [24]. The doses indicated are 0.5–1 mg/kg/day in children and adults (PeDRA consensus, 10, 20, 30 and 40 mg capsules containing soya) or 0.25–0.3 mg/kg/day initially with titration up to 0.5–1 mg/kg/day (French protocol); the first escalation studies used 1–7 mg/kg/day, with limiting skin toxicity and mean maintenance doses of 1.8–2.1 mg/kg/day, and few patients currently receive more than 1 mg/kg/day [17, 104]. Alitretinoin reduced erythema in a small series and is effective in forms with fine scale and erythema, at 10 mg/day in children and 10–30 mg/day in adults with thyroid monitoring (it can cause hypothyroidism, headache and benign intracranial hypertension) [17, 24]. Both are alternatives when there are plans for pregnancy in the short term, because of faster elimination (prohibited in pregnancy and for up to 1 month afterwards), or with hypersensitivity to aromatic retinoids, and their use in ichthyosis is off-label [17, 24]. Etretinate (Tigason®) is no longer available in Europe [17, 24]. Retinoic acid metabolism blocking agents were effective in studies but were not marketed [24].

Divergence on the choice in those with reproductive potential. The PeDRA consensus recommends isotretinoin as first line in patients with reproductive potential (I, A) and switching from acitretin to isotretinoin before puberty if there is a risk of pregnancy (III, C) [104]. The European guidelines prefer acitretin for long-term therapy and reserve isotretinoin or alitretinoin for the woman considering a future pregnancy (level 2, grade D) [24]. The PeDRA consensus also observes that acitretin causes more palmoplantar peeling and more persistent alopecia and isotretinoin more facial peeling [104]. In the syndromic ichthyoses, the European guideline allows oral retinoids with closer monitoring, with particular caution in forms with liver or biliary disease (Chanarin-Dorfman, NISCH) and in forms with skeletal abnormalities (Conradi-Hünermann-Happle) [24]. In IPS there are no published reports; according to the experience of the guideline authors, acitretin may improve dryness and scaling, but not intense pruritus [24]. In Netherton syndrome oral retinoids are generally not recommended, because they worsen the skin, and a single report described benefit with acitretin at 5 mg/day [24, 102].

Adverse effects and management. Teratogenicity is the main adverse effect [24]. Mucocutaneous effects (cheilitis, dryness and peeling, fragility, fissures of the finger pulps, pruritus, photosensitivity, ocular, oral and nasal dryness, epistaxis) are common, dose-dependent and reversible; telogen effluvium is common and curly hair may be permanent; nail fragility and periungual granulation occur with prolonged use [25, 98]. Elevation of liver enzymes is common and cholestatic hepatitis and cirrhosis are rare: in the US trials, 2 of 525 patients had jaundice attributed to acitretin, 2 of 1289 in the European trials had biopsy-proven toxic hepatitis, elevation of AST, ALT, GGT or LDH occurred in about 1 in 3 and discontinuation because of liver tests in 3.8%; in a liver biopsy study, 58% were unchanged, 25% improved and 17% worsened [25, 27]. Elevation of triglycerides and cholesterol is common, and triglycerides above 800 mg/dL have been associated with fatal fulminant pancreatitis [25, 27]. Benign intracranial hypertension is rare and contraindicates combination with tetracyclines; peripheral sensory neuropathy and myalgia with stiffness are rare [25]. Bone toxicity depends on dose and duration (I, A) — spinal and extraspinal hyperostosis, tendon and ligament calcifications, osteoporosis or osteopenia — is difficult to distinguish from age-related changes in adults and does not preclude prolonged use if the benefit is clear (III, C) [24, 104]. The 2019 European guideline associates higher skeletal risk with high cumulative dose, previous treatment with etretinate (longer half-life and prolonged bone exposure) and advanced age; it considers the risk of osteoporosis controversial, described after prolonged etretinate but not found in a short prospective study with acitretin or in a retrospective study of 23 patients followed over a long period, and records that growth retardation has not been described on retinoids [24]. With isotretinoin, unlike acitretin, skeletal toxicity has been described, and there was possible worsening of corneal neovascularisation in KID syndrome [24]. In children, premature epiphyseal closure has been described with etretinate at doses of up to 2.5 mg/kg/day and is uncommon with doses above 1 mg/kg/day for 4–6 years; a 3-year study with 0.14 mg/kg/day did not define a safe threshold, and severely affected children with weight faltering grew better after starting the retinoid [24, 104]. The US label records ossification of ligaments and tendons, hyperostoses, reduced bone mineral density and premature epiphyseal closure with other retinoids, without established causality for acitretin [27]. Osteoporosis may reflect the vitamin D deficiency inherent to ichthyosis; limiting dietary vitamin A and supplementing vitamin D is recommended [24, 25, 104]. Systemic retinoids can cause retinal dysfunction, night blindness and dry eye, worsening eye disease (I, A), and about 13.8% of adolescents with acne treated with isotretinoin have ocular effects [104]. Psychiatric symptoms should be monitored in all patients (I, A), with co-management with mental health services if there is a history of depression or anxiety (II, B) [104]. Persistent hyperlipidaemia can be controlled with a lipid-lowering agent while continuing the retinoid (II, C) [104].

Monitoring. The table brings together the laboratory and imaging schedule; the intervals are repeated in the surveillance table in section 11.

The adverse effects table of the 2019 guideline adds contact lens intolerance, photophobia, disturbances of night vision and colour perception, a fall in HDL cholesterol and myalgia, with the corresponding precautions — routine artificial tears, avoidance of contact lenses, a low-fat diet, avoidance of alcohol abuse and intense physical exercise — and measurement of creatine kinase once during follow-up [24]. The 2023 North American guide proposes a less frequent laboratory schedule, with transaminases, triglycerides and cholesterol at baseline, at the maximum dose and then twice a year, in addition to growth assessment in children [124].

Contraindications. Pregnancy or attempting to conceive; women with reproductive potential without a pregnancy prevention programme or without adherence to contraception; alcohol consumption in women of childbearing potential during treatment and for 2 months afterwards; breastfeeding; severe hepatic or renal impairment; hypervitaminosis A; chronic hyperlipidaemia; combination with tetracyclines, methotrexate, vitamin A or other retinoids; hypersensitivity; and glucose-galactose malabsorption (contraindication in the British SmPC, precaution in the 2019 European guideline) [24–27].

Pregnancy prevention. Acitretin forms etretinate in the presence of alcohol (half-life ≈120 days, elimination of more than 98% in 2–3 years), which underpins the requirement to avoid pregnancy for 3 years after discontinuation [26, 104]. Appendix S6 of Part 1 of the European guideline records that, since acitretin was marketed, a single case of human teratogenicity attributed to this drug has been published, but that acitretin, especially in the presence of ethanol, is converted to etretinate, with a much longer half-life, associated with several cases of retinoid embryopathy, including conceptions occurring 4 months and 1 year after discontinuation of maternal etretinate; this is the basis for the requirement not to become pregnant or breastfeed for at least 3 years after stopping treatment [24]. The British SmPC requires strict contraception from 4 weeks before, during and up to 3 years after treatment, with pregnancy tests before, ideally monthly during treatment and at 1–3-month intervals in the following 3 years, prescription ideally limited to 30 days and testing, prescription and dispensing on the same day [26]. The 2024 European update requires contraception and monthly pregnancy testing from one month before initiation, during treatment and for 36 months after discontinuation, strict alcohol abstinence during treatment and for at least 2 months afterwards, and prohibits blood donation during treatment and for the following 3 years [25]. The programme detailed in the 2019 supplement adds education and written informed consent; two negative laboratory pregnancy tests before starting, the second no more than 3 days old at the date of the first dose, with initiation on the 2nd or 3rd day of the next menstrual period; monthly visits with testing at 28-day intervals and a negative test no more than 3 days old before each renewal; tests every 1–3 months for at least 3 years after the last dose; no breastfeeding during treatment and for the following 3 years; and a prohibition on sharing the medicine [24]. In the USA, the P.P.E.T. programme (Pregnancy Prevention is Essential with Treatment) requires two negative pregnancy tests with a sensitivity of ≥25 mIU/mL before the first prescription, monthly testing and a maximum one-month supply, prohibits alcohol in women with reproductive potential during treatment and for 2 months afterwards and prohibits blood donation by men and women during treatment and for at least 3 years afterwards [27]. The malformations described include meningomyelocele, meningoencephalocele, multiple synostoses, facial dysmorphism, syndactyly, absent terminal phalanges, limb malformations, low-set ears, and cardiovascular, skull and cervical vertebral malformations [27]. Exposure through semen is considered insufficient for teratogenicity [26, 104]. The PeDRA consensus recommends highly effective contraception (intrauterine device, progestogen implant) in sexually active adolescents (I, A), two forms of contraception, one of them highly effective, with any systemic retinoid (I, A), and planning at a defined age (for example, 16 years) or before the onset of sexual activity [104]. In the USA, isotretinoin requires registration of the patient and prescriber in the iPLEDGE REMS (Risk Evaluation and Mitigation Strategy), in force since 2006, with consent, monthly visits, a maximum 30-day supply, two forms of contraception, monthly testing and a 7-day collection window; the programme has no exceptions for prolonged use in ichthyosis and imposes a significant burden (III, C) [2, 104].

7.6. Comparative regulatory status

Acitretin does not have a centralised authorisation from the European Medicines Agency; the SmPC authorised by INFARMED and the situation in Brazil (ANVISA) are not included in the sources consulted [26].

7.7. Management of complications

Eye. The aim is normal visual development and integrity of the ocular surface. Regular ophthalmological examination includes age-appropriate visual assessment, slit-lamp examination (or a portable alternative) and cycloplegic refraction, at a frequency ranging from monthly to once or twice a year depending on severity (level 4, grade D) [17, 102]. Lagophthalmos requires long-term lubrication, with preservative-free lubricants (carmellose 0.5–1%, hyaluronic acid), white soft paraffin or vitamin A ointment at bedtime if the lagophthalmos is nocturnal and lipid-containing eye drops in meibomian dysfunction, from one or two instillations a day up to every half hour in extreme cases [17, 102]. In ectropion, the first line is frequent lubricants for all, eyelid emollients and vertical massage; keratolytics (urea, lactic acid, 5–10% N-acetylcysteine in 5% urea) and tazarotene (one adult with ARCI and five children and newborns with LI) have case-based evidence (level 3, grade B); oral retinoids are second line, combined with topical agents; and eyelid skin grafting is the third line when symptomatic corneal exposure or epiphora persist, ideally before keratinisation of the palpebral conjunctiva, with frequent rapid recurrence [17, 102]. Repeated injections of hyaluronic acid gel have been described in a series of three infants with severe LI or HI, reserved for experienced ophthalmologists [102]. The 2024 update modified a recommendation on the use of topical retinoids before ectropion surgery [98].

The PNDS also mentions, as alternatives with minimal evidence, a single report of apremilast to limit recurrence of ectropion after surgery, without defined assessment criteria, and repeated hyaluronic acid injections in some children with severe ichthyosis [23]. Eyelid plasty, the third line, relies mainly on autologous grafts, with oral mucosa as donor when there is no healthy skin [23].

Ear. Hearing should be assessed at least every 6 months in children under 6 years, and the patient referred to ENT if there is pruritus, pain, otorrhoea, a blocked sensation or hearing loss (level 4, grade D) [17, 102]. Ceruminolytics help (in a randomised trial, docusate sodium was more effective than triethanolamine polypeptide), as does oil applied regularly if the tympanic membrane is intact; mechanical cleaning by ENT (microsuction, debridement, curettage) is done one to four times a year; oral retinoids are not a primary treatment for obstruction; and otitis externa is treated after cleaning with antibiotic drops, for example ciprofloxacin, with or without a corticosteroid [17, 102]. The 2023 North American guide reports professional debridement every 3–4 months in many children with LI and narrow ear canals and regular hearing assessment of young children with significant scale accumulation [124].

According to the PNDS, ear, nose and throat complications affect about 80% of ichthyoses; hearing loss, usually bilateral and sometimes asymmetric, is conductive, due to accumulation of scales in the child's narrow canal and thickening of the superficial layer of the tympanic membrane, except in forms with sensorineural deafness (KID and KIDAR syndromes) [23]. In adults with otitis externa, disinfection with boric hydrogen peroxide can be used, and keeping water out of the ears is recommended as far as possible [23]. Regular cleaning by ENT avoids self-cleaning by the patient, which causes microtrauma and superinfection [23].

Pruritus and pain. Regular topical care and exclusion of infection come first; if pruritus persists, antihistamines, wet wrapping or oral retinoids can be tried, the latter of which may either improve or provoke pruritus [17, 102]. Antihistamines and antidepressants used in other pruritic dermatoses are often ineffective or of limited effect, and wet wrapping with emollients also acts by cooling [102, 131]. Pain should be assessed and, in the absence of specific guidelines, those for epidermolysis bullosa and of the World Health Organization are followed [102].

Infections. Regular examination and microbiological sampling when infection is suspected are the basis; daily bathing with antiseptics applies if the risk is high; topical antibiotic is used for limited areas and oral antibiotic for extensive areas or comorbidities (level 4, grade D) [102]. Almost 10% of paediatric strains are resistant to retapamulin, mupirocin or fusidic acid, so topical ozenoxacin or antiseptics are alternatives, with attention to systemic absorption [102]. Extensive culture-confirmed tinea is treated with a systemic antifungal [102]. Bacterial skin or systemic infections are treated promptly according to the antibiogram [2]. In patients with recurrent infections, a series of six patients with ALOX12B-related ARCI suggests targeted immunological assessment (immunoglobulins, total IgE, lymphocyte subsets, vaccine responses): four had very high IgE, one had low IgG and two had isolated abnormal vaccine responses, without criteria for primary immunodeficiency; monthly intravenous immunoglobulin reduced the frequency and severity of infections in two siblings, without improving the skin [129].

The PNDS describes frequent bacterial infections by Staphylococcus aureus, sometimes meticillin-resistant, and group A streptococcus, with greater susceptibility in ARCI, the keratinopathic ichthyoses, Netherton syndrome and KID syndrome [23]. ARCI and KID syndrome also appear prone to dermatophytoses and candidiasis; on already scaly and erythematous skin, dermatophytosis manifests mainly as worsening of the picture and of pruritus, and the same occurs with scabies, whose pathognomonic lesions are often absent [23]. The unpleasant odour of some ichthyoses suggests an altered skin flora, although there are no microbiome studies in ichthyosis [23]. Treatment does not differ from that of a patient without ichthyosis, with easier recourse to the systemic route in extensive forms; Table 4 of the protocol indicates topical or systemic antifungals according to extent, ivermectin for scabies and systemic antivirals for viral infections, and recalls the increased transcutaneous absorption of topical agents, especially in children and on the scalp [23].

Growth, nutrition and vitamin D. After the neonatal period, height and weight are recorded on centile charts at a frequency inversely proportional to age, and growth or pubertal delay leads to referral to paediatric endocrinology and nutrition; children and adults with severe erythroderma need more calories, fluids and protein [2, 102]. 25-hydroxyvitamin D should be measured annually, or every six months with risk factors or a severe form (level 2++, grade B), with a target of ≥30 ng/mL (75 nmol/L) in adults and 20 or 30 ng/mL (50 or 75 nmol/L) in children; below 10 ng/mL (25 nmol/L), PTH, calcium, phosphate and urinary calcium are measured [17, 102]. Supplementation follows the general recommendations — in France, 400–800 IU/day from 0 to 18 years, daily up to 2 years and then possibly every 3 or 6 months — with vigorous correction, parenteral if there is malabsorption [17, 102]. Short-term high doses improved the skin in 5 children with ARCI and vitamin D deficiency, without follow-up and with 1 case of hypercalcaemia; their cutaneous efficacy and safety are not established [17, 102]. As ichthyosis is chronic, the 2019 guideline advises considering maintenance supplementation and records that oral retinoids have been implicated in vitamin D deficiency, although the lack of baseline measurements does not allow a conclusion [102]. The guideline attributes growth failure to increased epidermal turnover, chronic inflammation and cutaneous protein loss, with greatly increased resting energy expenditure in the inflammatory forms, and records successful growth hormone treatment in Netherton syndrome [102]. In a longitudinal study from the North American national ichthyosis registry, with 135 children and young people from 129 families with a genetic diagnosis, mean weight and height were below the 50th centile in the first 24 months (31.4th and 39.0th centiles) and did not differ from the population median thereafter; the early deficits associated with ABCA12 and KRT10 attenuated over time, whereas those with SPINK5 persisted between 25 and 48 months, and the authors propose growth surveillance as standard of care, especially in high-risk genotypes [133]. The 2023 North American guide recommends ensuring adequate intake of water, calories, protein and iron [124].

The 2021 French PNDS defines 25-hydroxyvitamin D deficiency as below 20 ng/mL (50 nmol/L) and severe deficiency as below 10 ng/mL (25 nmol/L), and recommends maintaining values above 30 ng/mL (75 nmol/L) to prevent demineralisation [23]. These thresholds differ from the classification of the 2016 global consensus, which considers sufficiency to be above 50 nmol/L, insufficiency between 30 and 50 nmol/L and deficiency below 30 nmol/L [125]. Severe deficiency may be associated with secondary hyperparathyroidism and suppressed urinary calcium (spot calcium/creatinine ratio below 0.10 mmol/mmol); it is treated with repeated doses of vitamin D until the target is reached, by the intramuscular or intravenous route if there is malabsorption or insufficient intake, and with dietary calcium until urinary calcium becomes positive and PTH normalises, also preventing phosphate deficiency in severe forms [23]. Risk factors are ARCI and the keratinopathic forms, severity, dark phototypes and winter and spring; the effect of oral retinoids is controversial [23]. 25-hydroxyvitamin D is preferably always measured in the same laboratory and rechecked after supplementation; DEXA densitometry, with paediatric norms, is performed if there is demineralisation and at least once during the course, and low values with pain justify radiological study and, if osteoporosis due to remodelling is suspected, bone turnover markers [23]. Children from migrant populations, in whom severe rickets is reappearing, should receive 800 IU per day with adjustment by biological monitoring, and the French Society of Paediatrics has warned of the risk of intoxication when vitamin D is given as a food supplement rather than as a medicine [23]. Some forms have an enteropathy with mild fat malabsorption without pancreatic involvement, and in ARC syndrome cholestasis and tubulopathy favour malabsorption; in adolescence, pubertal delay is sought [23].

Allergies and other comorbidities. In a North American cross-sectional survey of 115 patients and parents of children with physician-confirmed congenital ichthyosis, 68.2% reported at least one physician-diagnosed atopic disease (64.3% of children and 72.5% of adults), with rates of allergic rhinitis, food allergy and allergic asthma higher than those of the population of the same age; the highest rates occurred in the erythrodermic forms (Netherton syndrome, ichthyosis with confetti and HI) and in X-linked ichthyosis, and the authors recommend asking about allergies in routine care [109]. The English hospital records, described in section 3.4, also show more asthma, inflammatory arthropathies and atrial fibrillation in the rare ichthyoses, which justifies attention to joint and cardiac symptoms in adults [108]. Radiographs and densitometry are mandatory if there are skeletal symptoms [102].

Heat. Avoiding extreme temperatures and being outdoors during the hottest hours, appropriate clothing, frequent fluid intake, water sprays, baths, air conditioning, fans and cooling vests are recommended [2, 102]. The 2019 European guideline allows oral retinoids in severe thermal dysregulation (level 4, grade D), whereas the French protocol considers that they have no proven benefit for heat; acitretin may improve sweating [17, 19, 102].

Cold is often poorly tolerated in the inflammatory forms and worsens fissures of the hands and feet [23]. Heat intolerance is partly due to occlusion of the sweat ducts by hyperkeratosis, but also occurs in mild to moderate forms, which points to other mechanisms [23].

Hair and nails. Aggravating factors are sought (iron deficiency, thyroid dysfunction, drugs); a wig is an option in marked alopecia; there is no treatment for the nails [17, 102].

Physical limitations. Physiotherapy, night splints, assistive devices (wide-handled cutlery and pens, jar openers), topical agents and oral retinoids treat contractures; prevention of contractures is imperative in severe forms, and the German guideline recommends rehabilitation in centres with balneotherapy [2, 19, 102]. In older children and adults, physiotherapy treats contractures, arthritis and pain [2].

The PNDS adds that changes in the finger pulps may hinder or prevent the use of touch screens, that assistive devices include adapted pens and bottle openers, and that severe forms require coordination of nursing, physiotherapy, podiatry and a pain clinic [23].

Skin tumours. Skin cancers are treated by the usual methods, and annual surveillance is directed mainly at adults with a previous non-melanoma skin cancer [2].

Psychosocial support and education. Quality of life and disease burden are assessed with specific questionnaires — in 2024, the IQoL-32 from 15 years of age as first choice and the DLQI, the CDLQI or the cartoon CDLQI as second choice — and anxiety and depression with the PHQ-9, GAD-7 and PROMIS in adults and the SCARED and paediatric PROMIS from 8 years of age (caregiver version validated from 5 years) [25]. Psychological support is recommended early and throughout life, with family therapy if there is guilt, attention to siblings, a social worker for reimbursement and recognition of disability, "ichthyosis schools" and information about patient associations [19, 24]. Parents may experience grief for the "healthy child" and feelings of guilt, and benefit from social pedagogues, psychologists and contact with associations [19]. The 2019 guideline adds that support should be provided by a psychologist, with the participation of dermatologists, social workers and specialist nurses; that complications should be discussed frankly, not only in life-threatening situations at birth but also, at puberty and afterwards, in emotional and sexual life; that group interviews of patients or families are useful; that the physician and social worker can document ichthyosis as a disability and support vocational guidance; and that structured educational programmes exist in a minority of European countries, with very few data on their impact [24]. Bullying is a frequent concern of families and should be explored in the consultation, because of its association with stigma, poor peer relationships and caregiver distress [106]. In France, the estimated cost is ≈€400 per year per patient, mainly for emollients [17].

Appendix 6 of the PNDS reproduces the questionnaires and scoring rules, summarised in the table [23].

Psychological support should be offered as early as possible, to the child, the adult and the family, by a psychologist in individual or group interviews, and the PNDS advises that the genetic counsellor or geneticist work in partnership with the psychologist [23]. Few centres besides the reference centres have therapeutic education programmes, and distance is an obstacle; the e-ETPichtyose trial (NCT03641261), from Toulouse University Hospital, evaluated therapeutic education sessions delivered through an internet application and ended in February 2023 with 42 participants, with no results deposited in the registry at the date of consultation (November 2026) [23]. The diagnosis is announced as soon as it is established, preferably in a multidisciplinary consultation with a psychologist, and explanation of the variants is the responsibility of the prescriber, complemented by the geneticist or genetic counsellor [23].

Vocational guidance. Finding employment is more difficult and some occupations are poorly suited or inaccessible: the food sector, because of the scales; jobs involving contact with the public; outdoor work, because of exposure to heat and cold; and jobs involving contact with irritant or allergenic products, such as hairdressing [23]. Guidance should be discussed early with the patient, and in France recognition of disabled worker status (RQTH) gives access to adapted working hours and workstations, employment quotas and support for training (section 9.5) [23]. Hidden costs include wear on clothing and washing machines, which many families use once or twice a day or dedicate to the patient, and the purchase of water softener and non-reimbursed products (bath oils, lip balms on retinoids, shampoos, water mists in summer) [23].

Telemedicine. The 2024 update added a section on telemedicine, whose text was not read [25]. FIRST's Tele-Ichthyosis programme, which since 2009 has put clinicians of any specialty in contact with volunteer experts, analysed 88 cases over a decade: 66% were confirmed ichthyoses, questions concerned diagnosis (47%) or treatment (72%), and most clinicians who submitted cases considered the service easy to use (66.6%) and the response timely (61.1%), clear (66.6%) and useful (61.1%) [135]. In Europe, the European Commission's Clinical Patient Management System (CPMS) supports case discussion between ERN centres, and the networks recommend teleconsultation and telemedicine to maintain access to expertise when physical access is not possible [136]. In the international consensus on epidermolysis bullosa during the COVID-19 pandemic, a comparable genodermatosis, photographs sent by families and teledermatology became the first consultation for less severe patients, with surveillance tests carried out in laboratories close to home and assessment at the centre when the images were insufficient [137].

Vaccination. The 2024 update created a section on vaccination, whose content was not read and which none of the citing articles consulted summarises [98]. The sources consulted do not describe vaccine contraindications specific to ichthyosis or interactions between oral retinoids and vaccines. The question arises with the biologics and JAK inhibitors used off-label: by extrapolation from the recommendations for immune-mediated diseases treated with these drugs, live attenuated vaccines (measles-mumps-rubella, yellow fever, oral typhoid, oral polio) are contraindicated during treatment and should be given sufficiently in advance of initiation or after discontinuation; inactivated vaccines are generally safe, with a response similar to or greater than that of controls in most studies; the schedule should be reviewed and completed before starting the drug; and herpes zoster vaccination is recommended before any JAK inhibitor [138]. In the series of ALOX12B-related ARCI, two of six fully vaccinated patients had absent serological responses to some protein vaccines, and the authors recommend immunological assessment in selected cases, especially with recurrent infections [129]. In February 2021, the ERN coordinators issued joint COVID-19 vaccination recommendations for people with rare diseases [136].

7.8. Agents and situations to avoid

The following should be avoided: topical salicylic acid in children, because of absorption and toxicity (strictly contraindicated before 2 years and, in the newborn, an absolute contraindication); urea, lactic acid and silver sulfadiazine in the newborn; topical tacrolimus and vitamin D without precautions; iodine-based antiseptics; skin irritants; overheating; and invasive procedures in the infant with complications of prematurity [2, 25, 102]. With acitretin, alcohol (in women with reproductive potential, during treatment and for 2 months afterwards), tetracyclines, methotrexate, vitamin A and other retinoids, as well as hepatotoxic agents, should be avoided [25, 27].

7.9. Pregnancy and lactation

In women with ARCI there are no disease-specific risks in pregnancy, but overheating should be avoided [2]. Systemic retinoids are teratogenic and contraindicated; acitretin is also contraindicated in breastfeeding, because it is lipophilic and passes into milk [2, 26, 27]. Topical retinoids should not be used in pregnancy, and tazarotene is category X [24, 104]. Isotretinoin and acitretin may have a role in preventing skin cancers, which weighs on the decision to interrupt or resume treatment [2]. The MotherToBaby service is an information resource on exposures in pregnancy [2].

7.10. Perioperative period

The sources consulted do not include specific recommendations on anaesthesia in ARCI. The applicable measures derive from the general recommendations: avoid unnecessary invasive procedures and adhesives on fragile skin, maintain temperature and hydration, protect the cornea in the patient with lagophthalmos and consider percutaneous absorption of antiseptics and topical agents applied over a large surface area [2, 102]. Ectropion surgery with grafting is the most frequent elective procedure and should precede keratinisation of the palpebral conjunctiva [102].

7.11. Transition to adulthood

Transition involves three points: the choice of retinoid before puberty in girls at risk of pregnancy, with a switch from acitretin to isotretinoin according to the PeDRA consensus; planning of contraception at a defined age; and baseline bone study (radiographs and densitometry) on completion of growth, between 16 and 18 years, if therapy is prolonged [25, 104]. Dermatological follow-up becomes coordinated by the adult dermatologist, at least annually, with reassessment of the risk of skin tumours [2, 17]. Renewed genetic counselling, focused on family planning, should be offered to young adults [2].

7.12. Clinical trials

These trials do not allow indirect comparisons with each other, because they differ in population (isolated LI, ARCI with X-linked ichthyosis, mixed ichthyoses), age, outcome scale (IGA, VIIS, IASI, ISS) and timing of assessment. The vehicle response rate was high — 44.9% in ASCEND and 4/12 in CONTROL — which shows the weight of baseline topical care and of the expectation effect and means that any relative reduction must be read in the light of the absolute rate in the control group; the sponsor itself described the vehicle response as unexpectedly high [141, 144, 145]. ASCEND is a negative phase 3 trial: the sponsor stated that the results do not support an application to the FDA (Food and Drug Administration), and as of 10 October 2026 it had not been published as an article, only in the registry, in the press release and in a pharmacokinetic sub-study [144, 145, 155]. Trifarotene was terminated for futility, imsidolimab without analysis, and the liarozole trial lost power through premature termination [139, 146, 150]. The phase 1 data for KB105 come from a congress abstract with 4 patients and from a single phase 2 patient [153, 154].

7.13. Biological drugs and targeted therapies

The rationale for biologics rests on the IL-17-dominated immune profile common to the main orphan ichthyoses [73]. In case reports, anti-IL-17 and anti-IL-12/23 antibodies (secukinumab, ustekinumab) improved the inflammatory components (erythema, arthropathy) with a smaller effect on hyperkeratosis and scaling; in one patient with ARCI due to homozygous NIPAL4, ustekinumab markedly improved the skin and the associated arthropathy [2, 39, 156, 157]. The controlled trial of secukinumab was negative in adult ichthyoses as a whole [147]. The 2025 classification summarises the experience: biologics (anti-IL-12/23, anti-IL-17A, anti-IL-4/IL-13 receptor) have limited to no value in TGM1-nEDD and KRT10-related epidermolytic ichthyosis and appear promising in the more erythrodermic forms with altered ceramide synthesis or transport and in several sEDD [3]. In 2026 two paediatric cases of genetically confirmed HI were described with improvement in pruritus, erythema, scaling and well-being on dupilumab, used off-label and with case-report level evidence [158]. In a 2025 Italian series, three patients with ichthyosis (an 11-year-old with NIPAL4, a 7-year-old with ABCA12 and an adult without a genetic diagnosis) were treated with dupilumab at atopic dermatitis doses; in the two who completed the questionnaires, the DLQI improved by 40–90% and the numerical pain and pruritus scales fell by 16.7–87.5% and 28.6–80% at 6 months, without significant adverse effects over 12 months [159]. A patient with CYP4F22-related CIE and atopic dermatitis improved in erythema, pruritus and frequency of infections with dupilumab combined with guselkumab [124]. A Russian phase 4 study comparing secukinumab, ustekinumab and dupilumab with symptomatic treatment in children aged 6 months to 18 years has had "unknown" status in the registry since 2021 [160]. No biologic has an approved indication for ARCI.

The largest published series is an international retrospective observational study from 22 specialised centres in 9 countries, with ERN-Skin members, which included consecutive patients with congenital ichthyosis (excluding ichthyosis vulgaris and X-linked ichthyosis) seen between January 2018 and August 2023 and treated with a biologic for at least 3 months [28]. The 98 patients had a mean age of 19.7 years (0.6–69), 63% lived in Europe and 33% in the USA, 30% had Netherton syndrome and 21.4% CIE, and 84.7% had severe or very severe disease; the first biologic was, in about one third of cases each, an IL-17 inhibitor, an IL-12/IL-23 inhibitor or an IL-4 receptor inhibitor, with a mean duration of 22 months [28]. Response was measured by the change in Investigator Global Assessment (IGA), assigned retrospectively by two investigators: 45 patients (45.9%) responded and 18 (18%) had a good response (improvement of at least 2 grades), all with erythrodermic forms — 11 with Netherton syndrome, 4 with CIE (2 due to NIPAL4, 1 to CYP4F22 and 1 to ALOX12B), 1 with HI and 2 with SAM syndrome (severe dermatitis, multiple allergies and metabolic wasting) — and no patient with LI or epidermolytic ichthyosis had a good response [28]. In CIE, 75% of those treated with the IL-4 receptor inhibitor responded (95% confidence interval 28.9–96%), 57.1% with the IL-12/IL-23 inhibitor and 44.4% with the IL-17 inhibitor; in Netherton syndrome, 85.7%, 66.7% and 50%, respectively. Age did not influence response. There were adverse effects in 16 patients (16.3%), mainly headache, and 2 discontinuations because of adverse effects. In the parallel literature review, the 49 published patients had 85.7% responders with a mean treatment duration of 11.5 months, a difference the authors attribute to publication bias. The retrospective design, confounding by indication, heterogeneity and the absence of assessments at fixed time points prevented statistical comparisons [28]. A 2024 systematic review, with 104 studies and 166 patients with inherited disorders of keratinisation published up to July 2023, included 27 patients with ARCI (16.3%), treated mainly with secukinumab (19, including those in the controlled trial), ustekinumab (5) and dupilumab (3); across the 207 biologic administrations in all diseases, there was complete remission in 4.8%, partial remission in 62.3% and no or limited response in 32.4%, with safety information in fewer than half, and the authors consider the evidence low-level and heterogeneous [161].

A 2026 single-centre retrospective Italian series included 8 adults with severe congenital ichthyosis (7 with LI and 1 with Chanarin-Dorfman syndrome) treated with secukinumab 300 mg subcutaneously every 4 weeks after induction, for at least 6 months, with a median follow-up of 39.5 months (6–56). At the last visit, the proportion of patients with some improvement was 8/8 for erythema, 7/8 for scaling of the trunk and limbs, 7/7 for the scalp, 6/8 for palmoplantar hyperkeratosis and 6/7 for pruritus, with no adverse effects recorded; the absence of a control group, concomitant treatments (acitretin in 3 patients, phototherapy in 1) and the unavailability of the genetic reports limit interpretation [162]. This result diverges from the international series, in which no patient with LI had a good response; the response criteria (any improvement versus improvement of at least 2 IGA grades) and patient selection differ between the two studies [28, 162].

The text of the section of the 2024 European update on biologics and small molecules was not consulted directly. According to a review of Netherton syndrome published in 2025, that update recommends biologics mainly in the severe erythrodermic forms of congenital ichthyosis [25, 29]. In a 2025 commentary, the first author of the guidelines describes them as maintaining emollients and oral retinoids as the reference treatment and considers the results of biologics disappointing, with a good response limited to a subset of erythrodermic forms and absent in epidermolytic ichthyosis [123]. For Netherton syndrome, part 2 of the update, as summarised in the same review, limits topical calcineurin inhibitors to short, localised use in flares, does not recommend phototherapy, even short-term, because of the risk of skin cancer, and does not routinely recommend systemic immunoglobulins, because of limited evidence and lack of long-term data [29, 98]. In 2019, the European guideline did not recommend biologics in Netherton syndrome (level 3, grade D), based on the few data on infliximab and the risk of infections and non-melanoma skin cancer associated with TNF-α inhibitors, nor PUVA nor ciclosporin; it allowed weak to moderate potency topical corticosteroids (classes I–II) for a limited period, topical calcineurin inhibitors only in short, localised flares, with blood level measurement if used outside these conditions, and considered the evidence for long-term systemic immunoglobulins insufficient [102]. The position on biologics reversed between 2019 and the update, as series with IL-17, IL-12/23 and IL-4 receptor inhibitors accumulated [28, 29, 102]. The sources consulted do not describe the update's recommendations on JAK inhibitors; the international series mentions a report of transient efficacy of upadacitinib (a selective JAK1 inhibitor) in an adult with Netherton syndrome, with relapse at 3 months [28]. The rationale for JAK inhibitors comes mainly from mechanistic data: in a three-dimensional HI skin model, the STAT1–inducible nitric oxide synthase (NOS2) pathway was activated, and tofacitinib, a JAK1/3 inhibitor, restored epidermal differentiation and the lipid barrier in vitro [163]; in a Vietnamese cohort of 36 patients with seven subtypes of congenital ichthyosis, skin dysbiosis was associated with increased production of inflammatory cytokines and activation of the Th17 and JAK/STAT pathways in peripheral blood mononuclear cells [164]. Clinically, there are isolated reports. A 27-year-old man with ARCI due to a homozygous TGM1 missense variant, whose lesional skin showed aberrant JAK/STAT signalling, received oral tofacitinib 11 mg per day for 26 weeks, with rapid improvement in erythema and fissures in the first month, a sustained fall in pruritus (5-D scale) and DLQI and normalisation of TG1 distribution without recovery of enzyme activity; transepidermal water loss fell in the first 10 weeks and then rose [165]. A report of NIPAL4-related ARCI treated with upadacitinib has also been published, whose text was not obtained [166]. In Netherton syndrome, a 2025 review brings together one case with tofacitinib, one with baricitinib, four with upadacitinib, with variable response, and two with abrocitinib, with good response, and mentions an ongoing randomised placebo-controlled trial of spesolimab (anti-IL-36 receptor) (NCT05856526) [167]. No JAK inhibitor has an indication in the ichthyoses, and the clinical evidence is limited to case reports.

7.14. Gene therapy, gene editing and enzyme replacement

Transfer of wild-type TGM1 by a retroviral vector corrected keratinocytes from patients with LI in vitro in 1996 [50]. KB105 is a topical gel with a non-replicating, non-integrating vector derived from herpes simplex virus type 1 (HSV-1), carrying two copies of human TGM1, applied to exfoliated skin; it has orphan drug designation from the FDA and EMA and Fast Track and Rare Pediatric Disease designations from the FDA [154]. Phase 1/2 began in September 2019; the sponsor estimated 2000–6000 patients with TGM1-ARCI in the USA and Europe and planned to resume phase 2 recruitment in 2024; the registry entry for the controlled phase 2 has had "unknown" status since February 2023, and the annual report of February 2026 no longer mentions KB105 in the description of the pipeline [152, 154, 168]. Absence from the report does not amount to a formally announced discontinuation. GeneReviews refers to KB105 simultaneously as a phase II study and as a preclinical trial, an internal contradiction that the registries resolve in favour of phase 1/2 and phase 2 clinical studies [2, 151]. The rapid turnover of TG1 limited the duration of effect in the treated patient [154].

In the preclinical field, enzyme replacement with thermosensitive nanogels containing transglutaminase 1 attenuated the phenotype in full-thickness skin equivalents from patients with TGM1-related ARCI, with cytotoxicity limitations [2, 169]. A human cellular model of LI obtained by CRISPR-Cas9 ablation of TGM1 in clonogenic keratinocytes was corrected ex vivo with a self-inactivating γ-retroviral vector carrying TGM1 under its own promoter, with integration into holoclones (epidermal stem cells) [170]. Delivery of TGM1 by adeno-associated virus has been evaluated in rat and pig skin [171]. Adenine base editors corrected the TGM1 nonsense variant c.607C>T in cells and in human embryos generated in vitro by intracytoplasmic sperm injection, restoring the wild-type sequence in 2/7 and 5/8 embryos, without off-target editing in DNA but with many single-nucleotide variations in RNA; this is a laboratory demonstration that requires improvements in safety and efficacy before any clinical application [84]. In February 2026, a cytosine base editor applied topically in lipid nanoparticles, after barrier modulation, corrected the TGM1 variant c.877-2A>G in situ in human skin models, with restoration of ≈30% of TG1 activity, a favourable off-target profile and no detected systemic distribution [80]. The 2025 classification also mentions preclinical correction with KB105 in keratinocytes and in vivo [3].

Enzyme and lipid replacement, repurposing of biologics, and gene replacement and editing are the four pathogenesis-based approaches in development; the registered trials for ARCI were few and without published results at the date of the last GeneReviews revision, which precludes conclusions about long-term efficacy and safety [2, 172]. Accumulation of free fatty acids or proximal metabolites and enzyme cytotoxicity are recognised limitations of enzyme replacement [2]. The 2024 European update added a section on therapeutic perspectives, whose text was not read [25]. The 2023 reviews group the pathogenesis-based approaches into enzyme or lipid replacement, immunomodulatory biologics, small-molecule inhibitors and gene therapy [124, 131]. TG1 replacement is under evaluation in LI; the topical combination of a statin and cholesterol (typically 2% lovastatin and 2% cholesterol) improved CHILD syndrome and the porokeratoses, whereas cholesterol alone did not correct the defect, and lipid replacement is being considered in forms of CIE with altered ceramide synthesis; retroviral systems for TGM1, non-viral systems for ABCA12 and gene correction of TGM1 are at the in vitro or in vivo stage [131]. In HI, topical application of kallikreins has been proposed, which reduced hyperkeratosis in mice [127]. A 2026 review proposes stratifying the choice of biologics by genotype, immunoendotype (Th17 predominance, with a Th2 or IL-36 contribution in some subtypes) and skin microbiome, which in EDD shows loss of commensals (Cutibacterium acnes, Malassezia) and enrichment in Staphylococcus and Corynebacterium, a model that still requires prospective validation [173]. In a 2025 commentary, the first author of the guidelines argues that future approaches should be targeted and based on the functional pathways affected, an aim that guided the EDD reclassification, which groups the diseases by protein function in order to link them to therapeutic targets and repurposable drugs [123].

7.15. Developments in the last twelve months

Between October 2025 and October 2026, the clinically relevant developments, classified by level of evidence, are as follows. In genetics, the description of GLTP as a new nEDD gene with generalised scaling, in five families, with an animal model and pharmacological correction in vitro of the cellular defects (descriptive human study plus preclinical work), and a second series of five patients that broadened the variant spectrum [16, 97]. In nomenclature, consolidation of the EDD classification, with its announcement in the Journal of the American Academy of Dermatology at the beginning of 2026 [63]. In topical therapy, publication of the ASCEND maximal-use sub-study, in which 34 patients with moderate to severe congenital ichthyosis applied 0.05% topical isotretinoin twice a day to 75–90% of the body surface area for 14 days, with systemic exposure to the drug and its metabolites less than 1% of that observed after a single oral dose of 80 mg of isotretinoin in healthy adults, local tolerability problems in most patients, mainly mild, and no systemic toxicity (single-arm open-label trial, pharmacokinetics) [155]; the development programme remains halted after the negative result of the phase 3 trial announced in August 2024 [145]. In biologics, two paediatric cases of HI treated off-label with dupilumab with symptomatic improvement (case reports) and an Italian retrospective series of secukinumab in 8 adults, mainly with LI, with improvement in erythema and pruritus and a smaller effect on palmoplantar hyperkeratosis (uncontrolled case series) [158, 162]. In preclinical research, in situ correction of the TGM1 variant c.877-2A>G by base editing in topical lipid nanoparticles in human skin models and evaluation of TGM1 delivery by adeno-associated virus in animal skin [80, 171]. In epidemiology and outcomes, the systematic review of HI case reports, with a mortality of 60.3% and a mean age at death of 47.19 days, subject to publication bias, and the report of survival of a newborn with HI in a hospital with limited resources [112, 130]. In comorbidities, the description of three cases of cutaneous T-cell lymphoma in NIPAL4-nEDD, read only through its metadata [111]; the English national hospital records study, with more asthma, inflammatory arthropathies and atrial fibrillation and earlier deaths in the rare ichthyoses (registry study) [108]; the North American survey with 68.2% physician-diagnosed atopic diseases (cross-sectional study) [109]; and the longitudinal growth study, with deficits limited to the first 24 months except in SPINK5 genotypes (registry cohort) [133]. A French observational study of the lymphocyte phenotype in NIPAL4-nEDD is under way, with ten patients planned and a start in April 2026 [174]. A phase 1/2 trial of erlotinib, an epidermal growth factor receptor inhibitor, is planned for 2027 in keratinopathies, outside the scope of ARCI [175]. In this period, there was no new regulatory authorisation for the treatment of the congenital ichthyoses in the sources consulted.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

Inheritance is autosomal recessive. The parents of a proband are presumed to be heterozygous and, when the molecular diagnosis is established, should be tested to confirm heterozygosity and allow a reliable risk estimate [2, 17]. For the siblings of a proband with both parents heterozygous, the risk is 25% of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier, at each conception, equal in both sexes [2, 15]. The offspring of a patient are obligate heterozygotes, unless the partner is affected or a carrier, and the siblings of the proband's parents have a 50% risk of being carriers [2]. The French protocol adds that, in the dominant forms, the risk is 50% (maximum in post-zygotic mosaicism) and, in X-linked recessive inheritance, a carrier mother has a 25% risk of an affected child, corresponding to 50% of boys [17]. Germline mosaicism is rare, but should be considered in unaffected parents of sporadic cases, especially in the dominant and X-linked forms [25].

When only one parent carries the variant found in the child, with maternity and paternity confirmed, the hypotheses are a de novo variant in the proband or a post-zygotic variant in a mosaic parent [2]. When the proband appears homozygous, a deletion of one or more exons not detected by sequencing and uniparental isodisomy of the chromosome carrying the variant should be excluded, because both alter the counselling given to the parents [2].

8.2. Cascade testing and carrier detection

Carrier detection requires prior identification of the familial variants [2]. Gene-targeted testing is offered to the partners of known carriers and of patients, especially if they are of the same geographical or ethnic origin, because of the existence of founder variants in people of Scandinavian, Norwegian, German, Galician, Spanish, Moroccan and Finnish ancestry [2, 49, 82]. The French protocol considers, on the contrary, that the risk of heterozygosity in the general population is extremely low and that systematic screening of the partner is not justified, except in consanguinity or in very anxious couples, by a multidisciplinary decision weighing feasibility, sensitivity and the risk of finding VUS; in France there is a legal obligation to inform relatives at risk [17]. Heterozygotes are asymptomatic and not at risk of disease, a central point in counselling [2]. In probands without a molecular diagnosis, DNA banking for future reanalysis should be considered [2].

8.3. Prenatal diagnosis and preimplantation genetic testing

The ideal time to assess risk and discuss prenatal or preimplantation testing is before pregnancy, and counselling should be offered to young adults who are affected, carriers or at risk [2]. The molecular diagnosis should be obtained as early as possible, because it defines the prognosis and answers questions about carrier status, family planning, predictive testing, prenatal diagnosis and preimplantation testing, and may guide future personalised treatments [25].

Prenatal diagnosis and preimplantation genetic testing are possible once the familial variants have been identified [2]. Samples are obtained by chorionic villus sampling from the 10th–12th week, according to the German guideline, or from 12 weeks of gestation, according to the French protocol, and by amniocentesis from the 14th or 15th week, with a miscarriage risk of less than 0.5% [17, 19]. Identification of ABCA12 allowed prenatal diagnosis of HI to be made by DNA, earlier and with lower risk than fetal skin biopsy, which has fallen into disuse [15, 53, 54, 91]. Non-invasive prenatal diagnosis on maternal blood, from 10 weeks, applies only under strict conditions and, in recessive diseases with compound heterozygosity, only allows exclusion of fetuses carrying only the maternal variant or neither [17]. Fetal ultrasound and magnetic resonance imaging provide late clues, without a definitive diagnosis: three- or four-dimensional ultrasound can identify fetuses with HI from the second trimester in families with a history, through the signs described in section 4 [2, 17, 114, 115]. Preimplantation testing is an option in selected cases, which in France requires criteria of severity and incurability and is performed in five centres [17, 19]. There are differences of perspective on the use of prenatal diagnosis and preimplantation testing, and the decision is personal [2]. The 2024 European update created a section dedicated to prenatal diagnosis and preimplantation testing, whose text was not read [25]. A 2024 review of 408 publications on 13 types of ichthyosis and four types of test concludes that biochemical tests are diagnostic only in trichothiodystrophy and require, except in X-linked ichthyosis, invasive sampling; that histology and cytology of fetal skin biopsy or amniocytes are inferior, because keratinisation is late and microscopy does not distinguish the types; that imaging is acceptable but operator-dependent, non-specific and late; and that molecular tests are described in at-risk pregnancies, with no description of testing on cell-free fetal DNA [176]. A 2026 review of fetal ultrasound adds that the signs of HI (ectropion, eclabium or persistently open mouth, flattened nose, hands and feet in fixed flexion, abnormal skin surface, echogenic amniotic fluid, polyhydramnios) are non-specific and may appear only in the second half of pregnancy, so an earlier normal ultrasound does not exclude the disease; that a confirmed TGM1 case had facial findings similar to those of HI; that IPS has a late-gestation pattern described in small series; and that the accuracy of three-dimensional ultrasound is not established and fetal magnetic resonance imaging is only adjunctive [177]. A collodion baby due to compound heterozygous TGM1 variants detected at the routine 21-week ultrasound through ectropion, flattened nose and eclabium has been described [178]. The 2023 Nature Reviews Disease Primers review considers molecular testing for the familial variants the method of choice, observes that in many countries preimplantation testing is not considered appropriate for ichthyosis and mentions reports of termination of pregnancy in HI and X-linked ichthyosis [131].

8.4. Content and organisation of counselling

The diagnosis should be communicated as soon as it is known (level 4, grade D), ideally in a multidisciplinary consultation bringing together a clinical geneticist, a psychologist and a dermatologist, because explaining a severe congenital ichthyosis is a delicate situation [24, 25]. Genetic counselling is the responsibility of the clinical geneticist and covers the inheritance pattern, the risk for relatives and offspring and the options for prenatal, predictive and preimplantation testing [24]. In the neonatal period, it should be explained that the final form is defined only after the collodion membrane has shed and that about 10% of cases evolve to the self-improving form, so that the prognosis is not communicated more pessimistically than the data allow [2, 36]. In young adults, renewed counselling focuses on family planning and, in women, on coordinating retinoid therapy with plans for pregnancy, given the need to avoid pregnancy for three years after acitretin [2, 25]. Two ongoing studies in Maastricht are investigating reproductive options and reproductive counselling in genodermatoses, one with 650 planned participants and the other qualitative with 25 [179, 180].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each estimate measures

Estimates of ARCI frequency are heterogeneous in method and denominator, and none of them is a worldwide prevalence [18, 20]. Orphanet recorded, in the version consulted, a point prevalence in Europe of 0.5/100,000 for ARCI (validated value, in the class of 1–9 per million), an annual incidence of 1.1/100,000 in Norway, attributed to the TGM1 founder effect, and an annual incidence of 0.5/100,000 in the USA; for lamellar ichthyosis, 1.1/100,000 in Norway and 0.35/100,000 in Spain; for CIE, 0.3–0.5/100,000 in Europe; unknown frequency for harlequin ichthyosis; and less than 1 per million for IPS and bathing suit ichthyosis [6, 14]. The national survey of Denmark and Sweden estimated the prevalence of ARCI in Scandinavia at about 1:100,000 [18]. The German guideline cites, without its own denominator, 1:60,000 to 1:200,000 for ARCI, 1:100 to 1:250 for ichthyosis vulgaris, 1:4,000 for recessive X-linked ichthyosis and 1:200,000 to 1:500,000 for the epidermolytic ichthyoses, and classifies all forms other than X-linked ichthyosis as extremely rare [19]. The Sorèze consensus gave 1:250–1:1,000 for ichthyosis vulgaris and 1:2,000–1:6,000 for X-linked ichthyosis [1]. The Brazilian textbook of genetic syndromes attributes to lamellar ichthyosis 1:200,000–300,000 births and to harlequin ichthyosis a prevalence of 1 per million live births, explicitly acknowledging that the incidence of the disease is not known [15].

The most methodologically explicit study is the Spanish population-based study, using capture-recapture from three sources (dermatology departments, genetics laboratory and the Spanish ichthyosis association): it identified 144 living patients with ARCI, 62.5% with classic lamellar ichthyosis and 30.6% with CIE, and estimated the prevalence in children under 10 years — considered the least biased estimate — at 16.2 per million inhabitants (95% CI 13.3–23.0) [20]. The model estimated that 71% of patients were not followed in reference units, 92% had no genetic diagnosis and 78% did not belong to the association, and found fewer elderly patients than expected, which may reflect lower life expectancy or under-ascertainment; the authors limit generalisation to Spain [20]. Orphanet recorded 0.77/100,000 for Spain as a non-validated value, whereas the primary estimate in children under 10 years corresponds to 1.62/100,000 in that age group; these are different measures (estimated overall prevalence versus prevalence in an age band) and should not be presented as alternatives for the same parameter [14, 20]. For harlequin ichthyosis, the most cited figure is that of about 200 cases described worldwide, and a recent review cites an incidence of approximately 1:300,000 births without a verified primary source [21, 181].

In France, a capture-recapture study with three lists (reference and competence centres, patient association and internet network), carried out in five regions over a closed period, estimated the prevalence of the inherited ichthyoses, excluding very mild forms, at 13.3 per million (95% CI 10.9–17.6); for ARCI, 7 per million (95% CI 5.7–9.2), with 4.5 per million for LI and 1.9 per million for CIE; for the keratinopathic forms, 1.1 per million; and for the syndromic forms, together, 1.9 per million [22]. This is the value cited by the 2021 PNDS [23]. The French estimate for ARCI covers all ages and is lower than the Spanish estimate of 16.2 per million, restricted to children under 10 years, which is consistent with the loss of adult patients to follow-up described in the Spanish study.

In England, a national study of National Health Service hospital records (1998–2024) estimated, in June 2023, a recorded point prevalence of 51.6 per million (95% CI 49.7–53.5) for the rare ichthyoses as a whole, with 5.0 per million for LI, 4.0 for HI, 6.1 for epidermolytic ichthyosis and 26.1 for unspecified congenital ichthyoses; as it is based on ICD-10 codes and only 7.8% of cases were validated by clinicians, the subtype values are coded diagnoses and not confirmed prevalences [108]. The same study cites a prevalence of 160 per million in Denmark (952 patients, all ichthyoses) and an incidence of 67 per million of moderate to severe ichthyoses in the USA [108].

9.2. Geography, ancestry and founder effects

The distribution of genes follows the history of populations. In Scandinavia, TGM1 is the most frequent gene, with the splicing variant c.877-2A>G common in Norway, Finland and North America, and NIPAL4 accounts for 12.5% of ARCI and for about 90% of cases without a collodion membrane and without TGM1 variants in Sweden, Denmark and Norway; SLC27A4 accounts for 4–5% of ARCI in Scandinavia and northern Europe [2]. In Finland, an isolated population, five different TGM1 variants were found in patients with LI and CIE, the most common shared on a founder haplotype [49]. In Galicia, the TGM1 variants c.2278C>T and c.1223_1227delACACA have a founder effect, and a single Galician patient had ALOXE3 [2, 182]. In Spain, in a cohort of 92 patients with ARCI, CYP4F22 was mutated in 8 families, 3 of them of Moroccan origin, and the recurrent variant c.1303C>T p.(His435Tyr) was present in 7 of these 8 families, on a shared 2.52 Mb haplotype in the Spaniards with a 1.2 Mb core shared with the Moroccans; the estimated age of the variant is 2925 to 4925 years and the common ancestor of the Spanish families dates to the 13th century, with probable African origin [82]. A founder effect of ABCA12 variants has also been described in the Spanish population [183]. In Austria, ALOXE3 and SDR9C7 are more frequent (respectively more common and 6% of variants), and in Iran PNPLA1 (15% of variants) and CERS3 (5.6%) predominate, with a high prevalence of PNPLA1 also in North Africa and Spain, probably due to founder variants [2]. In the Middle East, LIPN accounts for 5% of variants, and CASP14 has been described in Algerian families with a shared haplotype [2, 83]. In Japan, a founder variant of SDR9C7 is associated with recurrent generalised dermatophytosis [44]. In the consanguineous populations of Iran, North Africa, the Middle East and South Asia, homozygosity and rare genes are proportionally more frequent [45, 75].

In the USA and Western Europe, data come mainly from reference centre cohorts and registries: the English National Health Service cohort of 146 patients, the North American analysis of 1000 families with ichthyosis, the Italian series of 74 patients and the German laboratory with 770 families studied over 22 years [36, 38, 79, 89]. One sponsor estimated 2000 to 6000 patients with TGM1-ARCI in the USA and Europe, a commercial rather than epidemiological estimate [154]. In the English study, people of Pakistani ancestry were over-represented (9.1% of the cohort versus 2.8% of the reference population), especially in the autosomal recessive ichthyoses such as LI, which the authors relate to consanguinity, and 48.1% of patients lived in the two most deprived quintiles; between 2021 and 2024 only 160 patients had genetic testing data, with a pathogenic variant in 56.3%, and STS, TGM1 and NIPAL4 were the most frequent genes [108].

9.3. Portugal and Brazil

The sources consulted contain no data on the prevalence of ARCI in Portugal. For Brazil, the textbook of genetic syndromes states explicitly that there are no national epidemiological data for harlequin ichthyosis, and lists Brazilian case reports published in national journals, not read for this article; the series on melanocytic naevi in the inherited ichthyoses was published by authors from São Paulo [15, 103]. The absence of these data in the sources consulted does not demonstrate that no studies have been published in the two countries.

9.4. Special populations

Pigmented skin. The 2025 classification illustrates how the same genotype presents differently according to phototype: in TGM1-nEDD, the large scales on the legs appear darker in patients with dark phototypes and light brown in light phototypes [3]. Pigmented skin is also a risk factor for vitamin D deficiency in patients with ichthyosis [102].

Prematurity. As a large proportion of newborns with ARCI are born preterm and those with IPS are so by definition, management combines the problems of prematurity with those of the skin barrier [2, 46].

Climate. Heat worsens bathing suit ichthyosis, and hot, humid weather justifies reducing or pausing acitretin; in regions with a hot climate occlusives are unsuitable [17, 25, 98]. Cold and dry climates are poorly tolerated in the erythrodermic forms [98].

Limited resources. The survival of a newborn with HI has been described in a rural hospital without modern incubators, with improvised measures, which indicates that part of the benefit of intensive care is reproducible with simple means [130].

9.5. Reference networks and patient associations

The relevant European network is ERN-Skin, the European Reference Network for rare and complex skin diseases, which includes an ichthyosis subgroup responsible for the European guidelines and provides the English version of the emergency sheet on the inherited ichthyoses [24, 30, 116]. The European Network for Ichthyosis brings together the European national associations [25, 31]. In the USA, the Foundation for Ichthyosis and Related Skin Types maintains patient information and the National Registry for Ichthyosis and Related Skin Types, and NORD (National Organization for Rare Disorders) and the Camp Discovery and Camp Wonder programmes complete the support; the MotherToBaby service provides information on exposures in pregnancy [2, 32]. National associations include the Ichthyosis Support Group in the United Kingdom, Selbsthilfe Ichthyose in Germany, a partner in the S1 guideline and the German ichthyosis registry, and the Association Ichtyose France, a partner in the French national protocol and the FIMARAD network [17, 19, 33–35]. The sources consulted do not identify specific associations in Portugal or Brazil. Informing patients and families about these associations is a formal recommendation of the European guidelines [24].

In France, the 2021 PNDS places the care pathway under the responsibility of a reference dermatologist, preferably hospital-based and linked to a reference or competence centre, who coordinates a community-hospital network; the initial assessment ideally takes place in a day hospital or multiprofessional consultation [23]. There are two reference centres for the inherited ichthyoses in the FIMARAD filière: the "Sud" centre, coordinated in Bordeaux with sites in Toulouse and Nice, and the "Nord" centre, coordinated at Hôpital Necker (Paris) with sites at Paris-Cochin, Paris-Saint-Louis, Angers, Dijon and Tours; the 11 competence centres are located in Brest, Lille, Nantes, La Réunion, Rouen, Saint-Étienne, Montpellier, Nancy, Lyon, Bobigny (Avicenne) and Marseille [23]. The list of molecular diagnostic laboratories is published by FIMARAD and Orphanet, and these laboratories can use the two national very-high-throughput sequencing platforms, SeqOIA and AURAGen [23]. The association Ichtyose France, founded in 1991 by parents, informs and supports patients, defends their rights and supports research, and the Orphanet Urgences series has a French sheet "Ichtyoses héréditaires" to take to the emergency department [23]. Social support is described as a difficult pathway, with frequent refusals due to lack of knowledge of the disease, and the PNDS considers the involvement of a hospital social worker experienced in the ichthyoses essential [23]. The table summarises the French support measures described in the protocol; the amounts are those of 2021.

10. Illustrative Clinical Case

The following account summarises two cases published in 2026 by a team from Palermo and Bologna, with open-access full text and figures [81].

Case 1 — TGM1-nEDD. A female newborn of 38 weeks and 6 days, delivered vaginally, the second child of healthy non-consanguineous parents; her brother had autism spectrum disorder with a variant in CDH8, and targeted sequencing of that gene on chorionic villi in this pregnancy had been negative. TORCH serologies and group B Streptococcus screening were negative and the prenatal ultrasounds normal. The Apgar score was 9/10, with a weight of 3345 g (71st centile), length of 49 cm (50th centile) and head circumference of 34 cm (59th centile). At birth, the skin was parchment-like, shiny and taut over the whole erythematous surface, with fissures and macerated areas, accompanied by eclabium, ectropion, joint stiffness, deformity of the auricular cartilages with folded ears and semiflexed fingers (Figure 1a–c of the article). Sucking was weak and the palmoplantar grasp reflexes slightly diminished; the metabolic work-up, full blood count and liver and renal function were normal, as were the cranial, cardiac and abdominal ultrasounds and the ophthalmological and audiological assessments. A 54-gene next-generation sequencing panel identified two variants in TGM1 (NM_000359.3): c.1147G>A, p.(Val383Met), of maternal origin and previously described as pathogenic, and c.860C>T, p.(Thr287Ile), of paternal origin, novel and classified as likely pathogenic; the brother had neither of them. Management consisted of an incubator with 70% humidity to prevent hypernatraemic dehydration and hypothermia, parenteral nutrition for 48 hours followed by enteral formula feeding, daily white soft paraffin, fusidic acid cream twice a day on the fissures and cleansing with a vitamin-enriched lipid oil; the latter two were stopped at two weeks because of erythema of the trunk, neck and face and replaced by an emollient cream alone. Discharge took place at three weeks, with good weight gain and residual scaling of the back and limbs, and follow-up was multidisciplinary (dermatology, neurodevelopment and genetics). At 7 months there was marked improvement, with residual areas on the back, right flank, groin and axilla (Figure 2a–c), and at 9 months and 21 days the weight was 9870 g (90th centile), length 70 cm (33rd centile) and head circumference 44 cm (47th centile), with mild xerosis and lamellar scaling remaining on the right side of the neck and on the left flank and groin (Figure 3a,b), with normal neuromotor development. No systemic retinoid was used.

Case 2 — CYP4F22-nEDD (suggestive diagnosis). A female newborn of 39 weeks, delivered by caesarean section because of a non-reassuring cardiotocograph, the first child of healthy non-consanguineous parents; Apgar 9/10, weight 2920 g (28th centile), length 49 cm and head circumference 35 cm (86th centile). She had a translucent, shiny membrane over almost the whole body surface, thick whitish scaling plaques and mild ectropion and eclabium (Figure 4a,b). Neurological examination, ultrasounds, hearing and ophthalmological assessment were normal. A 56-gene panel identified in CYP4F22 (NM_173483.4) the variant c.1084C>T, p.(Arg362Ter), pathogenic, and c.543_545del, p.(Ile181del), of uncertain significance; the parents declined segregation testing, so the allelic phase was not established and the diagnosis was considered suggestive. At 4 months, the weight was about 6300 g (50th centile), length 62 cm (50th centile) and head circumference 41 cm (70th centile), with almost complete resolution of the picture — minimal erythema and dryness of the upper eyelids remained (Figure 5a–c) — a self-improving course.

Comment. The two cases illustrate points developed in the preceding sections: the common neonatal presentation (collodion baby with ectropion and eclabium), the sequence of supportive care with high humidity, nutritional support and simple emollients, and the fact that the neonatal phenotype does not predict the course, both in TGM1-nEDD and in the self-improving form of case 2 [36, 81]. They also show that severity in TGM1-nEDD depends more on the functional consequences of the variants than on zygosity, and that panel sequencing is essential when phenotypes overlap [81]. Two particularities of the management described should not be read as routine. The first is the discontinuation of the topical antibiotic and the oil because of a skin reaction, an individual decision that does not contradict the guidelines but does not derive from them either. The second is the 70% humidity in the incubator, which lies within the 60–80% range recommended by the European guideline for the start of treatment, although above the 50–70% indicated by GeneReviews, and which should be reduced progressively, given the risk of infection associated with high humidity [2, 102]. Neither case received a systemic retinoid, which is consistent with the recommendations for the collodion baby without functional compromise [102]. The figures cited were confirmed as accessible in the PubMed Central repository on 10 October 2026, at the addresses of figures 1 to 5 of the article [81].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis by form

Harlequin ichthyosis retains the most guarded prognosis: overall survival was 56% in the series of 45 cases with ABCA12 analysis, with survivors aged between 10 months and 25 years and deaths concentrated in the first three months, due to sepsis and/or respiratory failure in 75% of cases [92]. GeneReviews retains this estimate and expects it to improve with neonatal intensive care and early topical and systemic retinoids [2]. The systematic review of case reports published in 2026 describes a mortality of 60.3%, with a mean age at death of 47.19 days, a value that reflects the case literature and not a population cohort [112]. In survivors, the disease is severe and chronic, with the complications described in section 3 [2, 21].

Lamellar ichthyosis and congenital ichthyosiform erythroderma are lifelong diseases: scaling, hypohidrosis and heat intolerance persist, and the Sorèze consensus considers that LI probably never clears completely [1, 2]. The French protocol classifies congenital ichthyosis as a lifelong chronic disease, except in the self-resolving or self-improving forms of the collodion baby, with transient exacerbations associated with stress, infections and climate [17]. The self-improving collodion baby, about 10% of cases, leaves mild residual findings — xerosis, focal scaling, hyperlinear palms, red cheeks, anhidrosis — and, in the German prospective study, brachydactyly of the 4th and 5th fingers and folded helix deformity in some patients [2, 95]. Ichthyosis prematurity syndrome generally has an excellent prognosis after the perinatal period, with estimated survival of 87.6% at 6 months (95% CI 78.8–97.4) and 10.2% fulminant cases, leaving atopy and chronic pruritus [2, 46].

The risk of skin tumours is uncertain. Several case reports describe multiple SCCs and BCCs between 25 and 51 years of age, but the true incidence is not established and the French protocol considers that there is no demonstrated increase in risk in ARCI, reserving systematic tumour screening for Netherton syndrome, KID syndrome and ichthyosis with confetti [2, 17, 110]. The description, in 2026, of three cases of cutaneous T-cell lymphoma in NIPAL4-nEDD is an observation awaiting confirmation [111]. The Spanish prevalence study found fewer elderly patients than expected, which may indicate lower life expectancy, a hypothesis the authors left open [20]. In the English national study, 18.5% of deaths of people with ichthyosis occurred before the age of 25, compared with 1% of deaths registered in England in 2023, and the median age at death was 0 years in patients coded as HI or LI; congenital ichthyosis was the second recorded cause of deaths before 25 years, and death certificates tend to record underlying diseases rather than immediate causes [108].

11.2. Surveillance table

11.3. Prognosis with treatment

Systemic retinoids improve scaling, hyperkeratosis, hypohidrosis, ectropion, eclabium and hearing and reduce daily care time, but do not alter the genetic course of the disease and their effect disappears shortly after discontinuation [24, 104]. There are no long-term prospective studies on maintenance, tachyphylaxis has not been observed, and intermittent regimens — pauses or twice-weekly administration — have not been studied [104]. In HI, the association between retinoids and survival is observational and subject to confounding by indication [92, 102]. Severely affected children with weight faltering grew better after starting the retinoid [24]. Intensive topical treatment remains necessary in most patients even on systemic therapy, and the phenotype observed in a treated patient is not that of the natural history: LI on an oral retinoid may evolve into erythroderma with finer scale [1, 19]. Follow-up should be at least annual and coordinated by a dermatologist experienced in the disease, in liaison with the multidisciplinary network [17].

12. Summary and Final Considerations

The autosomal recessive congenital ichthyoses are a group of thirteen or more monogenic entities that share a defect of the epidermal barrier, almost always in the acylceramide pathway or in assembly of the cornified envelope, and that manifest at birth as a collodion membrane, as exfoliative erythroderma or, in the most severe form, as the fissured armour of harlequin ichthyosis. The 2025 classification replaced the morphological names with gene-based designations, from TGM1-nEDD to ABCA12-nEDD, and incorporated the former ichthyosis prematurity syndrome into the non-syndromic forms; the historical terms remain useful as phenotypic descriptors and persist in the literature and databases.

In practice, recognition is clinical and urgent. The newborn with a collodion membrane needs neonatal intensive care with a humidified incubator, thermal and electrolyte control, nutritional support, simple emollients and active surveillance for infection, with attention to the signs that require immediate action: hypernatraemia, sepsis, respiratory compromise and constrictive bands with ischaemia. The definitive form becomes evident only after the membrane has shed, and about one in ten of these newborns evolves to a self-improving picture, a reason for caution in communicating the prognosis. Diagnosis of the type requires a multigene panel with copy number variation analysis, with a yield close to 90% in expert centres, so a negative result does not exclude the disease; in situ transglutaminase 1 activity remains useful as a rapid screen, with two known exceptions, bathing suit ichthyosis and the self-improving collodion baby, in which the test may be positive.

Treatment is symptomatic and lifelong: prolonged bathing, mechanical keratolysis, emollients and keratolytics with strict age limits — no keratolytic before 2 years according to the French protocol, salicylic acid strictly contraindicated at that age, urea used with caution in the newborn — and topical retinoids on limited areas. Acitretin is the systemic retinoid of choice in Europe, with an indication for severe congenital ichthyosis in the British SmPC and off-label use in the USA, where the paediatric consensus prefers isotretinoin in patients with reproductive potential; most patients do not need more than 0.5 mg/kg/day, hepatic, lipid, bone and ophthalmological monitoring is mandatory, and teratogenicity imposes contraception and pregnancy testing for up to three years after discontinuation. Recent trials of targeted interventions have, on the whole, been negative: topical isotretinoin failed its primary endpoint in phase 3, trifarotene was stopped for futility and secukinumab did not reduce severity across the spectrum of adult ichthyoses. The most promising approaches — topical TGM1 gene therapy, base editing, enzyme replacement — remain at an early or preclinical stage, and no disease-modifying therapy is authorised.

Follow-up is organised around four axes: the skin and its infectious complications, the eye and the ear, growth with vitamin D, and psychosocial impact, with screening for anxiety and depression, whose screen-positive prevalence reaches about one third of patients. Genetic counselling rests on a recurrence risk of 25% per pregnancy, on confirmation of parental heterozygosity, on attention to alternative explanations for apparent homozygosity and on the offer of prenatal diagnosis and preimplantation testing once the familial variants have been identified. The most salient gaps in knowledge are the absence of a global prevalence estimate obtained with a homogeneous method, uncertainty about the true risk of skin tumours and about life expectancy in the severe forms, and the lack of adequately sized randomised trials to support the doses and durations used today.

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