Sjögren-Larsson Syndrome

Syndromic ichthyosis due to fatty aldehyde dehydrogenase deficiency (ALDH3A2-sEDD)

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

The following entities share with SLS the association of congenital ichthyosis with neurological or systemic disease due to a defect in the metabolism of the lipids of the epidermal barrier and myelin, and are covered in this article [22–24].

1. Introduction

1.1. Original description and eponym

In 1956 and 1957, Torsten Sjögren and Tage Larsson described, in a clinical and genetic monograph, the association of oligophrenia, congenital ichthyosis and spastic disorder in 28 patients from northern Sweden, and established autosomal recessive transmission [10, 40, 41]. The authors proposed that all cases derived from a single mutation that had arisen about six centuries earlier and estimated that about 1.3% of the population of northern Sweden would be heterozygous [8]. The eponym refers to Torsten Sjögren and not to the ophthalmologist Henrik Sjögren, after whom the autoimmune sicca syndrome is named; for this reason, part of the older literature uses the designation «T. Sjögren syndrome» [8]. The same homonymy separates this disease from Marinesco-Sjögren syndrome, a cerebellar ataxia with cataracts and myopathy.

1.2. Biochemical and molecular milestones

In 1988 the disease was shown to result from a defect in lipid metabolism; in 1991, Rizzo and Craft showed that, within the fatty alcohol:NAD+ oxidoreductase (FAO) complex, the deficient enzyme is fatty aldehyde dehydrogenase and not fatty alcohol dehydrogenase, and that obligate heterozygotes have about 50% of normal activity with octadecanal as substrate [8, 41]. The locus was mapped to chromosome 17 by linkage and allelic association in Swedish families (1994) and confirmed in families of Arab, mixed European, Native American and Swedish origin, indicating genetic homogeneity [8]. In 1996, De Laurenzi and colleagues cloned the human FALDH complementary DNA, localised it to the SLS locus at 17p11.2 and identified distinct mutations in three unrelated patients [42]. These were followed by the identification of the Swedish founder variant c.943C>T (p.Pro315Ser) in 1997 [43], the first large mutational series (63 families, 49 mutations) in 1999 [44] and, in 2019, a patient-centred variant database with 178 individuals and 90 pathogenic variants [14].

1.3. Nomenclature and classification

The 2009 Sorèze classification and the 2017 German S1 guideline place SLS among the ichthyosiform syndromes, that is, inherited ichthyoses with involvement of other organs, alongside Netherton, KID, Refsum, MEDNIK, CEDNIK and Chanarin-Dorfman syndromes, multiple sulfatase deficiency and trichothiodystrophy; the defect is described there as FALDH deficiency with phase separation in the lamellar membranes of the stratum corneum [45, 46]. The 2025 international reclassification initiative replaced the term «ichthyosis» with «epidermal differentiation disorders» (EDD), with names built from the gene and the subgroup (non-syndromic, nEDD; syndromic, sEDD; palmoplantar, pEDD); SLS is now designated ALDH3A2-sEDD [2, 3, 47]. In the context of inborn errors of metabolism, SLS belongs to the group of disorders of fatty acid elongation and of fatty acid, alcohol and aldehyde homeostasis, alongside FATP4, CYP4F22, ELOVL1, ELOVL4 and ELOVL5 deficiencies [15].

1.4. Definition

SLS is an autosomal recessive neurocutaneous disease caused by biallelic loss-of-function variants in ALDH3A2, which lead to FALDH deficiency and to the accumulation of long-chain fatty aldehydes and alcohols and of lipids derived from them; it is defined clinically by congenital ichthyosis, spastic diplegia or tetraplegia and intellectual disability, together with a characteristic crystalline maculopathy, leukoencephalopathy, intense pruritus, preterm birth and seizures [1, 6, 8]. Since the enzyme deficiency and the variants began to be used to confirm the diagnosis, the spectrum has been recognised as broader than the classic triad: there are patients with normal intelligence and mild spasticity of adolescent onset and, at the opposite extreme, children with a neurodegenerative course [41, 48, 49].

1.5. Related entities: history and definition

Chanarin-Dorfman syndrome. In 1953, Jordans described fat-containing vacuoles in the cytoplasm of leucocytes from two brothers with progressive muscular dystrophy, without ichthyosis; Rozenszajn and colleagues found the same vacuoles in 1966 in two sisters with ichthyosis, and Dorfman and colleagues published in 1974 the course of these patients, one of whom developed at the age of 35 fatty degeneration of the liver, cataracts, nystagmus, hearing loss and ataxia [24, 50]. In 1975, Chanarin and colleagues described a 22-year-old woman with congenital ichthyosis, Jordans anomaly and triglyceride accumulation in the gastrointestinal epithelium, bone marrow, cultured fibroblasts and striated muscle, and named the condition neutral lipid storage disease [24, 51]. A genome scan in consanguineous families localised a form of non-bullous congenital ichthyosis to 3p21 (NCIE2 locus) in 2000, and in 2001 Lefèvre and colleagues identified, in nine families from the Mediterranean basin, homozygous variants in CGI-58, now ABHD5, on eight different haplotypes [24, 52]. The 2025 classification of inherited epidermal differentiation disorders designates the entity ABHD5-sEDD [28]. It is defined as an autosomal recessive, non-lysosomal disorder of intracellular triglyceride catabolism, with constant non-bullous congenital ichthyosiform erythroderma, triglyceride droplets in the cytoplasm of almost all cell types and variable involvement of the liver, muscle, eye, inner ear and central nervous system [24, 29].

ISQMR. Before 2011, ELOVL4 variants were known for autosomal dominant Stargardt-like macular dystrophy (STGD3) [15]. Aldahmesh and colleagues, combining autozygosity mapping and exome sequencing, described in 2011 two patients, one Saudi and one Indian, born to consanguineous parents, with biallelic ELOVL4 variants, ichthyosis, seizures, intellectual disability and spasticity, a picture reminiscent of SLS but with more severe neurological disease [22, 53]. A Pakistani family (2014), two Italian children (2021) and four families from the Middle East (2023) extended the series [32, 54, 55]. ISQMR is defined as an autosomal recessive neuro-ichthyosis caused by biallelic loss of function of ELOVL4, with ichthyosis from birth, profound psychomotor delay, spastic quadriplegia and epilepsy [22].

ELOVL1 deficiency. In 2018 and 2019, two groups, one Polish and one German, independently described the same two unrelated Polish boys, heterozygous for the de novo variant p.(Ser165Phe) in ELOVL1, with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features, the condition OMIM designates IKSHD [23, 38, 56]. In 2022 the first autosomal recessive form was described, in two Turkish siblings with a homozygous splicing variant, and in 2025 a series of seven patients with biallelic variants defined a phenotype of hypomyelinating leukodystrophy, ichthyosis and complex movement disorder [26, 30]. ELOVL1 deficiency is defined as a neuro-ichthyosis due to defective elongation of saturated and monounsaturated very-long-chain fatty acids (VLCFA) of 22 to 26 carbons, with dominant or recessive inheritance depending on the variant [15, 26].

2. Molecular Genetics and Pathophysiology

2.1. The ALDH3A2 gene and the protein

The ALDH3A2 gene spans about 31 kb at 17p11.2, in the vicinity of other genes of the aldehyde dehydrogenase family such as ALDH3A1, and has 11 exons numbered 1 to 10 plus an alternative exon 9' [6, 8, 10]. The main transcript (exons 1–10) encodes a protein of 485 amino acids anchored to the endoplasmic reticulum membrane by a hydrophobic carboxy-terminal domain of 35 residues; the minor transcript, which includes exon 9', accounts for less than 10% of the protein and encodes a 508-amino-acid isoform (FALDHv) targeted to peroxisomes [6, 10, 14]. The enzyme is a constitutive protein, expressed in all tissues and nucleated cells; in rodents, the promoter has a peroxisome proliferator-activated receptor alpha (PPAR-α) response element and is induced by fibrates, phytol and some fatty acids [6]. FALDH functions as a homodimer of two 54 kDa subunits and uses NAD+ to irreversibly oxidise aliphatic aldehydes of 6 to 24 carbons, with a preference for those of 16 to 20 carbons; retinal is not a substrate [6, 10]. The crystal structure revealed three domains (catalytic, cofactor-binding and dimerisation) and a hydrophobic «gatekeeper» helix that covers the substrate entry tunnel and orients the enzyme towards the lipid bilayer; dimerisation is required for activity [6, 14].

2.2. Metabolic pathways that depend on FALDH

FALDH is the point of convergence of several pathways that generate fatty aldehydes. In the first, the fatty alcohol cycle, long-chain alcohols produced from acyl-CoA by the reductase FAR1 are reoxidised to fatty acids by the sequential action of fatty alcohol dehydrogenase and FALDH, which together form FAO; in the deficiency, C16:0 and C18:0 alcohols accumulate in plasma and cells, with a greater relative increase in octadecanol than in hexadecanol, and up to 25 times more fatty alcohols in keratinocytes [6, 10, 15]. In the second, the degradation of ether glycerolipids (including plasmalogens) releases long-chain aldehydes from the 1-O-alkylglycerol backbone; in the third, sphingosine-1-phosphate lyase produces trans-2-hexadecenal, which FALDH oxidises to hexadecenoic acid; in the fourth, ω-oxidation of leukotriene B4 (LTB4) proceeds through an ω-aldehyde that must be oxidised by FALDH to 20-carboxy-LTB4 [6, 15]. FALDH is also involved in the α-oxidation of phytanic acid (oxidation of pristanal), in the oxidation of the isoprenols farnesol and geranylgeraniol and, according to recent work, in the degradation of sphingolipids with C24 2-hydroxylated fatty acids, whose C23 aldehyde, generated by HACL2, is converted to C23 alcohol when the enzyme is lacking [6, 15]. Despite its role in phytol metabolism, patients do not accumulate phytol or phytanic acid in plasma, indicating alternative pathways [6, 10].

2.3. Mechanisms of injury

Pathogenesis cannot yet be reduced to a single lipid, and the lack of correlation between the severity of the ichthyosis and that of the neurological deficit suggests different mechanisms in different tissues [6]. Fatty aldehydes are reactive and form Schiff base adducts with amine groups of proteins and lipids; in patient fibroblasts, 1-O-alkylglycerol metabolism generates four times more N-alkyl-phosphatidylethanolamine (NAPE) than in controls, and deficient cells are more sensitive to aldehyde cytotoxicity [6, 57]. Excess fatty alcohols are diverted to the synthesis of wax esters and ether glycerolipids: in the stratum corneum of patients, saturated C15–C20 1-O-alkylglycerols are increased 97-fold (range 86–169) [58]. In the skin, the structural consequence is defective formation of the lamellar bodies of the stratum granulosum, which contain granular material instead of the membranes that should be secreted; the intercellular membranes of the stratum corneum become abnormal, the barrier loses water and the epidermis responds with hyperproliferation and hyperkeratosis [6, 10]. Acylceramide (ceramide 1) is reduced in the scales, another likely contributor to barrier dysfunction [6]. Pruritus is related, at least in part, to the failure to inactivate LTB4: LTB4 and 20-hydroxy-LTB4 are markedly raised in patients' urine, and subcutaneous injection of LTB4 induces intense pruritus in animals [6, 17].

In the central nervous system, plasmalogens make up 40–50% of myelin phosphatidylethanolamine and turn over within a few days, so that their degradation is a continuous source of aldehydes [6, 10]. The only brain autopsy studied with lipidomics, from a 65-year-old woman with a genetic diagnosis, showed white matter pallor due to myelin deficiency with a preserved number of oligodendrocytes, lipid droplets in the neuropil and astrogliosis, and an accumulation of C18–C24 fatty alcohols (C21–C24 increased 17-fold in the white matter), including odd-chain ones, and of long-chain unsaturated ether lipids, also in the grey matter [59]. These data, together with volume reduction of the cerebellar cortex, brainstem, thalami and pallidum in two Brazilian sisters, indicate that SLS is not a pure leukoencephalopathy [59, 60]. In the retina, intraretinal deposition of lipid metabolites and the lack of macular pigment (lutein and zeaxanthin), which protects against light-induced oxidation, are the proposed mechanisms for the maculopathy [10, 61, 62].

2.4. Variant spectrum

In the 2019 LOVD database (178 patients, literature up to September 2018), the 90 pathogenic variants were distributed across all exons except 9' and 10, so that all affect both isoforms; frameshift variants accounted for 32.2%, missense for 33.3%, intronic for 15.6%, nonsense for 10.0%, in-frame insertions/deletions for 5.6% and large rearrangements for 3.3% [14]. Of the missense variants, 45.8% affected the catalytic domain, 41.0% the cofactor-binding domain and 10.8% the dimerisation domain [14]. About three quarters of patients were homozygous (74.7%), reflecting consanguinity and founder effects [14]. Large deletions, including contiguous deletions of 352 kb and 1.44 Mb that remove ALDH3A2 and neighbouring genes, may account for up to 5% of alleles [10, 16].

The following table lists the recurrent variants, normalised in VariantValidator on the MANE Select transcript NM_000382.3 [7].

Some review sources write the last variant as «p.Lys266Asp»; conversion in VariantValidator confirms p.(Lys266Asn) [7]. Together, the variants c.943C>T and c.1297_1298del explained 48% of alleles and were present in 66% of the European probands studied in 1997, which justified targeted screening for them before sequencing became widespread [63]. In Sweden, the distribution of carriers points to a centre of dispersal in Västerbotten county at least 700 years ago [69].

2.5. Genotype-phenotype correlations, penetrance and modifiers

Most patients have a severe phenotype regardless of genotype [70]. In the LOVD database, the known residual activity for 46 variants ranged from 0% to 23% of normal, with no difference in phenotype between groups defined by predicted activity; part of the difficulty stems from cell homogenates retaining up to 8% of aldehyde-oxidising activity from other dehydrogenases [14]. Patients with the same genotype, including siblings, may differ in severity, and identical twins have different patterns of retinal inclusions, which points to modifier genes or environmental factors [6, 62]. In 2026, a Chinese series of 22 patients showed a predominance of compound heterozygotes (59.1%) and missense variants, in contrast with the 72.5% of homozygotes in the global analysis of 200 patients [67]. In published series, almost all patients with a biallelic genotype have ichthyosis, but there are exceptions: in a review of mild forms, a 7-year-old child with the enzyme deficiency had no skin changes, and a Dutch patient had only very mild skin and ocular changes, without neurological involvement; neurological and cognitive expression is the most variable component [41, 70]. No allelic disorders of ALDH3A2 with dominant inheritance have been described [5].

2.6. Related entities: genes, mechanisms and variants

A common pathway. The permeability barrier of the cornified layer depends on ω-O-acylceramides, ceramides with an ω-hydroxylated ultra-long-chain fatty acid to which linoleic acid is ester-linked. Synthesis begins with the elongation of long-chain fatty acids by ELOVL4 to ultra-long chains, continues with ω-hydroxylation by CYP4F22 and N-acylation by ceramide synthase 3, and ends with transacylation of linoleic acid from triglycerides by PNPLA1, stimulated by ABHD5 [28]. ELOVL1, in turn, produces the 24- and 26-carbon VLCFA that enter the ceramides and sphingomyelins of myelin and skin [26, 38]. ELOVL4, ELOVL1 and ABHD5 thus act in the same network of complex lipids in which FALDH eliminates fatty aldehydes and alcohols, which explains the association of ichthyosis with white matter disease in all four entities [15, 71].

ELOVL4 and ISQMR. ELOVL4 is the only elongase that produces saturated and polyunsaturated VLCFA with 28 or more carbons, and is expressed mainly in the brain, retina and skin [32]. The gene is associated with three Mendelian disorders. STGD3, autosomal dominant, results from truncating variants in the last exon, with onset of visual loss between 3 and 50 years (mean 14) and a dominant-negative effect of the mutant protein, rather than haploinsufficiency [15]. Spinocerebellar ataxia 34 (SCA34, OMIM #133190), also dominant, combines ataxia and erythrokeratodermia, first described in a French-Canadian family [15, 32]. ISQMR, recessive, results from biallelic loss of function [22]. Mice homozygous for a null Elovl4 allele have scaly skin with a severely compromised epidermal barrier and die a few hours after birth; the epidermis lacks ω-O-acylceramides and shows an overall reduction in VLCFA with more than 28 carbons [22]. In patients, plasma VLCFA were normal or with slightly raised C26:0, and the C28:0/C26:0 ratio of lysophosphatidylcholines in dried blood spots was reduced in the two patients studied, in parallel with the mouse model [32].

ELOVL1. ELOVL1 elongates saturated and monounsaturated acyl-CoAs of 22 to 26 carbons [38]. The p.(Ser165Phe) variant lacks catalytic activity, reduces ceramides and sphingomyelins with 24 or more carbons in fibroblasts and increases those with 20 and 22 carbons; in transfected cells, it decreases C24:0 to C28:0 fatty acids, with the maximum effect on C26:0 [15, 56]. The fact that a single allele causes disease has been attributed to a dominant-negative effect of the mutant protein on the elongation complex [34, 38]. In the fibroblast transcriptome, epidermal development and keratinisation modules were increased and those of myelination and synaptogenesis decreased, with many genes carrying PPARα and PPARγ binding motifs [38]. In the biallelic form, the nonsense variant p.(Trp154*) reduces messenger RNA through nonsense-mediated decay, abolishes the protein in fibroblasts, decreases plasma sphingomyelins and alters the expression of the other elongases (ELOVL3 and ELOVL4 decreased, ELOVL2 and ELOVL6 increased) [26]; the splicing variant c.376-2A>G causes exon skipping and reduces acylceramides in the cornified layer, with shortening of fatty acid chains [30].

ABHD5 and Chanarin-Dorfman syndrome. ABHD5 is a coactivator of adipose triglyceride lipase (ATGL, encoded by PNPLA2), the enzyme that initiates hydrolysis of the triglycerides stored in lipid droplets; it also has lysophosphatidic acid acyltransferase activity [29]. In its absence, triglycerides accumulate in droplets in the cytoplasm of almost all cells, even without an excess of circulating fatty acids, and serum lipids are normal [28, 29]. In the epidermis, ABHD5 directs PNPLA1 to lipid droplets and stimulates acylceramide synthesis; disease-associated mutants lose this capacity, and patients have acylceramide deficiency with massive accumulation of ω-hydroxyceramides, which explains the ichthyosis and the similarity to ichthyoses due to PNPLA1 variants [28]. ATGL deficiency causes neutral lipid storage disease with myopathy (NLSDM, OMIM #610717), without ichthyosis [24, 31]. In one patient with a certain clinical diagnosis no ABHD5 variant was found, suggesting genetic heterogeneity [29].

Genotype-phenotype correlation. In ELOVL1 deficiency, head tremor, myoclonus and intellectual disability (mild, in four patients) occurred only in homozygotes, hearing loss in the first four patients described (two heterozygotes and two homozygous siblings) but in none of the seven in the 2025 series, and ichthyosis was absent in two homozygous siblings [26]. In ISQMR, two members of the Pakistani family homozygous for p.(Tyr26*) had only ichthyosis, without neurological disease, showing variable expressivity within the same family [32, 54]. In Chanarin-Dorfman syndrome, almost every family has its own variant and severity varies widely, with no correlation of prognostic value [35, 72].

All variants in the table were normalised in VariantValidator (GRCh38, MANE Select transcripts), except the large deletions, which keep the published designation, and the Tunisian variant, confirmed in ClinVar [7, 73]. The ELOVL1 variants of the 2025 series were published on version NM_022821.3, with the same c. numbering in version 4 [7, 26].

3. Clinical Spectrum and Manifestations by System

3.1. Sources of natural history data

Frequency figures come from four types of source, with different limitations. The LOVD database brings together 178 published cases with genotype, but phenotypic reporting is heterogeneous: pruritus, prematurity, abnormal myelination, photophobia and seizures were neither stated nor excluded in more than half of the cases [14]. Single-centre cohorts have systematic assessment: 34 Swedish patients examined, some for more than 25 years, by the same investigator [74]; the Dutch Nijmegen cohort, with more than 30 patients, from which come the series of 17 patients (motor function), 19 patients (clinical and biochemical), 22 patients (optical coherence tomography) and 33 patients (gestational age) [13, 70, 75, 76]; and the longitudinal natural history study at the University of Nebraska (2013–2023, 20 participants), whose overall results have not been posted on the registry [77]. National series based on literature review complete the picture (58 Turkish, 35 Egyptian and 22 Chinese patients) [65, 67, 68]. All these data describe the disease under symptomatic treatment; there is no untreated natural history cohort.

3.2. Prenatal and neonatal period

Prematurity is a feature of the disease: in the Dutch cohort, 24 of 33 patients with known gestational age (73%) were born preterm, with a median of 36 weeks, and in the literature 13 of 22 (59%) [13]. In the LOVD database, the mean of the 32 cases with recorded length of gestation was 34 weeks, but the information was missing in most reports [14]. The proposed explanation is increased fetal urinary excretion of LTB4 into the amniotic fluid, given that products of the lipoxygenase pathway take part in uterine contractility [10, 13]. Prematurity has not been documented in patients with a mild phenotype [41]. Histological skin changes are present at 23 weeks of gestation, but a biopsy at 19 weeks was histologically normal in an affected fetus [10, 78]. At birth, the skin is erythematous and hyperkeratotic and progresses over days to weeks to a dry, scaly ichthyosis; the collodion membrane is absent in the great majority (never observed in the 36 Swedish patients alive in 1980) and has rarely been described [8, 10, 12]. The infant may have erythroderma [2, 15].

3.3. Skin and appendages

The ichthyosis is generalised, with relative sparing of the central face, and most marked on the neck (nape), lower abdomen and flexures, where the scales are often dark or brown; the scale is fine on the periphery of the face, coarser on the trunk and limbs and in larger plates on the legs, and the skin may have a yellowish tinge with accentuated skin markings [2, 8, 12]. Palmoplantar keratoderma and hypohidrosis were found in most of the 34 Swedish patients, which may cause heat intolerance; hair and nails are normal [10, 12, 74]. In the LOVD database, ichthyosis described by severity was mild in 17 of 97 patients (17.5%), moderate in 21 (21.6%) and severe in 59 (60.8%); in Swedish patients, the degree of scaling ranged from moderate to severe between individuals with no evident change with age [14, 74]. Pruritus is the symptom that distinguishes the ichthyosis of SLS from other disorders of cornification; it is almost universal in single-centre cohorts (all 19 Dutch patients, most of the Swedish ones), causes excoriations with bleeding and disturbs sleep, but in the LOVD database it was recorded in only about 40%, reflecting under-reporting; its intensity does not track the severity of the ichthyosis [14, 15, 70, 74]. In questionnaires to parents and carers of 16 Dutch patients (11–58 years), pruritus was the most frequently reported problem, ahead of reduced mobility and dependence [79]. Histology shows hyperkeratosis, papillomatosis, acanthosis and epidermal hyperplasia, with a preserved granular layer [6, 80].

3.4. Nervous system

Neurological signs appear in the first or second year of life, with delay in sitting, crawling and walking, due to spasticity with hyperreflexia, Babinski sign and ankle clonus [6, 10]. Spasticity predominates in the lower limbs (hamstrings, hip adductors and gastrocnemius), with diplegia in most and tetraplegia in a few; in the LOVD database, severity was mild in 3 of 107 patients (2.8%), moderate in 32 (29.9%) and severe in 72 (67.3%) [14, 75]. All Dutch patients over 7 years of age had lower-limb contractures, and limitations covered all dimensions of the Gross Motor Function Measure (GMFM) except lying and rolling; in Sweden, 20 of 34 patients (59%) were wheelchair-dependent [74, 75]. None of the adolescents assessed walked without support, some walk with orthoses and elbow crutches, and everyday motor performance reaches at best that of a 12-year-old child [12, 15]. Contractures of the hips and lower limbs are the rule, those of the upper limbs are uncommon; deformities of the feet (26 patients in LOVD), of the spine and scoliosis (17% in the Turkish series) and developmental dysplasia of the hip are described [12, 14, 65, 67].

Intellectual disability is almost constant and is distributed roughly equally between mild (31.0%), moderate (35.7%) and severe (33.3%) grades in the 84 LOVD patients with grading; the median intelligence quotient (IQ) in 12 tested patients was 54.5 (39–65) [14]. There is no cognitive deterioration at least in the first three to four decades [10]. Speech develops late and mild to moderate pseudobulbar dysarthria is almost universal; language correlates with cognition rather than with motor function [10, 15]. Dysphagia and drooling are described, and 75% of the 16 Dutch patients surveyed had feeding or swallowing problems [12, 79].

Seizures occur in 35–40% of patients (37.1% in LOVD; 38% of Swedish patients on antiseizure treatment; 28% in the Turkish series); they are usually generalised tonic-clonic, infrequent and controlled with antiseizure medications, with no preferred drug; the interictal electroencephalogram (EEG) is normal or shows slowing of background activity [10, 14, 65, 70, 74].

3.5. Eye

Crystalline maculopathy is the characteristic ocular sign. In 15 patients with proven enzyme deficiency, all had bilateral, yellowish-white, glistening crystalline deposits in the innermost layers of the retina, appearing in the first two years of life and increasingly numerous with age; the sign was obligatory and early in all 30 Swedish patients examined [8, 11]. Optical coherence tomography (OCT) localises the crystals to the nerve fibre, inner plexiform and outer plexiform layers [62, 76]. In 22 Dutch patients followed by OCT between 2008 and 2017 (3–47 years), macular morphology was abnormal in both eyes from the youngest age, the physiological thickening of the photoreceptors beneath the fovea was absent, half had pseudocysts (all under 30 years), three older patients had frank atrophy of the retinal pigment epithelium and one had neovascularisation; the fovea was thinner than in controls and thinned during follow-up [76]. Macular pigment is almost absent (foveal optical density 0.10±0.07 versus 0.69±0.17 in controls), a genetic deficiency of macular pigment unparalleled in other diseases [61]. OCT angiography shows perifoveal capillary rarefaction and enlargement of the foveal avascular zone (0.70 versus 0.34 mm²) [81]. The inclusions are not inert: on serial photographs of 4 patients over 1–3 years new inclusions formed and others regressed [62]. Photophobia, dry eye, myopia and astigmatism are common; visual acuity is mildly to moderately reduced but, as a rule, preserved into adulthood; visual evoked potentials are abnormal in 6 of 8 patients tested, while electroretinography is normal [11, 12, 82]. In a 58-year-old woman, the maculopathy had reached an end stage with retinal atrophy [83]. Crystals may be absent in the first months and, in Egyptian and Chinese series, were not found in all patients [10, 67, 84].

3.6. Other systems

Short stature is common [4, 8]. In Swedish adults, poor circulation in the legs and oedema of the feet are common [74]. Enamel hypoplasia, severe caries and gingivitis have been described [66, 85]. An association with central precocious puberty has been reported in a single boy, with no causality established [86]. An Indian series described claw hands due to intrinsic muscle weakness in two siblings [87].

3.7. Neuroimaging

Magnetic resonance imaging (MRI) shows delayed myelination and an area of T2 and FLAIR hyperintensity in the periventricular white matter, with frontal or parieto-occipital predominance, sparing of the cerebellar white matter and, in the early stages, of the subcortical fibres; T1 is normal or slightly hypointense [10, 60, 88]. Proton magnetic resonance spectroscopy (MRS) of the white matter reveals a prominent lipid peak at 1.3 ppm and a smaller one at 0.8–0.9 ppm, with normal N-acetylaspartate and increased creatine (+14%), choline (+18%) and myo-inositol (+54%); grey matter is normal on MRS [6, 88]. In patients followed from the first years, these changes appear progressively and then stabilise; the lipid peak may precede visible dysmyelination and may be absent in mild patients [41, 48, 88]. The degree of the changes and the height of the peak do not correlate with neurological severity [70]. Mild cerebral atrophy appears after the age of 10 and was described in 10% of Turkish patients [15, 65].

3.8. Atypical forms

Mild phenotype. Two Dutch men aged 45 and 61, compound heterozygotes (c.682C>T/c.943C>T and c.551C>T/c.943C>T), with confirmed enzyme deficiency, had moderate ichthyosis of atypical pattern but pruritic, spastic paraplegia of adolescent or adult onset with independent walking for decades, normal intelligence (one with an IQ of 83) and typical maculopathy; one of them had no lipid peak on MRS [41]. The literature review found 10 children with a mild phenotype (absence of one core symptom or two mild core symptoms), 8 with normal intellect and 3 born at term, with no correlation with genotype [41].

Neurodegenerative phenotype. The disease is considered a static leukoencephalopathy, but 8 paediatric cases with regression between 6–7 months and 12 years have been published; 5 had poorly controlled seizures, and in one case regression followed a febrile rotavirus infection and progressed over three years to loss of motor milestones, a fall in IQ from 88 to 40, dystonia, gastrostomy and tracheostomy [49]. Regression after a seizure at 9 months was reversible in another patient [49]. A woman homozygous for a 352 kb deletion had oromotor deterioration and loss of walking [16].

3.9. Related entities: clinical spectrum

ISQMR. The 2023 review brought together 15 patients from 9 families (Saudi, Pakistani, Indian and Italian), 8 of 9 families consanguineous, all homozygous or compound heterozygous for ELOVL4 variants [32]. Ichthyosis was present in 15 of 15, with erythema in 11 of 15 and collodion membrane in 5 of 13; neurological manifestations included profound global delay (12 of 15), epilepsy (12 of 15, refractory in one patient and controlled with antiseizure medications in several), peripheral hypertonia (10 of 13) and axial hypotonia (8 of 11), with contractures, scissoring of the lower limbs and brisk reflexes [32]. The electroencephalogram showed slowing of background activity in 7 of 7 and epileptiform activity in 7 of 8, including hypsarrhythmia; MRI showed cerebral atrophy in 6 of 8, delayed myelination in 5 of 8 and a thin corpus callosum in 5 of 8 [32]. Outside the nervous system, growth retardation (12 of 15), dysphagia requiring tube feeding or gastrostomy (6 of 11), gastro-oesophageal reflux (6 of 12), asthma (5 of 11), dental anomalies (5 of 7), mild dysmorphic features (6 of 14) and aspiration pneumonias were common; ophthalmological assessment, performed in few patients, revealed macular changes (3 of 7), including cone-rod dystrophy, optic atrophy (3 of 7) and myopia with amblyopia (2 of 7) [32, 55]. Five of the 15 patients died between 2 and 17 years of age, and an affected sibling died at 6 months; the Indian patient died of aspiration at 2 years, and hospitalisations for aspiration pneumonia and respiratory failure were frequent in the series [22, 32]. In the Pakistani family homozygous for p.(Tyr26*), two adult members (22 and 24 years) had only ichthyosis and macular changes, without delay or seizures, which extends the spectrum to exclusively cutaneous forms [32, 54]. Heterozygous ELOVL4 variants have been associated with isolated cutaneous manifestations or with ataxia: erythrokeratodermia in a child and acral collodion membrane followed by ichthyosis with a geometric pattern in a twin [89, 90].

ELOVL1 deficiency. In the 2025 series, seven patients from five consanguineous families, aged 4 to 21 years at last assessment, had uneventful pregnancy and delivery; congenital ichthyosis of the trunk and limbs was present in 5 of 7 [26]. Motor development was delayed in all, although all sat without support by 16 months and three achieved walking; progressive spasticity, predominantly in the lower limbs, occurred in 7 of 7 and led to loss of walking in one patient [26]. The movement disorder combined axial hypotonia (6 of 6), head tremor (7 of 7), rest myoclonus worsened by voluntary movement (6 of 7), dystonia (4 of 7) and dysarthria (6 of 6); nystagmus was present in 5 of 6, photophobia in 2 and intellectual disability, mild, in 4 of 5, with communication preserved in all [26]. MRI showed hypomyelinating leukodystrophy, also cerebellar, in 6 of 6 and hypoplasia of the corpus callosum in 5 of 6, without progression on repeat scans [26]. In the dominant form, ichthyosis appeared in the first year and the picture includes keratoderma, acanthosis nigricans, spastic paraplegia, high-frequency sensorineural hearing loss and optic atrophy with visual field reduction, with normal cognition [23, 38]. An Italian girl heterozygous de novo, followed up to 15 years, was born with a collodion membrane, progressed to ichthyotic erythroderma with islands of normal skin that enlarged with age, had nystagmus at 18 months and slowly progressive spastic paraparesis, retained independent walking and a full-scale intelligence quotient of 95, and the white matter changes increased slightly between 2 and 10 years, with thinning of the corpus callosum and no lipid peak on spectroscopy [33]. A newborn girl homozygous for p.(Trp153*), born to consanguineous parents and sister of a child who had died of liver disease at 2 months, had severe cholestasis with total bilirubin of 46 mg/dL at 5 months, low VLCFA levels and ichthyosis, extending the phenotype to primary liver disease [34].

Chanarin-Dorfman syndrome. The skin shows non-bullous congenital ichthyosiform erythroderma with fine scales on an erythematous background, often in the flexures, scalp and face, with palmoplantar hyperkeratosis and pruritus; some newborns are collodion babies, sometimes with bilateral ectropion [29, 31]. In a literature review cited in a 2025 publication, steatohepatitis was described in 60–70% of patients, myopathy in about 60%, ocular changes (nystagmus, strabismus, cataracts, retinal dysfunction) in 42%, ectropion in 29%, splenomegaly in 19–24% and intellectual disability in 8% [35, 72]. The liver shows steatosis with aminotransferases two to four times above normal, which may progress to steatohepatitis, fibrosis and cirrhosis, the main cause of morbidity and mortality [31, 72]. Muscle shows accumulation of neutral lipids in type 1 and 2 fibres and raised CK, even without weakness: of the seven Italian patients reviewed, all had raised CK and only three had clinical myopathy [24, 31]. Sensorineural hearing loss, cataract, non-progressive psychomotor delay, ataxia and spasticity are described; cardiomyopathy is rare, but cardiac MRI in a 26-year-old man showed intramyocardial lipid accumulation and fibrosis with a normal echocardiogram [31, 35]. In two patients investigated for suspected SLS, magnetic resonance spectroscopy showed lipid accumulation in the white matter, cortex and basal ganglia, the first record of brain involvement in the disease [91].

The largest published series brought together 15 patients from 12 families from the Kerkennah islands, in Tunisia, all homozygous for the same founder allele, aged between 7 months and 58 years [37]. All had congenital ichthyosiform erythroderma, and Jordans anomaly was found in all 8 investigated; ultrasound showed hepatic steatosis in 9, without signs of cirrhosis, and poorly differentiated renal parenchyma in 4 of 10 [37]. Audiometry revealed sensorineural hearing loss in 8 of 8, but only 2 had complaints; 4 of 10 had ocular changes (ectropion, with cataract in 3), all aged 30 to 52 years [37]. Thyroid function was abnormal in 7 of 12, all aged 30 years or older, with abnormal ultrasound and fatty infiltration of the parenchyma on cervical MRI in two patients; the association with age was significant (p = 0.04) and healthy relatives had normal function, although the endogamy of the island does not allow a chance association to be excluded [37]. The Sicilian patient described at 5 years by Angelini and colleagues had, at 33 years, mild weakness after prolonged exercise, progressive hearing loss and slight elevation of CK and aminotransferases [24].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

In the newborn or infant, suspicion should arise in the presence of generalised erythema and hyperkeratosis without a collodion membrane, especially in a preterm infant, accentuated in the flexures and sparing the central face, and with intense pruritus from the first months [10, 13]. The complete triad is rarely present before 3–4 years, and the diagnosis is therefore often delayed [12, 15]. In the young child, the association of ichthyosis with motor delay and lower-limb spasticity is the main warning sign; the finding of perifoveal crystalline dots from 1–2 years of age allows the ophthalmologist to make a reliable clinical diagnosis in the neurocutaneous context [11, 82]. In the adult with chronic spastic paraparesis, ichthyosis points to SLS, Refsum disease or ELOVL4 deficiency [92]. Mild forms may present in neurology as paraparesis attributed to prematurity, in ophthalmology as crystalline maculopathy or in dermatology as isolated pruritic ichthyosis [41].

In a congenital ichthyosis, some findings point to the related entities. An association with hepatomegaly, raised aminotransferases or raised CK, or with vacuoles in neutrophils seen incidentally on a blood count, should prompt targeted examination of the blood smear for Chanarin-Dorfman syndrome [31, 36]. Ichthyosis with profound global delay, epilepsy beginning in the first months and microcephaly suggests ISQMR [32]. Ichthyosis or keratoderma with nystagmus, spasticity, head tremor, myoclonus and hypomyelination on MRI suggests ELOVL1 deficiency, as does neonatal cholestasis in a newborn with ichthyosis and low VLCFA [26, 34]. There is no newborn screening targeting these disorders; in the newborn screening of the girl with p.(Trp153*), the C26 value was recorded as zero [34].

4.2. Warning and emergency signs

Loss of motor or cognitive milestones, especially after a febrile infection or with poorly controlled seizures, departs from the usual course and warrants urgent neurological assessment [49]. Recurrent seizures, signs of skin infection over excoriated skin, heat intolerance due to hypohidrosis and swallowing difficulties with nutritional risk are other reasons for targeted assessment [12, 74, 79, 93]. There is no newborn screening for SLS.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal diagnostic criteria published by scientific societies. In practice, the diagnosis rests on the combination of a compatible phenotype (pruritic congenital ichthyosis with spasticity and intellectual disability, or part of this triad with crystalline maculopathy and leukoencephalopathy) with the demonstration of biallelic pathogenic variants in ALDH3A2 or of the enzyme deficiency [10, 12]. The presence of perifoveal glistening white dots with ichthyosis and spasticity is considered highly characteristic; the lipid peak on MRS is a supporting finding; and ichthyosis and retinopathy, although constant, are not in isolation pathognomonic [4, 48].

5.2. Tests in order

Research lipid biomarkers extend these options: untargeted lipidomics identified in plasma alkylphosphocholines and alkylphosphoethanolamines more than 600 times above controls and five compounds with ubiquinol and phosphocholine 100 to 1000 times above, the first plasma biomarkers of SLS [95]; and stratum corneum 1-O-alkylglycerols are increased about 100-fold, in a non-invasive test [58]. None of these tests is validated for routine clinical use in the sources consulted.

5.3. Practical algorithm

In a child with congenital ichthyosis and motor delay or spasticity, the first step is genetic testing covering ALDH3A2 and copy-number variants, in parallel with ophthalmological examination with fundoscopy and, where possible, OCT [12, 82]. MRI with MRS documents the leukoencephalopathy and the lipid peak and is useful in the differential diagnosis with other leukodystrophies, but often requires sedation [12, 88]. If genetic testing shows only one variant, a variant of uncertain significance or a negative result with a suggestive phenotype, measurement of enzyme activity in fibroblasts or leucocytes and testing for plasma fatty alcohols resolve most cases [10, 15]. An apparently homozygous variant in a child of non-consanguineous parents should prompt parental testing, because it may represent hemizygosity due to a deletion on the other allele: in one child, the variant c.407C>T (p.Pro136Leu) appeared homozygous and was in trans with a 1.44 Mb deletion [16].

5.4. Content of the genetic report

The report should state the gene, the transcript with version (NM_000382.3, MANE Select), the variant in HGVS nomenclature at DNA and protein level, the zygosity, the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and the need for segregation analysis [7, 14, 67]. Part of the literature uses version NM_000382.2, with the same c. numbering for the recurrent variants; historical nomenclature (for example, «C943T» or «GA del 1297-1298») must be converted before comparing results [14, 43, 63]. The proposed checklist for case reports recommends recording both alleles in HGVS, parental segregation, consanguinity and the explicit presence or absence of the nine main symptoms with age at onset [14].

5.5. Prenatal diagnosis

Prenatal diagnosis is possible by analysis of the familial variants in chorionic villi or amniocytes, first described in a Swedish family carrying c.943C>T in 1997 [96]. Before the molecular era, FAO and FALDH deficiency was measured in second-trimester amniocytes and first-trimester chorionic villi, with correct predictions in four at-risk pregnancies [97]; a later assay in chorionic villus fibroblasts measures the conversion of phytol to phytenic acid [98]. Fetal skin biopsy, used historically, gave a false-negative histological result at 19 weeks and was positive only at 23.5 weeks [78].

5.6. Diagnosis of the related entities

Chanarin-Dorfman syndrome. The peripheral blood smear stained with May-Grünwald-Giemsa shows vacuoles in the cytoplasm of neutrophils, which appear empty on Giemsa and stain red with Oil Red O or Nile red, confirming their lipid nature; they may also be present in eosinophils, monocytes and platelets [29, 31, 36]. The presence of this Jordans anomaly in a patient with ichthyosis greatly increases the probability of the diagnosis and should be looked for carefully [31]. Skin biopsy, performed in the investigation of congenital ichthyoses, is usually negative for neutral fat droplets, because standard fixation removes the lipids [31]. Serum lipids are normal, aminotransferases and CK are often raised, and ATGL deficiency also causes Jordans anomaly, but without ichthyosis [29, 31]. Confirmation is by molecular analysis of ABHD5, often within a congenital ichthyosis panel, with CNV analysis, because large deletions escape exon sequencing; a negative result in a patient with a typical picture does not exclude the diagnosis [29, 31]. Heterozygotes may have vacuoles in circulating eosinophils, a useful finding in family studies [24]. FALDH activity and fatty alcohols are normal, but magnetic resonance spectroscopy may show cerebral lipid accumulation, so the lipid peak does not by itself distinguish SLS from this syndrome [91].

ISQMR. The diagnosis is molecular. Clinical exome with CNV analysis from the sequencing data detected the homozygous deletion of exon 1 of ELOVL4 in two families, after a neurological panel lacking the gene had been negative; in one of the patients, the microarray had six absent probes in a region of homozygosity, below the reporting threshold [32]. Small homozygous intragenic CNVs frequently escape microarrays and should be looked for when they fall within a region of homozygosity, especially in populations with consanguinity [32]. Plasma VLCFA do not discriminate; the C28:0/C26:0 ratio of lysophosphatidylcholines in dried blood spots, reduced in two patients, is a biomarker under study, still without clinical validation [32]. The electroencephalogram, MRI and ophthalmological assessment with electroretinogram and visual evoked potentials complete the characterisation [32, 55].

ELOVL1 deficiency. The diagnosis is also molecular, by exome or by panels for ichthyoses, erythrokeratodermias or leukodystrophies [26, 33]. In the dominant form, serum VLCFA from C20:0 to C26:0 were normal, but the C24:0/C22:0 ratio was decreased; in one biallelic patient, C24:0 and C26:0 were decreased, and in the newborn with cholestasis VLCFA were low [26, 34, 56]. By the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), only the nonsense variant of the 2025 series reached the pathogenic class; the four homozygous missense variants remained of uncertain significance, despite segregation and the specificity of the phenotype, which shows the value of lipid studies in fibroblasts and of family segregation [26]. MRI shows diffuse, non-progressive hypomyelination in the biallelic form, and milder changes, sparing the U-fibres, in the dominant form [26, 33].

The report should state the MANE transcript (NM_022726.4 for ELOVL4, NM_022821.4 for ELOVL1, NM_016006.6 for ABHD5), the variant in HGVS, the zygosity, the ACMG/AMP class and segregation; in ELOVL1 deficiency, confirmation of de novo origin or of homozygosity defines the inheritance model [7, 26, 30]. Prenatal diagnosis and preimplantation genetic testing are possible when the familial variants have been identified [32].

6. Differential Diagnosis

6.1. Ichthyosis with spasticity and intellectual disability

The closest differential is the group of disorders of complex lipid metabolism that combine ichthyosis and spastic paraplegia [71]. Biallelic ELOVL4 deficiency (ichthyosis, spastic quadriplegia and impaired intellectual development syndrome, ISQMR) is described as an SLS mimic, but with profound psychomotor delay, early refractory seizures and a collodion membrane in one of the index cases [15, 22]. ELOVL1 deficiency, described in few patients, combines ichthyotic keratoderma, spasticity, dysmorphic features and hypomyelination [15]. OMIM designates it ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic facial features (IKSHD, #618527; ELOVL1, 1p34.2) and records two inheritance patterns: the p.Ser165Phe variant arose de novo in the heterozygous state in two unrelated Polish boys, with no common founder haplotype, and a homozygous splicing variant with exon skipping was found in two siblings of consanguineous Turkish parents, with reduced skin acylceramides (especially C25/C26 and longer) and defective synthesis of very-long-chain fatty acids [23]. Unlike SLS, cognitive development was normal in all four patients, and the picture includes progressive high-frequency sensorineural hearing loss from the first decade, nystagmus and, in the two Polish boys, optic atrophy with thinning of the peripapillary nerve fibre layer on optical coherence tomography, photophobia and visual field constriction; MRI showed non-progressive hypomyelination in the posterior limb of the internal capsule and the optic radiations, the Polish boys became wheelchair-dependent and one of them had a neurogenic bladder with detrusor-sphincter dyssynergia [23]. Multiple sulfatase deficiency (SUMF1) adds to ichthyosis a neurological deterioration of the metachromatic leukodystrophy type, organomegaly and skeletal anomalies [99]. CEDNIK syndrome (SNAP29) combines cerebral dysgenesis, neuropathy, ichthyosis and palmoplantar keratoderma [100]. Serine synthesis deficiencies, some congenital disorders of glycosylation (MPDU1-CDG, DK1-CDG, SRD5A3-CDG) and Gaucher disease type 2 complete the group of ichthyoses with neurological involvement [71].

6.2. Other syndromic and non-syndromic ichthyoses

Chanarin-Dorfman syndrome (ABHD5) presents with non-bullous ichthyosiform erythroderma and lipid vacuoles in granulocytes visible on a blood smear, with variable hepatic, muscular, ocular and auditory involvement [24]. Classic Refsum disease (PHYH) has occasional ichthyosis, pigmentary retinopathy, neuropathy, ataxia and raised phytanic acid, which is normal in SLS [10, 101]. Ichthyosis prematurity syndrome (SLC27A4, now SLC27A4-nEDD) shares preterm birth, but without neurological disease [15, 47]. The non-syndromic autosomal recessive congenital ichthyoses and the general approach to ichthyoses provide the framework; congenital ichthyosiform erythroderma is the non-syndromic ichthyosis closest in appearance [8]. A Norwegian family with SLS-type ichthyosis without neurological involvement was described as a separate entity (OMIM 270220) [8].

6.3. Spastic paraparesis and leukoencephalopathy

In the adult, metabolic causes of chronic spastic paraparesis include cerebrotendinous xanthomatosis, SPG5 (CYP7B1), adrenomyeloneuropathy, peroxisome biogenesis disorders, adult polyglucosan body disease and the paraplegias due to defects in complex lipid synthesis (SPG28, SPG54 due to DDHD2, SPG56, SPG39, SPG35 due to FA2H, SPG46 due to GBA2, SPG26, PLA2G6, PCYT2, ELOVL4) [92]. SPG54 due to DDHD2 appears alongside SLS among the leukoencephalopathies with a thin corpus callosum [71]. One mildly affected adult patient had his paraparesis attributed for decades to prematurity, a differential to consider in cerebral palsy without a clear perinatal insult [41].

6.4. Differential table

6.5. Differential among the neurocutaneous ichthyoses of lipid metabolism

SLS is distinguished from the three related entities by the crystalline maculopathy, the lipid peak at 1.3 ppm and FALDH deficiency, but none of these elements is exclusive on its own: spectroscopy may show lipids in Chanarin-Dorfman syndrome and did not show them in dominant ELOVL1 deficiency [33, 91]. Chanarin-Dorfman syndrome is separated from the others by the blood smear and by liver and muscle disease, with mild or absent neurological involvement in most [31, 35]. ISQMR has the most severe neurological picture, with profound delay, early epilepsy and death in childhood in some patients [32]. ELOVL1 deficiency resembles the hypomyelinating leukodystrophies, such as Pelizaeus-Merzbacher disease, through nystagmus, spasticity and relatively preserved cognition, but head tremor and myoclonus are atypical in those diseases; TUBB4A-related leukodystrophy also has dystonia, but is accompanied by atrophy of the basal ganglia and cerebellum, absent in ELOVL1 deficiency [26].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation

There is no approved treatment directed at the metabolic defect and no SLS-specific guideline or consensus; management is symptomatic, lifelong and coordinated by a multidisciplinary team of dermatology, paediatric neurology and neurology, ophthalmology, physical and rehabilitation medicine, orthopaedics, metabolic diseases, nutrition, speech therapy and psychology [4, 10]. For skin care, the ERN-Skin congenital ichthyosis guidelines (2019, with a 2024 update published in 2025), the Pediatric Dermatology Research Alliance (PeDRA) consensus on retinoids in children (2021), the French national protocol (PNDS, 2024) and the German S1 guideline (2017) apply, all of them applicable to the syndromic ichthyoses; the 2024 update expressly lists pruritus as a characteristic finding of SLS [18, 46, 102–105]. Anaesthesia recommendations derive from a case series [12].

7.2. Ichthyosis: topical care

Emollients are indicated in all ichthyoses (level of evidence 1, grade of recommendation B), at least twice a day and preferably after bathing; urea-containing emollients are not applied to inflamed skin, flexures or erosions [102]. In SLS, 2–10% urea creams once or twice a day, daily baths and keratolytics such as lactic acid and urea to remove the scale are in routine use [10, 12]. For thick scale, keratolytics (urea 10% or higher, up to 20% and 40% on localised areas; alpha-hydroxy acids at 5–12%; propylene glycol above 20%; salicylic acid above 2%) are applied once or twice a day, avoiding the face, flexures and fissures; keratolytics are not recommended in newborns or young infants, and salicylic acid is contraindicated before 2 years of age [18, 102, 105]. The German guideline advises against urea in the first year of life [46]. Topical calcipotriol improves the ichthyosis, but extensive application carries a risk of hypercalcaemia; topical tazarotene, off-label, is used for limited areas [6, 10]. One group reported slight improvement with topical cholesterol and lovastatin [6]. In the experience of American twin girls, 40% urea and 0.005% calcipotriol were poorly tolerated, and 0.1% triamcinolone, 0.03% tacrolimus and 0.1% tazarotene had minimal effect on pruritus and thickening [2].

7.3. Ichthyosis: acitretin

Systemic retinoids improve the skin in most ichthyoses, including SLS, and the PeDRA consensus includes SLS among the subtypes with described improvement (level II, grade B) [6, 104]. In Sweden, 19 of 34 patients (56%) were on oral acitretin [74]. In eight Turkish children, a maintenance dose of 0.25 mg/kg/day reduced the severity of the ichthyosis in all and improved the quality of life of patients and carers [66]. The French PNDS states that the oral retinoid generally improves pruritus in SLS, and the European guideline allows oral retinoids for persistent pruritus, noting that they may either improve or provoke pruritus [93, 105]. Retinoids have no effect on neurological symptoms [6].

Acitretin (Neotigason® in Portugal and the United Kingdom; Soriatane® in the USA, a discontinued brand, with generics) is an aromatic retinoid that modulates keratinocyte proliferation and differentiation through nuclear retinoid receptors [6, 106, 107]. The table compares the guideline dose (reference) with those of the labels.

The 75 mg/day dose cited by the guideline and the consensus exceeds the maximum maintenance dose of the Portuguese SmPC for keratinisation disorders (50 mg/day), and the SmPC paediatric maximum of 35 mg/day does not appear in the guidelines [102, 104, 106]. Acitretin is teratogenic: in the Portuguese SmPC, it is contraindicated in women of childbearing potential outside a pregnancy prevention programme, with effective contraception from before the start until 3 years after the end and pregnancy tests at 1–3-month intervals during those 3 years; the European guideline proposes monthly testing during treatment and for up to 36 months afterwards [18, 106]. Monitoring includes liver function tests before, every 2 weeks for the first 2 months, every 3 months in the first year and then 1–2 times a year, with discontinuation if transaminases exceed 3 times the upper limit of normal, as well as lipids and, under 18 years, annual growth assessment [18, 104]. The most common adverse effects are cheilitis, dryness of the skin and mucous membranes, skin fragility and fissures, dry eye and photosensitivity [18]. In SLS, published experience is limited and concerns about lipids, bone and teratogenicity have limited widespread chronic use [6].

7.4. Pruritus

Pruritus is the most troublesome symptom and the one most often reported by families, and it responds poorly to usual topical treatment [2, 79]. The first step, according to the European guideline, is to optimise topical care and exclude infection (including dermatophytosis and scabies, which are harder to recognise on scaly skin); oral antihistamines and oral retinoids are options if pruritus persists (level 4, grade D) [93].

Zileuton. Zileuton inhibits 5-lipoxygenase and thus the synthesis of LTB4 and the cysteinyl leukotrienes [108]. In a 3-month open-label study in 5 patients, it reduced the pruritus score (P=0.006), improved general well-being and EEG background activity and lowered urinary LTB4 and ω-OH-LTB4 (P=0.02 and P=0.003), with no change in MRI, MRS or neuropsychological tests [108]. The randomised, double-blind, placebo-controlled crossover trial that followed, with 10 patients, showed consistent benefit in only one patient and no effect on the ichthyosis or neurology; the authors nonetheless considered a 4–6-week therapeutic trial reasonable in severe disabling pruritus [6, 10, 109]. Zileuton is not authorised in the European Union through the centralised procedure; in the USA, the label of the extended-release tablet restricts it to the prophylaxis and chronic treatment of asthma from 12 years of age, at a dose of two 600 mg tablets twice a day (2400 mg/day, the total daily dose on the label, with no separate maximum dose defined) within one hour after meals, and declares it unsuitable below 12 years because of the risk of hepatotoxicity [110, 111]. Use in SLS is off-label; the dose used in the Dutch study is not given in the abstract consulted, and the reference dose is that of the asthma label, with the extrapolation declared. The label requires measurement of alanine aminotransferase (ALT) before starting, monthly for the first 3 months, every 2 to 3 months for the rest of the first year and periodically thereafter, contraindicates the drug in active liver disease or with transaminases persistently at or above 3 times the upper limit of normal, requires discontinuation if they reach 5 times that limit and warns of neuropsychiatric events, including sleep and behavioural changes [111].

Dupilumab. Dupilumab (Dupixent®) is a monoclonal antibody against the alpha subunit of the interleukin-4 receptor, which blocks IL-4 and IL-13 signalling [2, 112]. In 4-year-old twin girls with SLS and pruritus of mean intensity 7/10 and maximum 10/10, dupilumab 300 mg every 4 weeks reduced mean pruritus to 2–3/10 and maximum pruritus to 5/10 at 16 weeks, with improvement in sleep maintained at one year; a 3-month pause brought maximum pruritus back to 8–9/10, and worsening in the week before each injection led to the interval being shortened to 3 weeks; immunoglobulin E (IgE) was normal before treatment and there were no adverse effects [2]. This is a report of two cases, with no control group. The dose used corresponds to that of the US label for atopic dermatitis between 6 months and 5 years with 15 to less than 30 kg (300 mg every 4 weeks, with no loading dose); the 3-week interval is off-label [112]. In the European Union, Dupixent® has been authorised since 26/09/2017, with indications in moderate to severe atopic dermatitis from 12 years and severe atopic dermatitis from 6 months to 11 years, and in prurigo nodularis in adults, with no indication for ichthyosis [110, 113]. Alternatives acting on the IL-31 or Janus kinase pathways were, at the time of the report, limited to adolescents and adults [2]. Biologics (anti-IL-12/23, anti-IL-17A, anti-IL-4R/IL-13) are considered promising in several syndromic ichthyoses in the 2025 classification [47].

7.5. Spasticity, mobility and rehabilitation

Early and intensive physiotherapy is the mainstay of spasticity treatment and serves to maintain walking and prevent contractures [10, 15, 114]. Oral muscle relaxants, benzodiazepines, anticholinergics and oral baclofen have systemic effects (incoordination, drowsiness, fatigue, nausea) that limit their use, and are considered of little efficacy in SLS [12, 114]. Botulinum toxin, with or without serial casting, gives a temporary benefit that may wane with repetition; orthopaedic surgery (tendon lengthening, adductor release, hamstring release) and dorsal rhizotomy give a more lasting benefit for walking [10, 12, 67, 114].

Intrathecal baclofen was used with a favourable response in two patients from Nebraska and New York [114]. The protocol included a trial with a 50 µg lumbar bolus given over 1 minute and assessment on the Modified Ashworth Scale before and 2, 4 and 6 hours afterwards; after pump implantation, the starting dose was 25–40 µg/day, adjusted to age, weight, prior medication and response to the trial, with inpatient rehabilitation for 4 weeks and refills about every 3 months [114]. In a 5-year-old boy, the dose rose from 25 to 215 µg/day over one year, with less scissor gait and better hip and trunk mobility; skin irritation over the pump at 15 months led to its subfascial repositioning, without infection. In a 19-year-old woman, previously on oral baclofen 10 mg three times a day, the dose went from 39.9 to 135 µg/day, intermittently excessive (knees giving way), and stabilised at 86 µg/day at 3 years [114]. In the general literature on paediatric pumps, dehiscence or infection occurs in 10–32% of implantations and infection in 20% of subcutaneous pumps versus 4% of subfascial ones, which is why the authors propose subfascial placement in low-weight children with congenital skin disease [114]. These doses come from two cases and must be titrated individually.

7.6. Seizures, cognition, communication and feeding

Seizures are usually controlled with conventional antiseizure medications, with no preferred drug described [10, 14]. Given the risk of neurological regression associated with poorly controlled seizures and febrile infections in some patients, the authors of the neurodegenerative series recommend treating both actively [49]. Early speech therapy intervention is recommended, because language follows cognitive development [10]. Feeding and swallowing difficulties (75% of patients surveyed in the Netherlands) warrant swallowing and nutritional assessment; in one child with regression a gastrostomy was required [49, 79]. Oral health should be part of the care plan, given the description of enamel hypoplasia, severe caries and gingivitis, with dental treatment often under general anaesthesia [12, 66, 85].

7.7. Eye

There is no effective treatment for the maculopathy [82]. Measures are supportive: optical correction of myopia and astigmatism, artificial tears for dry eye and sunglasses for photophobia [12, 83]. The European ichthyosis guideline recommends regular ophthalmological review, from monthly to once or twice a year depending on severity, and preservative-free lubrication when the ocular surface is exposed [93]. The dynamic nature of the retinal inclusions suggests that an effective metabolic therapy might modify part of the maculopathy, and fundus photography with image analysis has been proposed for monitoring future trials [62].

7.8. Diet

Low-fat diets supplemented with medium-chain triglycerides or essential fatty acids have been tried with anecdotal reports of skin improvement, and a historical OMIM entry still mentions clinical improvement with fat restriction [6, 8]. However, in 5 children treated from 5 months to 8 years of age with a diet low in fat and with medium-chain fatty acids, plasma octadecanol did not change and the skin and neurology did not improve; two also did not respond to polyunsaturated fatty acids [115]. The current conclusion is that diet is generally ineffective, even when started early, and has no convincing neurological effect [6, 115]. Restriction of phytol and phytanic acid has not been studied and has no rationale, because these compounds are not raised [6].

7.9. Anaesthesia and the perioperative period

In the Nebraska series (14 patients, 48 anaesthetics between 2013 and 2019, mean age 10 years, mainly for research MRI, dental treatment, botulinum toxin, baclofen pumps and tendon release), inhalational or intravenous induction with propofol, laryngeal mask (31 cases), intubation (10) and one epidural anaesthetic proceeded without serious adverse events or hyperthermia [12]. The problems were poor adhesion of electrodes and catheter dressings to the ichthyotic skin and superficial lacerations on removing adhesives [12]. Practical recommendations are: prior neurocognitive assessment and possible premedication; review of seizures and of interactions between antiseizure medications and anaesthetics; examination of contractures for positioning and access; attention to photophobia under theatre lights; stopping topical lotions 7 days beforehand; securing electrodes, oximeter and catheters with self-adherent bandage; clip-on rather than adhesive oximeter; careful removal of adhesives and cutting of the MRI-compatible electrode to reduce the adhesive area; temperature monitoring because of heat intolerance; usual fasting; the airway is usually normal and securing the tube is easy because the central face is spared; no additional postoperative monitoring is needed because of SLS [12]. A Japanese case of deep sedation with propofol and remifentanil infusions confirmed the difficulties with adhesives and added soft-tissue airway obstruction [116].

7.10. Pregnancy, transition and agents to avoid

The sources consulted do not describe pregnancies in women with classic SLS; a man with a mild phenotype had two healthy children [41]. In women of childbearing age, acitretin requires effective contraception and monitoring until 3 years after discontinuation, and topical tazarotene is contraindicated in pregnancy [104, 106]. Transition to adult care is relevant because most patients survive into adulthood and because complications of the maculopathy, contractures and lower-limb circulation become more marked with age [6, 74, 76]. The agents to avoid derive from the symptomatic treatments: topical salicylic acid before 2 years of age and on large surfaces, keratolytics in the newborn, calcipotriol on large areas because of the risk of hypercalcaemia, and zileuton below 12 years according to the label [6, 102, 111].

7.11. Investigational therapies

The most developed rationale is that of aldehyde-sequestering agents, molecules with amine groups that react with fatty aldehydes and prevent adduct formation [6]. In FALDH-deficient cells, ADX-102 (reproxalap, formerly NS2) protected against octadecanal-induced cytotoxicity and apoptosis, inhibited its conversion to octadecanol and normalised after 4 days the N-alkyl-phosphatidylethanolamine adducts, which were 5 times above normal [57]. Other approaches remain preclinical: bezafibrate, a PPAR-α agonist, increased transcription and residual FALDH activity in fibroblasts with missense variants [6, 10]; the activator Alda-89 tripled FALDH activity in vitro [6]; JNK cascade inhibitors and antioxidants are hypotheses [6]; and gene transfer with an adeno-associated virus type 2 vector increased activity in patient keratinocytes on average 15-fold, to 60–70% of normal, and restored resistance to long-chain aldehydes (84% survival versus 17% in untreated cells) [10]. The Aldh3a2 null mouse model has hardly any ichthyosis or evident neurological disease, which limits preclinical evaluation [6].

The reproxalap trials are small, the phase 3 result posted on the registry refers only to the treated arm and the sponsor maintains a restrictive publication agreement; no trial has so far shown comparative benefit on the ichthyosis, pruritus or neurology, and the trials are not comparable with one another [117, 118].

7.12. Regulatory status and developments in the last 12 months

In the last 12 months, the FDA issued on 17/03/2026 the third CRL on the marketing application for reproxalap in dry eye (level of evidence: regulatory decision reported by the sponsor in an SEC Form 8-K filing and covered by the specialist press), which does not concern SLS but keeps the drug without any authorisation [119]. According to a press summary from October 2025 of the Aldeyra announcement, the company discontinued its own clinical development of ADX-629, while maintaining the investigator-initiated trials, including the one in SLS (level: press release, secondary source) [120]. The ADX-629 trial in SLS ended in April 2026 without published results [19]. The report of dupilumab in twins (2026) and the plasma lipidomic biomarkers (2024) are the remaining clinical and diagnostic developments [2, 95]. In 2025, the new classification of epidermal differentiation disorders renamed the disease ALDH3A2-sEDD [3].

7.13. Related entities: treatment

None of the three entities has an approved targeted treatment. In November 2026, a search of ClinicalTrials.gov found no interventional trials in these diseases; the only study covering them is an international observational registry of neutral lipid storage diseases, coordinated in Japan and recruiting since 2014, which includes CGI-58 deficiency [121]. Skin care follows the ichthyosis guidelines applied to SLS, with emollients, keratolytics and, when indicated, acitretin at the doses in subsection 7.3 [18].

Chanarin-Dorfman syndrome. Restriction of dietary long-chain fatty acids with medium-chain triglyceride supplementation is the most frequently described measure, supported by case reports: in a Sicilian child, the medium-chain triglyceride diet led to regression of hepatosplenomegaly, and in a 4-year-old child followed at a university hospital in Catalonia, six months of diet reduced the areas of scaly skin, with no change in aminotransferases [24, 36]. In a man followed up to the age of 26, a low-fat diet (initial target below 10 g/day, then 20 g and finally 30 g/day, with about 1.4 g/kg/day of protein), medium-chain triglyceride oil and coenzyme Q10 stabilised muscle symptoms and energy, with no long-term gain in strength; ursodeoxycholic acid with vitamin E for about one year did not change liver function tests, and bezafibrate did not improve muscle symptoms [35]. Adherence to lipid restriction was difficult in this patient [35]. Systemic retinoids improved the skin in case reports, but liver disease, common in this condition, limits their use: the Portuguese acitretin SmPC contraindicates it in severe hepatic impairment and requires liver function tests before and during treatment [31, 35, 106]. Triheptanoin, a synthetic medium-chain triglyceride, has been described with muscular benefit in the myopathic form due to ATGL deficiency, not in Chanarin-Dorfman syndrome [35]. In decompensated cirrhosis, a 17-year-old girl received a deceased-donor liver in January 2019 and five years later still had normal liver function tests, without rejection or recurrence; transplantation does not correct the extrahepatic disease [39]. In preclinical research, a repurposing screen of about 2500 FDA-approved drugs in fibroblasts from one patient identified compounds that reduce the area and number of lipid droplets, among them tafenoquine, MitoQ and lomitapide, and re-expression of functional ABHD5 reduced the droplets in these cells; there are no data in patients [35, 122].

ISQMR. Treatment is supportive: antiseizure medications, with epilepsy often difficult to control; tube or gastrostomy feeding for dysphagia with aspiration; treatment of reflux and asthma; and skin care with emollients [32, 55]. In an Italian child, trihexyphenidyl reduced dystonic posturing [55]. There is no therapy that restores VLCFA of 28 or more carbons [32].

ELOVL1 deficiency. Treatment is also supportive, with management of spasticity, movement disorder and skin similar to that of SLS [26]. In the newborn with cholestasis, ursodeoxycholic acid coincided with worsening, and its replacement by cholic acid was followed by a fall in bilirubin and progressive normalisation of liver function tests, a single-case result with an unexplained mechanism [34]. C22:0 supplementation increased C24:0 ceramides and sphingomyelins in patient fibroblasts, and PPAR binding motifs in the dysregulated genes led to PPAR modulators being proposed; both hypotheses are preclinical [38].

Developments in the last 12 months: the 2025 series of biallelic ELOVL1 deficiency and the 2026 cases with neonatal cholestasis and with prolonged follow-up of the dominant form (human studies, descriptive); the 2025 study on the role of ABHD5 in epidermal acylceramide synthesis and the 2025 drug screen in fibroblasts (preclinical); a 2025 report of neuromuscular, cardiac and hepatic course in an adult and a 2024 report of liver transplantation with five years of follow-up (human studies, isolated cases) [26, 28, 33–35, 39, 122].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

SLS is transmitted in an autosomal recessive manner. When both parents are carriers, each pregnancy has a 25% probability of an affected child, 50% of an asymptomatic carrier and 25% of a non-carrier; the unaffected siblings of a patient have a two-thirds probability of being carriers [8]. Heterozygotes are asymptomatic and have about 50% of normal FALDH activity, which makes the enzyme assay unreliable for identifying carriers and reinforces the use of genetics [8]. In the absence of consanguinity, most patients have no family history [12]. The children of a patient are obligate carriers, and the risk of their having an affected child depends on the carrier frequency in the other parent's population; in Sweden, that frequency was estimated at 0.5% for the country as a whole and 2.0% in Västerbotten [9]. In consanguineous and extended families, family studies may identify other affected individuals and carriers, as in a Saudi family with five individuals affected by the same variant [123].

8.2. Confirmation of phase and deletions

Parental testing is needed to confirm that the two variants are in trans and to detect a large deletion that mimics homozygosity, with direct implications for carrier testing of relatives and for prenatal diagnosis [10, 16]. The sources consulted do not describe germline mosaicism or de novo variants in ALDH3A2; the well-demarcated skin pattern of two mildly affected patients did not correspond to any known pattern of mosaicism [41].

8.3. Prenatal and preimplantation diagnosis

With the familial variants known, prenatal diagnosis is made by molecular analysis in chorionic villi or amniocytes [96]. Enzymatic methods in amniocytes and chorionic villi and the phytol assay in chorionic villus fibroblasts are historical alternatives when the variant is not known [97, 98]. Fetal skin biopsy is not reliable before 23 weeks [78]. The sources consulted do not describe cases of preimplantation genetic testing in SLS.

8.4. Counselling

Counselling should address the variability in severity, including the existence of mild forms with normal intelligence and rare neurodegenerative forms, the absence of a genotype-phenotype correlation useful for predicting the course and the lack, to date, of targeted treatment [14, 41, 49].

8.5. Related entities: counselling

In ISQMR, Chanarin-Dorfman syndrome and the recessive form of ELOVL1 deficiency, the recurrence risk for each pregnancy of a carrier couple is 25% [22, 24, 26]. In Chanarin-Dorfman syndrome, pseudodominance has been described in a consanguineous family from the Middle East, with the father and three children affected, and heterozygotes can be recognised by vacuoles in eosinophils [24]; a heterozygote with one severely deficient allele may develop hepatic steatosis or dyslipidaemia, which justifies metabolic assessment of the parents [31]. In ISQMR, a heterozygous father had drusen-like macular deposits, possibly attributed to smoking, and macular changes were described in another parent, which makes it reasonable to offer ophthalmological examination to carriers, although no formal recommendation exists [22, 32]. In the dominant form of ELOVL1 deficiency, the p.(Ser165Phe) variant arose de novo in all patients tested, so the risk for siblings is low, but not zero, because of the possibility of germline mosaicism; the affected patient transmits the variant to 50% of their children [33, 38]. In a consanguineous family with ISQMR, the exome revealed in the extended family a second recessive disease (a TBCK variant), and testing for both variants was recommended to the couple seeking preimplantation genetic testing; about 10% of consanguineous couples with an affected child share a second pathogenic or likely pathogenic variant [32].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Sweden and founder populations

The only population-based study is the 1981 Swedish national survey: 58 patients in 41 families (35 alive), 45 born in a restricted area of the north-east of the country; the mean incidence between 1901 and 1977 was 0.6/100,000 in Sweden, 10.2/100,000 in Västerbotten and 2.7/100,000 in Norrbotten, and the prevalence on 31/12/1978 was 0.4, 8.3 and 2.6/100,000, respectively, with gene frequencies of 0.002, 0.010 and 0.005 [9]. These values reflect a founder effect, with the centre of dispersal in Västerbotten at least 700 years ago, and do not apply to other populations [4, 69]. The estimate of about 1/250,000, used in reviews, does not derive from a population-based study [6, 49]. Orphanet places European prevalence in the class 1–9/1,000,000 [1].

Outside Sweden, clusters due to founder effect or consanguinity are known: the c.1297_1298del variant in Western Europe and the Netherlands, where admixture with the Swedish allele is visible; c.682C>T in Israel; c.1108-1G>C in Brazil and Turkey; c.24_25delinsTT and c.683G>A in Turkey and the Middle East; c.1094C>T and c.24_25delinsTT in Egypt; and c.1157A>G in China and Japan [14, 65, 67, 68]. In Turkey, a review of 58 patients from 36 families found consanguinity in 73% and homozygosity in all families [65]. In the USA, the diversity of genotypes reflects immigration [14]. The geographical distribution of published cases measures research activity and access to diagnosis, not incidence [14, 67].

9.2. Portugal and Brazil

In Brazil, SLS is due mainly to the splice variant c.1108-1G>C, found in the homozygous state in the 9 Brazilian patients in the LOVD database and in a small, isolated community studied in Campinas, with a founder effect; typical cases have also been published by the Hospital das Clínicas of the University of São Paulo [14, 60, 64, 124]. The sources consulted do not include epidemiological data or series of Portuguese patients; a 2011 European report with a novel variant has no geographical origin identifiable in the metadata [125]. In Spain, three cases were published in 2021 [126]. The absence of data in the sources consulted does not demonstrate that there are no patients in these countries.

9.3. Special populations

Adult patients are a growing population, with their own problems (advanced maculopathy, contractures, lower-limb oedema, dependence) [74, 76, 83]. In patients with intellectual disability and limited communication, assessment of pruritus, pain and quality of life relies on informants; in a survey of parents and carers, median quality of life was 73 (26–100), with mood problems rarely reported [79].

9.4. European networks and patient organisations

European patients can be referred to ERN-Skin, whose ichthyosis subgroup produced the European guidelines, and to MetabERN, for the metabolic and neurological aspects [20, 21, 102]. Patient organisations include the Foundation for Ichthyosis & Related Skin Types (FIRST), in the USA, and the Ichthyosis Support Group, in the United Kingdom [127, 128]. The ALDH3A2 LOVD database collects variants and phenotypes [14, 129].

9.5. Related entities: epidemiology

The three entities have no prevalence studies. Chanarin-Dorfman syndrome has about 120–130 published patients, most from Mediterranean and Middle Eastern countries, especially Turkey, which may be related to the frequency of consanguineous marriages; there are also families from Saudi Arabia, India and Japan [29, 36]. In Europe, Italian (Sicily, Molise), Greek and Cypriot families have been described, as well as one case diagnosed in Catalonia, and in the Kerkennah islands, in Tunisia, a founder allele affects at least 12 families of an endogamous population [29, 36, 37]. ISQMR has been described in families from Saudi Arabia, Pakistan, India and Italy, with a probable founder exon 1 deletion in a Saudi tribe, testing for which the authors advise in patients from the Middle East [32]. ELOVL1 deficiency has been described in patients from Poland, Turkey and Italy and in consanguineous families of other origins [26, 30, 33, 56]. The sources consulted do not include patients from Portugal or Brazil. European patients can be referred to ERN-Skin and MetabERN [20, 21].

10. Illustrative Clinical Case

Staps and colleagues described, in 2020, a 45-year-old Dutch man with SLS diagnosed in adulthood [41]. He had been born late preterm with dry skin and developed in childhood an ichthyosis mainly of the trunk, with well-demarcated hyperpigmented plaques, documented in photographs at 3 and 17 years; from the age of 30 the ichthyosis became milder, but the pruritus remained considerable. In childhood and early adulthood he was considered «clumsy», without stiffness or need for adapted footwear; at 30 years, after a road traffic accident, neurological examination showed for the first time a mild spastic gait, which was attributed to prematurity. He had worn glasses from an early age and had photophobia. He had completed secondary education and worked in a warehouse, with cognition considered normal and unremarkable speech; his parents were not consanguineous. At 45 years, a neurologist brought the findings together and requested targeted testing. Examination showed ichthyosis in the axillae, groins, lumbar region and inner aspect of the arms, with mild diffuse scaling on the legs, with the face, neck, most of the trunk and outer aspect of the arms spared, and spastic paraplegia with unsupported walking. Visual acuity was 0.5 in the right eye and 0.4 in the left; fundoscopy showed some perifoveal crystals and absence of the physiological macular darkening, and OCT a thin macula with hyperreflective dots and interruption of the photoreceptor layer. MRI showed subtle periventricular changes, and MRS lacked the lipid peak at 1.3 ppm. FALDH activity in lymphocytes was below the detection limit, and Sanger sequencing revealed compound heterozygosity for c.682C>T p.(Arg228Cys) and c.943C>T p.(Pro315Ser) in ALDH3A2 [41]. The skin photographs, the fundus photography with OCT and the MRI with MRS are available in figures 1 (https://pmc.ncbi.nlm.nih.gov/articles/PMC7203653/figure/jmd212099-fig-0001/), 2 (https://pmc.ncbi.nlm.nih.gov/articles/PMC7203653/figure/jmd212099-fig-0002/) and 3 (https://pmc.ncbi.nlm.nih.gov/articles/PMC7203653/figure/jmd212099-fig-0003/) of the article [41].

The case shows three points with practical consequences: SLS may present in the adult as spastic paraparesis with mild ichthyosis and normal intelligence; pruritus remains the main complaint even when the ichthyosis is subtle; and the absence of a lipid peak on MRS does not exclude the diagnosis [41]. Both variants have been described in patients with a classic phenotype, which reinforces the lack of genotype-phenotype correlation [41]. For the classic paediatric phenotype, the yellowish, thickened skin with accentuated skin markings of the twins treated with dupilumab is documented in figure 1 of the corresponding report (https://pmc.ncbi.nlm.nih.gov/articles/PMC13051042/figure/pde70073-fig-0001/) [2].

Complementary case (Chanarin-Dorfman syndrome). A 4-year-old child, with no relevant family history, followed at a university hospital in Reus (Catalonia), was referred to dermatology for an erythematous-scaly ichthyosiform syndrome since birth, with erythematous plaques with active scaly borders on the scalp, face, trunk, elbows, knees, palms and soles; the variable and migratory appearance led to consideration of erythrokeratodermia variabilis, and the biopsy showed hyperkeratosis compatible with seborrhoeic eczema [36]. Persistent hypertransaminasaemia led to review of the blood smear, which showed multiple cytoplasmic vacuoles in polymorphonuclear cells and platelets, absent in the parents; sequencing of ABHD5 revealed compound heterozygosity for p.(Arg312*), of paternal origin, and for a frameshift variant in exon 4, of maternal origin [36]. Screening for complications found mild sensorineural hearing loss and CK two to five times above normal, without muscle pain, with normal ophthalmological and neurological examinations; after six months of a diet restricting long-chain fatty acids with medium-chain supplementation, the areas of scaly skin decreased, with no relevant change in aminotransferases [36]. The case shows how liver disease and the blood smear redirect the diagnosis of a congenital ichthyosis; the response to diet is an isolated case result and not a pattern of efficacy [36].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The disease is chronic and lifelong, but in most descriptions life expectancy is not greatly reduced and most patients reach adulthood; one case report states that life expectancy is halved, without population data to support it [6, 12, 83]. Neurological signs tend to stabilise in adolescence, without cognitive deterioration in the first three to four decades, while contractures progress slowly and may lead to loss of walking; 59% of Swedish patients were wheelchair-dependent [10, 15, 74]. The severity of the ichthyosis did not change evidently with age in the Swedish cohort [74]. The maculopathy progresses, with foveal thinning over the years and, in adults, atrophy of the pigment epithelium or neovascularisation, although acuity usually remains useful [76, 82]. A minority of children have a neurodegenerative course, sometimes triggered by febrile infection or associated with poorly controlled seizures [49]. Mild forms retain walking and independence for decades [41].

11.2. Surveillance

There is no SLS-specific surveillance schedule published by societies. The table combines the recommendations of the ichthyosis guidelines, the labels and the clinical series.

11.3. Related entities: prognosis and surveillance

In ISQMR, one third of published patients died between 2 and 17 years of age, and survivors with neurological disease still had profound delay at the last assessment; the skin-only forms of the Pakistani family reached adulthood [32, 54]. In ELOVL1 deficiency, hypomyelination is stable, but spasticity and dysarthria progress slowly; biallelic patients were aged between 4 and 21 years at last assessment, and the dominant patient followed up to 15 years retained independent walking with mild motor worsening [26, 33]. In Chanarin-Dorfman syndrome, survival into adulthood is the rule in published series, with patients up to 58 years, but liver disease may progress to cirrhosis and require transplantation; in the Tunisian series, ocular changes and hypothyroidism were concentrated in patients aged 30 or older, and myopathy may progress in adulthood [35, 37, 39, 72]. None of the three entities has a surveillance schedule published by scientific societies; the table summarises the assessments proposed by the series and reports.

12. Summary and Final Considerations

Sjögren-Larsson syndrome, now designated ALDH3A2-sEDD, is an autosomal recessive neurocutaneous disease caused by deficiency of fatty aldehyde dehydrogenase, an endoplasmic reticulum enzyme that oxidises long-chain aldehydes derived from fatty alcohols, ether lipids, sphingosine-1-phosphate and leukotriene B4. Accumulation of aldehydes, fatty alcohols and ether lipids disrupts the epidermal barrier, myelin, grey matter and retina, and failure to inactivate LTB4 contributes to pruritus. The picture develops from birth: frequent preterm birth, pruritic ichthyosis without a collodion membrane and sparing the central face, spastic diplegia and developmental delay in the first two years, perifoveal crystalline maculopathy from 1–2 years and periventricular leukoencephalopathy with a lipid peak at 1.3 ppm on spectroscopy. The diagnosis is confirmed by sequencing of ALDH3A2 with deletion analysis and parental testing, supported, when necessary, by enzyme activity and plasma fatty alcohols. Variability is wide, from adults with normal intelligence and preserved walking to children with neurological regression, with no useful correlation with genotype. Treatment remains symptomatic and multidisciplinary: topical care and acitretin for the skin, topical optimisation and, in selected cases, off-label zileuton or dupilumab for pruritus, physiotherapy, botulinum toxin, orthopaedic surgery and intrathecal baclofen for spasticity, seizure control and ophthalmological care. Aldehyde-sequestering agents are the most advanced targeted approach, but topical reproxalap has not shown published comparative benefit and the trial of oral ADX-629 ended in 2026 without results being released. Epidemiology has been measured only in Sweden; in other countries the disease is known from case series and founder variants, including c.1108-1G>C in Brazil.

The neurocutaneous ichthyoses related to SLS result from defects at other points in the lipid network of the epidermal barrier and myelin. Chanarin-Dorfman syndrome (ABHD5) combines ichthyosiform erythroderma with triglyceride accumulation in almost all tissues, is recognised from the blood smear and has liver disease as the main cause of morbidity. ISQMR (ELOVL4) is the most severe neurological form, with profound delay and early epilepsy, and its diagnosis may depend on the detection of small homozygous deletions. ELOVL1 deficiency has a dominant de novo form with hearing loss and optic atrophy and a recessive form with hypomyelinating leukodystrophy, head tremor and myoclonus. None has a targeted treatment, and counselling depends on the inheritance model confirmed in the family.

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