X-Linked Ichthyosis (Steroid Sulfatase Deficiency)

Recessive X-linked ichthyosis due to steroid sulfatase (STS) deficiency, Xp22.3 contiguous gene syndromes, placental steroid sulfatase deficiency and Xp22.31 duplication in the differential diagnosis.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

Table abbreviations: CDP, chondrodysplasia punctata; CMA, chromosomal microarray; ERN, European Reference Network; FISH, fluorescence in situ hybridisation; MLPA, multiplex ligation-dependent probe amplification; NIPT, non-invasive prenatal testing on circulating cell-free DNA; ADHD, attention deficit hyperactivity disorder; uE3, unconjugated oestriol in maternal serum.

1. Introduction

1.1. Historical overview

X-linked ichthyosis was recognised as a distinct genetic type by Wells and Kerr in 1965, in a classification of the inherited ichthyoses that separated four autosomal recessive forms, the autosomal dominant forms (ichthyosis vulgaris, bullous ichthyosiform erythroderma and ichthyosis hystrix) and a sex-linked recessive form [38, 39]. The following year, the same authors described the clinical features of the autosomal dominant and sex-linked forms in an English population [40]. OMIM records earlier family reports, among them a Hungarian family published by Csorsz in 1928 and ten families assembled by Orel in 1929, and the description by Wells and Jennings (1967), according to which onset occurred at birth and involvement included the scalp, ears, neck, some flexures and the anterior aspect of the legs down to the dorsum of the foot [18]. The large seven-generation Dutch family published by Went et al. (1969) added that no affected individual had signs at birth, that the scales appeared shortly afterwards or during the first year, that they were black or grey in about half and white in the other half, and that all reported improvement in summer [18].

The biochemical basis was identified in 1978. Webster, France, Shapiro and Weiss demonstrated, in cultured fibroblasts, deficiency of 3β-hydroxysteroid sulfate sulfatase in individuals with ichthyosis and a family history compatible with X-linked inheritance [41]. In the same year, Koppe et al. described three pregnant women with very low urinary oestrogen excretion whose sons, normal at birth, developed X-linked ichthyosis; the placenta had histochemical arylsulfatase C deficiency and the same deficiency was present in the skin of the boys and of nine unrelated adults with the disease [42]. This observation linked low oestriol in pregnancy to ichthyosis in the son, a relationship that had already been anticipated by the New Zealand family of France and Liggins (1969), in which several women had low oestrogen production during pregnancy, delayed onset of labour and relative resistance to oxytocin, and in which several men later developed ichthyosis in the first months of life [18].

Cloning of the STS cDNA by Yen et al. (1987) revealed a functional gene at Xp22.3, a pseudogene on the long arm of the Y chromosome and complete deletion of the gene in 8 of 10 patients, which led to the hypothesis of aberrant X-Y exchanges as the deletion mechanism [43]. In 1986, Ballabio et al. described an Italian family in which five of six men had ichthyosis, hypogonadotrophic hypogonadism and anosmia, with total STS deficiency and linkage to distal Xp markers, and in 1989 Bick et al. published an infant with ichthyosis, Kallmann syndrome and chondrodysplasia punctata due to a maternally inherited terminal Xp22.31 deletion, a model of contiguous gene syndrome [44, 45]. The gene for X-linked Kallmann syndrome was cloned in 1991 (ADMLX, later KAL1, now ANOS1) and, in 1995, Franco et al. identified a cluster of sulfatase genes at Xp22.3, with variants in one of them (ARSE, now ARSL) in patients with X-linked chondrodysplasia punctata and inhibition of activity by warfarin [46, 47]. Terminal Xp deletion with chondrodysplasia punctata had already been documented by Curry et al. in 1984 [48].

1.2. Nomenclature and classification

The 2009 Sorèze consensus classified recessive X-linked ichthyosis (RXLI) among the "common ichthyoses", alongside ichthyosis vulgaris (IV), and defined it as the only ichthyosis classified as non-syndromic when isolated and as syndromic when accompanied by associated manifestations, for example undescended testis [2]. Orphanet follows this division, with ORPHA:461 for the non-syndromic form, ORPHA:281090 for the syndromic form, ORPHA:1643 for Xp22.3 microdeletion syndrome and the clinical group ORPHA:281210 [1, 4–6]. The abbreviations XLI, RXLI and XRI (the latter used in the German guideline) coexist in the literature [30]. A 2026 review proposed the designation STS-sEDD, syndromic epidermal differentiation disorder associated with STS deficiency, to emphasise its multisystem character; the proposal does not result from a consensus conference [3]. The names of the contiguous genes have also changed: KAL1 became ANOS1 (anosmin-1) and ARSE became ARSL (arylsulfatase L) [14, 20].

1.3. Definition of the entities within scope

Non-syndromic recessive X-linked ichthyosis is steroid sulfatase (STS) deficiency caused by deletion or a pathogenic variant of STS, with retention ichthyosis and the extracutaneous manifestations of the enzyme deficiency itself (corneal opacities, cryptorchidism, neurodevelopmental and cardiac rhythm abnormalities) [2, 49]. The syndromic form and Xp22.3 microdeletion syndrome correspond to larger deletions, terminal or interstitial, that also remove neighbouring genes and add Kallmann syndrome (ANOS1), X-linked recessive chondrodysplasia punctata, CDPX1 (ARSL), short stature or Léri-Weill dyschondrosteosis (SHOX), intellectual disability and autism spectrum disorder (ASD) (NLGN4X, VCX genes) and ocular albinism type 1 (GPR143) [5, 13]. Placental STS deficiency is the expression of the same deficiency in a pregnancy with an affected male fetus, with low maternal oestriol and abnormalities of labour [7]. Xp22.31 duplication is included only as a differential diagnosis and a problem in interpreting microarray results [9].

Ichthyosis vulgaris and the interaction between FLG variants and STS deficiency, CDPX1 and the other chondrodysplasias punctata, ANOS1-related hypogonadotrophic hypogonadism, SHOX deficiency, ASD and the autosomal recessive congenital ichthyoses (ARCI) are covered within the differential diagnosis and comorbidities.

2. Molecular Genetics and Pathophysiology

2.1. The STS gene and the enzyme

The STS gene is located at Xp22.31 (GRCh38 X:7,147,290–7,354,641), has 10 exons and spans about 146 kb [11]. It encodes steroid sulfatase (EC 3.1.6.2), also called arylsulfatase C isozyme S, a ubiquitously expressed microsomal enzyme with 583 deduced amino acids, a signal peptide of 21 to 23 residues, four potential N-glycosylation sites and two transmembrane domains, located mainly in the endoplasmic reticulum [11]. STS hydrolyses sulfated 3β-hydroxysteroids, such as dehydroepiandrosterone sulfate (DHEAS) and oestrone sulfate, to the free steroids, and desulfates cholesterol sulfate [11, 13]. Like all sulfatases, it depends on the post-translational conversion of an active-site cysteine to Cα-formylglycine by the formylglycine-generating enzyme (FGE), encoded by SUMF1; hence SUMF1 deficiency produces multiple sulfatase deficiency, which includes STS deficiency [14, 50]. Most patients have no immunologically detectable protein, which is consistent with the predominance of deletions [51].

The historical numbering of the protein has changed: Yen et al. (1987) numbered the initial methionine as −22 to reflect the signal peptide, and Alperin and Shapiro (1997) renumbered nucleotides and amino acids from the initiator methionine, following the system of Stein et al. (1989) [11]. Older variants therefore appear with different numbers depending on the publication, and comparison between sources requires attention to the system used.

2.2. Epidermal mechanism: retention ichthyosis

Cholesterol sulfate is produced in the epidermis by the cholesterol sulfotransferase SULT2B1b and desulfated by STS in the outer layers, in a "cholesterol sulfate cycle" that regulates differentiation, the permeability barrier and desquamation [52]. In the scales of eight patients, Williams and Elias (1981) measured cholesterol sulfate at 12.5±0.8% of total lipid, five times normal, with reduced neutral lipids and free sterols, whereas in other ichthyoses the value was normal [53]. Zettersten et al. (1998) documented an approximately 10-fold increase in cholesterol sulfate and a 50% reduction in cholesterol in the stratum corneum, with an abnormal barrier under basal conditions, delayed recovery after insult and phase separation in the lipid lamellae; topical cholesterol corrected the abnormalities, and cholesterol sulfate applied to normal skin reproduced them, indicating that accumulation of cholesterol sulfate, rather than lack of cholesterol, is the main cause [54]. Cholesterol sulfate inhibits proteolysis of the corneodesmosomes, which are retained in the stratum corneum; the result is a non-proliferative retention hyperkeratosis [2, 13].

2.3. Placental and endocrine mechanism

The placenta is fetal tissue. During pregnancy, the fetal adrenals produce DHEAS and 16α-hydroxy-DHEAS, which the placenta desulfates before aromatising them to oestrogens; when the male fetus has STS deficiency, the placenta cannot perform this step and maternal serum and urinary oestriol fall [8, 13]. The associated findings are a negative DHEAS loading test, raised DHEAS in amniotic fluid with normal DHEAS in cord plasma, and reduced placental sulfatase activity [8]. The deficiency is confined to fetal tissues: the mother has no deficiency in her own tissues [18]. Outside pregnancy, the reservoir of sulfated precursors is not converted to active oestrogens and androgens, and androgen activation before and after puberty is altered [13].

2.4. Escape from X inactivation and consequences in carriers

The STS gene escapes X inactivation, in both humans and mice [43]. Shapiro et al. (1979) showed that STS was expressed in all clones of doubly heterozygous fibroblasts, regardless of the active X, and Muller et al. (1980) observed higher activity in women than in men and a clear distinction between heterozygotes, non-carrier women and affected men [11]. The escape is partial: Migeon et al. (1982) estimated that the allele on the inactive X is expressed at about half the level of the active X, and the mean female:male ratio of activity in fibroblasts and placenta was 1.6 [11]. Escape from inactivation explains why carriers rarely have ichthyosis and why enzyme activity can be used to identify carriers, and it provides the rationale for the neuropsychiatric and puerperal phenotypes studied in women [11, 55].

2.5. Architecture of the Xp22.31 region and the recurrent deletion

Among genetic diseases, XLI has one of the highest proportions of deletions; complete deletion of STS has been found in up to 90% of patients [56]. The typical deletion, of about 1.5 to 1.7 Mb, is mediated by non-allelic homologous recombination between low-copy repeats (LCR) flanking the region, enriched in a recombination hotspot motif [9]. In the UK Biobank, the consensus deletion measured on average 1.60±0.01 Mb (ChrX:6,487,716–8,087,815, GRCh37) and included PUDP (HDHD1), STS, VCX, PNPLA4 and MIR4767 [23]. PNPLA4 encodes a patatin-family phospholipase and has a pseudogene on the Y, and the VCX/VCY family is expressed exclusively in male germ cells, is copy-number polymorphic and has unknown function [57, 58]. In the Dutch Maastricht cohort, the most frequent deletion removed all of STS and the flanking gene PUDP, with the minimal interval chrX.hg19:g.(?_6968202)_(7269849_?)del [29]. Among 80 Mexican patients with isolated XLI and normal intelligence, 62 had deletion of STS, VCX3A and VCX and 18 had breakpoints on both sides of STS without including VCX3A [18]. Recurrence of the same deletion in unrelated families, with different haplotypes, has been documented in the North Caucasus and in Tunisia, which favours repeated origin at a hotspot rather than a founder effect [59, 60].

Deletions are generated by unequal crossing-over in female meiosis or by illegitimate X-Y exchanges in male meiosis, a mechanism supported by the existence of the STS pseudogene on Yq and by familial X;Y translocations with STS deletion [18, 43]. About 85% of deletions are transmitted by carrier mothers and the remainder arise de novo [23]. In a Chinese prenatal diagnosis cohort, 89% (50/56) of fetal microdeletions were inherited (49 maternal and 1 paternal, the latter necessarily in a female fetus) and 11% (6/56) were de novo [17].

2.6. Intragenic variants, partial deletions and nomenclature

The proportion of cases without complete deletion varies with the method and the population. The clinical genetics reference textbook gives deletion in 85–90%, deletions extending to neighbouring loci in about 5% and point variants or other intragenic variants in about 10% [27]. In 40 Spanish patients, polymerase chain reaction (PCR) of exons 1, 5 and 10 showed 30 (75%) complete deletions and 10 (25%) partial deletions, a proportion of partial deletions higher than that described in other populations, with no correlation between deletion extent and phenotype [61]. A Mexican family with concurrent XLI and IV had the first partial deletion described, of exons 1 to 5 [62], and a Korean infant had a 719.3 kb deletion that included only a segment of STS, detected by a sequencing panel with copy number (CNV) analysis and confirmed by MLPA [63]. In 2026 a genomic deletion upstream of STS was described that abolishes expression of the isoforms expressed in the skin, a regulatory mechanism that escapes analysis of the coding exons [64].

In the Dutch cohort of 109 men with clinically suspected XLI, 71 (65%) had a pathogenic STS variant: 57 (80% of confirmed cases) with the recurrent deletion, 1 deletion of all of STS without PUDP, 1 deletion of exon 6, 1 duplication of exons 8–9 and, by Sanger sequencing, 1 splicing variant, 6 missense, 1 nonsense and 3 frameshift; 11 novel variants were described and the novel missense variants were interpreted by equivalent positions in paralogous sulfatases (GALNS, ARSL) [29]. The authors used the 10-exon transcript NM_000351.5, with alternative exons 1a and 1b for the different isoforms [29]. The current MANE Select transcript of STS is NM_001320752.2 (transcript variant 4), and its numbering differs from that of NM_000351: the variant NM_000351.5:c.1253A>G p.(Asp418Gly), classified as likely benign on the basis of normal STS activity in blood, corresponds to NM_001320752.2:c.1238A>G p.(Asp413Gly), NC_000023.11:g.7325495A>G (GRCh38) [12, 29]. The difference of 15 nucleotides and 5 amino acids in this region does not permit manual conversion of other variants; each must be validated in VariantValidator [12].

The six allelic variants selected in OMIM (.0001 to .0006) are in historical protein numbering, and ClinVar gives their correspondence on the MANE transcript [11, 65]: Trp372Arg (historical numbering, = NM_001320752.2:c.1099T>A p.(Trp367Arg)), Cys446Tyr (= NM_001320752.2:c.1322G>A p.(Cys441Tyr)), Ser341Leu (= NM_001320752.2:c.1007C>T p.(Ser336Leu), with conflicting classifications in ClinVar), Trp372Pro (designation published in OMIM; ClinVar records the change c.1100G>C, which corresponds to NM_001320752.2:c.1100G>C p.(Trp367Ser), of uncertain significance), His444Arg (= NM_001320752.2:c.1316A>G p.(His439Arg)) and the intron 8 donor-site variant IVS8+1G>T (= NM_001320752.2:c.1241+1G>T) [11, 65]. The variants described by Basler et al. (1990, 1992) and Alperin and Shapiro (1997) lie in a 105-amino-acid region of the C-terminal half of the protein [11]. The 5-residue difference between the historical numbering and that of the MANE transcript in this region matches the one observed for c.1253A>G [12, 65].

Deletions are written in ISCN (International System for Human Cytogenomic Nomenclature) notation with coordinates and genome build, for example arr[GRCh38] Xp22.31(6634671_8129471)x0 for a hemizygous boy or arr Xp22.31(6449836-8135568)x1 for a carrier mother [66, 67]. The unprocessed STS pseudogene on Yq (STSP1) can be co-amplified in sequencing: in Tunisia, eight patients from three families appeared to have the same 13 bp deletion in exon 4, but the change was in the Y pseudogene; MLPA revealed deletion of all of STS on the X in all of them, confirmed by FISH and delimited by array comparative genomic hybridisation (aCGH) [60].

2.7. Xp22.3 contiguous gene syndromes

Larger deletions, terminal or interstitial, remove genes adjacent to STS and add the phenotypes of each gene [13, 14]. Affected men may have terminal Xp deletions, interstitial deletions or X;Y translocations, and the phenotype of the Xpter deletion in males depends on the genes removed [14, 68]. FISH with probes for the various genes has been used to detect these deletions in children with chondrodysplasia punctata, ichthyosis, Kallmann syndrome and ocular albinism [69]. In British Columbia, among 30 boys with prenatally diagnosed STS deficiency, 29 had the isolated form and 1 a contiguous gene syndrome; in sporadic cases, the proportion of contiguous gene syndrome was 1 in 12 (8.3%) [22].

Published cases show the variability of these combinations. A boy with short stature, chondrodysplasia punctata and ichthyosis had a terminal Xp deletion with loss of all of STS and STS deficiency in fibroblasts [78], and a male fetus with chondrodysplasia punctata, STS deficiency and Kallmann syndrome due to an Xp22.31 deletion was diagnosed prenatally, with studies indicating that CDPX does not result from a defect of vitamin K metabolism [79]. A 13-year-old boy with an interstitial deletion of about 5.5 Mb had ichthyosis, chondrodysplasia punctata, intellectual disability with ADHD, lens opacities, deafness, minimal cleft palate and seven unerupted permanent teeth, and the pregnancy had low serum oestriol in the third trimester [80]. A boy with an 8.41 Mb distal deletion inherited from a mother with the mosaic karyotype mos 46,X,del(X)(p22)/45,X/46,XX had short stature, ichthyosis, severe intellectual disability, epilepsy, cortical heterotopias and Dandy-Walker malformation [81]. In a family with a 6 Mb terminal deletion that removed SHOX and ARSE but preserved VCX-A, two brothers had short stature, skeletal abnormalities, severe learning difficulties and ADHD, and the mother had a height more than 1 standard deviation below the family target and subtle Madelung deformity [73]. A Portuguese group described a terminal Xp22.3 deletion with Léri-Weill dyschondrosteosis, developmental delay and ichthyosis [82]. Two Chinese patients with Kallmann syndrome and XLI due to deletions of 3923 kb and 5807 kb (the latter including STS, ANOS1 and 24 further genes) also had obesity and strabismus, without developmental delay or autistic behaviour [83]. To put the Kallmann component in context, Kallmann syndrome of all causes affects about 1 in 8,000 men and 1 in 40,000 women according to the reference textbook, and in Finland the minimum incidence was 1 in 30,000 men and 1 in 125,000 women; ANOS1 accounts for 5–10% of cases, and intragenic deletions detected by targeted methods reached 4 of 33 patients in one study [20, 84–87]. Other reports associate Xp22.3 microdeletion with the microphthalmia with linear skin defects (MLS) picture, in a 19-year-old girl, and with the combination of microphthalmia, sclerocornea, linear skin defects and congenital heart disease [88, 89].

2.8. Xp22.31 duplication

Copy gains at Xp22.31 are frequent in microarray results and include recurrent and non-recurrent duplications, recurrent triplications and complex rearrangements; in a study of 61 unrelated patients with a gain, the authors found no evidence of pathogenicity of the duplication, while accepting that it may act as a risk factor and that triplications may be more penetrant [9]. A series of nine patients with microduplications of 294 kb to 1.6 Mb, detected during investigation of developmental delay, combined clubfoot, seizures and feeding difficulties, and the authors argued for a common phenotype [28]. In the UK Biobank, 414 male and 938 female duplication carriers (0.8 to 2.5 Mb, including STS) had cognition and educational attainment equal to those of controls, with only nominal associations (self-reported inguinal hernia and mania in men; gastro-oesophageal reflux and self-reported scaling skin disease in women), and the conclusion was that the duplications are largely benign [10]. Atrial fibrillation is not increased in men with the duplication [90].

2.9. Genotype-phenotype correlations and modifiers

In isolated XLI there is no demonstrated correlation between deletion extent and cutaneous severity [61]. Cutaneous severity also did not differ between men with and without cardiac rhythm abnormalities [90]. The neurobehavioural phenotype depends partly on the extent: ASD was concentrated in unusually large deletions that removed NLGN4X, whereas ADHD occurred with typical deletions and with point variants, which links it to STS deficiency itself [26]. Focal epilepsy of childhood occurs with deletions of the classic region, and a candidate region containing STS, PUDP and MIR4767 has been proposed [91, 92].

The main known modifier is the coexistence of FLG loss-of-function variants. In 51 patients with RXLI seen in dermatology in Münster, the prevalence of filaggrin deficiency was increased [93]. In the Dutch cohort, at least 4 patients (4%) had variants in STS and FLG, with possible worsening [29]. The coexistence of another X-linked disease from the same maternal lineage, such as RS1-related X-linked retinoschisis, has been described in two brothers, and the macular findings in these cases belong to retinoschisis and not to XLI [94].

3. Clinical Spectrum and Manifestations by System

3.1. Skin: onset and natural history

The neonatal presentation is subtle or absent. The Sorèze consensus describes onset with excessive scaling and/or erythroderma in the neonatal period, or late onset after about 2 to 6 months, sometimes with slightly "collodion-like" skin at birth; the fine superficial scaling of the first days may disappear within weeks and later reappear as overt ichthyosis [2]. The 2019 European guideline confirms that some babies with RXLI have red skin and scaling or a collodion-like presentation at birth [95]. In the Chinese prenatal diagnosis cohort, 37 of the 38 liveborn boys had scaling between 1 and 3 months and 1 had no manifestations at 4 months; the 10 carrier girls had no manifestations [17]. The North American patient association describes babies who are often normal at birth, with changes almost always present by the first birthday [96].

The established picture consists of polygonal or rhomboid scales, large or fine, adherent, dark brown or light grey, without erythema, distributed over the trunk, neck (often the most affected area), scalp in children and extensor surfaces of the limbs, sparing the flexures, palms, soles and central face [2, 13]. The white adherent scales of infancy darken with time, especially in the flexures [19]. Palmoplantar hyperlinearity is absent, hypohidrosis is possible, the course is stable and the skin often improves in summer [2, 96]. In a Spanish multicentre series of 30 patients (25 families) with non-syndromic XLI and STS deletion, all had dark scales of variable size on the extensor surfaces of the limbs, flexural sparing and pruritus were common but inconsistent, and palmoplantar hyperlinearity was absent in all but one; the authors concluded that, without genetic testing or family history, dark brown extensor scales and the absence of palmoplantar hyperlinearity are the most reliable findings [25]. The Brazilian textbook of genetic syndromes summarises the course as scales over the whole body (neck, abdomen, back, anterior aspect of the legs and feet), without ectropion [97]. Orphanet classifies the condition as fairly mild [1], and the UK patient group describes an average of about 3 hours a day devoted to skin care in the ichthyoses [98].

The mode of ascertainment alters the spectrum. At the Mayo Clinic, boys with STS deletion found among 23,172 consecutive postnatal microarrays requested for other reasons had a milder skin phenotype (dryness and/or eczema), without the typical dark polygonal scale, compared with patients with biochemically confirmed XLI seen in the dermatology clinic; the sample was small and the assessment was made by non-dermatologists [99]. In the UK Biobank, fewer than 6% of men aged 40 to 69 years with the deletion had a recorded skin diagnosis, and self-reported scaling skin disease was 4.7% versus 0.2% in controls [23]. These figures indicate that many men with STS deficiency are never diagnosed or are classified as having eczema or dry skin [13, 23].

3.2. Eye

The corneal opacities of XLI are deep stromal or pre-Descemet, asymptomatic and without impact on visual acuity, and the complications table of the 2024 update keeps them as a finding of recessive X-linked ichthyosis (and occasionally of lamellar ichthyosis) [27, 95, 100]. Their frequency depends on the method of examination and on age. Sever et al. (1968) described deep opacities in 17 of 17 men and in 7 of 8 heterozygous women, and Jay et al. (1968) found them in all patients over 25 years and in 5 of 8 under 25 years, which characterises them as a late finding [18]. In a Danish series of 76 cases in 50 families, slit-lamp examination showed opacities in 14 of 28 men [18]. In Naples, opacities were present in 23.7% of 38 patients and in 24.3% of carrier mothers; the authors attributed them to a physicochemical alteration of the corneal tissue rather than to cholesterol sulfate deposition [101]. Among Italian military recruits with XLI, 4 of 15 (26.6%) had opacities [102]. The Sorèze consensus reports subclinical opacities in about 50%, and the 2026 review gives 10 to 50% of men and about 25% of carriers, sometimes as the only manifestation in the carrier [2, 3]. Pre-Descemet corneal dystrophy has been documented in a patient with a microdeletion of about 1.7 Mb [103], and a 73-year-old man had superficial subepithelial and anterior stromal opacities [18]. The corneal clouding table of inherited metabolic diseases places STS deficiency among the opacities visible from late childhood to adulthood [104].

3.3. Testis and genitalia

Cryptorchidism is a manifestation of STS deficiency itself and not only of the contiguous genes. Traupe and Happle (1983) studied 25 patients with XLI: there were delivery complications in 9, of whom 4 had bilateral inguinal cryptorchidism and 1 unilateral; another had unilateral inguinal cryptorchidism without delivery complications and a boy born by forceps had bilateral abdominal cryptorchidism with severe hypogenitalism; in a literature review they assembled 30 cases of XLI with hypogenitalism and/or cryptorchidism [105]. In the Danish series of 76 cases, there was undescended testis in 9 [18]. In the Spanish series, 10% of patients had had a previous orchidopexy, compared with 3% in the general population [25]. The Sorèze consensus estimates cryptorchidism at 5–20% and other syntheses at about 20% [2, 23, 96]. In the UK Biobank, self-reported undescended testis did not differ (0.0% versus 0.1%), which the authors attributed to the limitations of self-report in older people [23]. The Brazilian textbook reports hypogonadism or cryptorchidism in boys [97].

The risk of germ cell tumour is uncertain. Lykkesfeldt et al. (1983) described two men with STS deficiency and testicular cancer (seminoma and embryonal carcinoma in one, seminoma in the other), both with descended testes, and in the 1985 series there were 2 cases of testicular cancer in men with descended testes [18]. Later syntheses consider the risk unclear, with isolated cases [23].

3.4. Pregnancy with an affected fetus and delivery

The obstetric consequences are failure of spontaneous onset of labour with prolonged gestation, poor cervical ripening, failure to progress, more instrumental or operative deliveries and a small increase in the risk of intrauterine death described in the reference textbook [13, 27]. The magnitude varies between sources. In the Danish series of 23 pregnancies with placental STS deficiency, 16 (70%) ended in vaginal delivery, with no notable pregnancy or neonatal complications and with birth weights tending to be low, and the authors concluded that intervention was unnecessary unless there were other obstetric indications [7]. Other syntheses estimate delayed or prolonged labour in about 60% of carriers, based on secondary references [23, 90]. In the Italian family with Kallmann syndrome and XLI, three deliveries ended in caesarean section for prolonged labour [18]. In the Traupe and Happle series, 9 of 25 boys had delivery complications [105]. The Sorèze consensus mentions insufficient cervical dilatation in carriers [2]. Hameister et al. (1979) described partial placental deficiency with failed induction of labour in three pregnancies, whose sons had no ichthyosis at 6 months [18].

3.5. Neurodevelopment, epilepsy and mental health

ADHD is the best-documented neuropsychiatric manifestation. In 25 boys from families identified through maternal oestriol screening, 40% met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for ADHD, 80% of them of the inattentive subtype, with both deletions and presumed point variants; ASD or language and communication difficulties occurred only in 5 boys from 3 families, all with an unusually large deletion including NLGN4X [26]. In the Spanish series of non-syndromic XLI, 30% had ADHD and 13% epilepsy [25]. The 2026 review reports ADHD in about 40% and ASD in about 25%; the latter figure does not agree with the data of Kent et al., in whom autism occurred only with NLGN4X deletion, and should not be taken as the prevalence in the isolated form [3, 26].

The epilepsy associated with the classic deletion has its own profile in males. Three boys (two maternal cousins) with XLI and maternal deletions of 0.9 to 1.66 Mb had focal epilepsy with onset between 7 and 10 years, easily controlled, resembling self-limited epilepsy with centrotemporal spikes, and a normal brain magnetic resonance imaging (MRI) in two [92]. In a review of 25 patients with epilepsy and Xp22.31 alterations, males had easily controlled focal epilepsy of childhood, with XLI and deletions of the classic region (863 kb to 2 Mb), whereas females had earlier onset, more refractory epilepsy, CNVs of 859 kb to 56.36 Mb that were rarely inherited and almost always additional CNVs [91]. Cases from 2026 illustrate the association, such as a 5-year-old Chinese boy with seizures, diffuse ichthyosis, short stature and ADHD and a deletion of about 1.47 Mb [106], and a 10-year-old Syrian boy, born at 26 weeks, with seizures, ADHD and ASD and a 1.65 Mb deletion, in whom extreme prematurity is a confounding factor [107].

Online survey studies describe a broader neurobehavioural and affective profile. In 58 adults and 24 young people with XLI, compared with unaffected siblings and population norms, there was an increased risk of developmental disorders and, in adults, of mood disorders, with higher scores for inattention, impulsivity, autistic traits, psychological distress and disruptive behaviour [108]. In another survey of 54 men with XLI and 83 carriers, compared with patients with IV and psoriasis, the lifetime prevalence of mood disorders was increased in all groups and that of neurodevelopmental disorders in the XLI groups; stigmatisation was associated with quality of life [109]. Adults with XLI (n=41) and carriers (n=79) reported more mood symptoms and lower satisfaction with memory, independently of mood, without major structural effects on UK Biobank MRI [110]. In the UK Biobank, the 86 men with the deletion had more mental distress (p=0.003), irritability (p<0.001) and depressive-anxious traits, with preserved educational attainment and slightly lower performance on the fluid intelligence test (d≤0.05) in both sexes [23]. The surveys are subject to response and self-report bias, and the UK Biobank data concern middle-aged adults from a volunteer cohort.

3.6. Heart and cardiac rhythm

The association with arrhythmias emerged from population data. In the UK Biobank, atrial fibrillation or flutter (AF) was diagnosed in 10.5% of the 86 men with the deletion versus 2.7% of the 190,577 control men (odds ratio, OR, 4.2; 95% confidence interval, 95% CI, 2.1–8.3; corrected p 0.009), with no increase in the 312 female carriers [23]. Reanalysis showed that the 9 men with AF were older (69.8±1.6 versus 65.3±0.9 years) and had more non-infectious gastroenteritis or colitis (2/9 versus 1/77); gene-based analysis associated STS with AF in men (p=0.041) but not in women, and the authors estimated that Xp22.31 deletions could account for up to 1 in 300 cases of AF in middle-aged men [90]. In the 2021 online survey, self-reported cardiac rhythm abnormalities occurred in 35% of adult men, 28% of carriers and 28% of boys; in men with abnormalities, AF had been diagnosed in 60% and tachycardia in 27%, in boys tachycardia (53%) and bradycardia (40%) predominated, stress was among the main precipitants and episodes resolved in less than 12 hours in more than 80% [90]. Valvular disease or malformation, anaemia, asthma and bowel problems were associated with rhythm abnormalities in the combined groups [90].

Case reports show isolated serious events. A 17-year-old Turkish boy had cardiac arrest due to ventricular fibrillation, with a hemizygous deletion including exons 2 to 11 of STS and mild ichthyosis recognised only after genetic testing; according to the authors, this was the first report of cardiac arrest associated with STS deletion [111]. In a Russian report, a boy with a 1.64 Mb deletion had sinus bradycardia from the age of 5 years, pauses of up to 3436 ms and asystoles on tilt testing, and received a pacemaker at 15 years [66]. In Sts-deficient mice, isolated hearts had spontaneous ventricular extrasystoles in about 30% under basal conditions and in about 60% under β-adrenergic stimulation, versus 0% in wild-type animals (preprint not peer reviewed) [112]. Proposed mechanisms include DHEAS and reduced triadin in tissues of STS-deficient mice [23].

Prospective paediatric data point in another direction. In a cohort of 14 boys aged 2 to 16 years with a genetic diagnosis, assessed with a 12-lead electrocardiogram (ECG), echocardiogram, exercise test and 5-day Holter monitoring, 9 (64%) were asymptomatic, ECG findings were considered age-related variants, the exercise test in 12 showed 1 isolated ventricular extrasystole and none of the 13 Holter recordings showed clinically significant arrhythmia; the 11 carrier mothers had a normal echocardiogram (2026 preprint, not peer reviewed) [113]. The authors advocate individualised cardiological assessment guided by symptoms, findings and family history, in contrast to the call for systematic screening made by UK investigators [113, 114].

3.7. Other comorbidities

Pyloric stenosis (five boys in two families), congenital abdominal wall defect, acute lymphoblastic leukaemia, periventricular nodular heterotopia, end-stage renal failure, Dupuytren contracture, coagulation abnormalities and fibrotic conditions have been described, at low frequency or in isolated cases [18, 23, 49, 111]. In the UK Biobank, men with the deletion reported more allergy, hypersensitivity or anaphylaxis (4.7% versus 0.5%) and eczema or dermatitis (7.0% versus 2.7%) [23]. Single-case associations, such as moyamoya angiopathy, do not allow causality to be inferred [115].

3.8. Female carriers

Carriers usually have no evident cutaneous, ocular or neurological physical phenotype, although Went et al. described mild skin changes in about a quarter of the obligate heterozygotes of a large family [18, 90]. Corneal opacities occur in about 25% [3, 101]. In a survey of 94 adult carriers, the profile was similar to that of men with XLI, with more developmental and mood disorders and more postpartum mental disorders, mainly mild depression, not explained by social factors; the authors related this to the escape of STS from X inactivation and to the increase in STS activity at the end of pregnancy and in the puerperium [55]. In the UK Biobank, female carriers did not have more non-cancer diseases and had slightly smaller volumes of the right putamen and left nucleus accumbens (d≤0.26) [23]. Rare homozygous women, daughters of a carrier mother and an affected father, have a phenotype identical to that of males [3]. Women with Xp22.31 deletion and epilepsy usually have additional CNVs [91], and a woman with 45,X Turner syndrome and X-linked ichthyosis has been described [18].

3.9. Syndromic forms

In the syndromic form, the skin picture is accompanied by the hypogonadotrophic hypogonadism with anosmia, synkinesis and renal agenesis of Kallmann syndrome; the nasal hypoplasia, brachytelephalangy, epiphyseal calcifications and cervical myelopathy of chondrodysplasia punctata; the short stature and Madelung deformity of SHOX deficiency; intellectual disability, ASD and epilepsy; and ocular albinism [13, 14, 20, 70]. Brachytelephalangic CDP with Xp22.3 microdeletion may present with cervical myelopathy as early as infancy, and outside these microdeletions there are no cataracts, contractures or skin changes [70]. The classic description of the X-linked recessive form of chondrodysplasia punctata in the dysmorphology textbook merges CDPX1 with the contiguous gene phenotype: ichthyosis, short stature, microcephaly, developmental delay, cataracts, deafness and, in some men, anosmia and hypogonadism [116]. In CDPX1, most men have minimal morbidity and skeletal improvement in adulthood, but some have respiratory problems, cervical stenosis or instability, mixed deafness or intellectual disability [14]. The family of Sunohara et al. (1986), with ichthyosis, anosmia, hypogonadism, nystagmus, strabismus, iris hypopigmentation, mirror movements and renal agenesis, illustrates the combination of Kallmann syndrome with ocular albinism [18].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age and context

In pregnancy, suspicion arises from a very low uE3 in second-trimester screening of a male fetus with a normal ultrasound, especially with a family history of ichthyosis in males of the maternal line, or from a maternal Xp22.31 deletion detected as an NIPT finding [13, 31, 117]. At delivery, unexplained failure of onset or progression of labour with a male child is a retrospective sign that should be sought in the history [13, 27]. In the newborn and infant, fine scaling or mild erythroderma, sometimes collodion-like, followed by scales that darken between 2 and 6 months, in a boy, raise the hypothesis [2, 17]. In children and adults, the typical picture is one of adherent dark brown scales on the neck, trunk and extensor surfaces, sparing the flexures and without palmoplantar hyperlinearity, particularly if there is cryptorchidism or corneal opacities [2, 25]. At any age, incidental detection of an Xp22.31 deletion on a microarray requested for developmental delay, epilepsy or ASD calls for examination of the skin, which may show only dryness or eczema [99].

4.2. Warning signs of a syndromic form

In a boy with X-linked ichthyosis, the following findings suggest a contiguous deletion and justify CMA to define its extent: anosmia or hyposmia, micropenis, bilateral cryptorchidism, delayed or absent puberty, bimanual synkinesis and renal agenesis (Kallmann component) [20, 36]; nasal hypoplasia, brachytelephalangy, stippled epiphyseal calcifications on radiographs in the first year and signs of cervical spinal cord compression (CDPX1 component) [14, 70]; disproportionate short stature or Madelung deformity, also in the women of the family (SHOX component) [72, 73]; intellectual disability, ASD or epilepsy more severe than self-limited focal epilepsy (NLGN4X/VCX and other components) [26, 81]; nystagmus, iris hypopigmentation and reduced visual acuity (ocular albinism) [18]. In the 2015 consensus on congenital hypogonadotrophic hypogonadism, cryptorchidism with or without micropenis, hyposmia, congenital deafness, bimanual synkinesis, dental agenesis and cleft lip or palate favour the diagnosis of hypogonadism over constitutional delay of puberty [36]. No test reliably distinguishes constitutional delay of puberty from isolated GnRH deficiency, which makes pubertal surveillance of the boy with an extensive deletion indispensable [20].

4.3. Emergency signs

Isolated XLI has no cutaneous emergencies of its own. The signs that require immediate assessment are extracutaneous: syncope, persistent palpitations, seizure with collapse or cardiac arrest, in view of the reports of ventricular fibrillation and prolonged sinus pauses [66, 111]; signs of cervical myelopathy in a child with a deletion that includes ARSL [14, 70]; and, in pregnancy, undetectable uE3 with raised alpha-fetoprotein (AFP), which is associated with existing or imminent fetal death and not with STS deficiency [118].

4.4. Newborn screening

There is no newborn screening for STS deficiency in the programmes described in the sources consulted. Early identification results, in practice, from biochemical or genomic prenatal screening directed at other conditions (Smith-Lemli-Opitz syndrome, aneuploidies), in which XLI emerges as a secondary finding [21, 67].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical and laboratory criteria

There are no validated formal diagnostic criteria. The Sorèze consensus describes the reference phenotype and the supporting investigations, summarised in the following table [2].

5.2. Biochemistry

STS activity is deficient in leucocytes, fibroblasts and epidermis, and its measurement in blood collected in EDTA confirms the biochemical diagnosis in a man with a compatible phenotype [30, 119]. Assays on nail clippings have been proposed for screening [120]. Plasma cholesterol sulfate is about 20 times higher than in controls and is concentrated in low-density lipoproteins, whose accelerated anodal electrophoretic mobility has been used as a diagnostic criterion [18, 101]. Measurement of cholesterol sulfate in scales is another alternative [53]. Enzyme activity identifies carriers, because escape from X inactivation avoids the variability of lyonisation [11]. In the Dutch cohort, leucocyte STS activity was used to classify inconclusive variants and classified c.1253A>G (NM_000351.5) as likely benign [29]. Enzyme assays do not define the size of the deletion and should be followed by dosage analysis or microarray [13].

The French PNDS (French National Diagnosis and Care Protocol) for the inherited ichthyoses (HAS, 2021) reserves leucocyte steroid sulfatase (arylsulfatase C) assay for specialised centres and describes collapsed activity in both the non-syndromic and the syndromic form [121]. The same protocol considers that, unlike the other inherited ichthyoses, ichthyosis vulgaris and X-linked ichthyosis do not require molecular study to confirm the diagnosis [121]. This 2021 French position refers only to diagnostic confirmation: the size of the deletion, which defines the risk of contiguous gene syndrome, and the identification of carriers require dosage analysis or microarray (section 5.3).

5.3. Genetic tests

The yield depends on the population tested. In the Dutch cohort of 109 men with clinically suspected XLI, the algorithm of MLPA, followed by Sanger sequencing and enzyme activity, found a pathogenic STS variant in 65%; 17% in fact had IV due to FLG variants, 3 had ARCI identified by exome sequencing (SDR9C7, ALOXE3, NIPAL4) and 15% remained undiagnosed, although only 30 of the 71 XLI cases were tested for both genes [29]. The authors recommend studying STS and FLG in men with suspected XLI and extending to the ARCI genes when no diagnosis is reached [29].

5.4. Limitations of the tests

A normal sequencing result does not exclude XLI, because most cases are deletions [13]. Conversely, a normal dosage result does not exclude point variants, partial deletions outside the probes or regulatory deletions upstream of the gene, such as the one described in 2026 [29, 64]. Sanger sequencing can be misled by the Yq pseudogene and produce a "variant" that is not on the X [60]. The size of the same deletion may vary between methods (for example 1.47 Mb on the son's exome and 1.14 Mb in the mother, in the same family), so coordinates should be compared using the same method and the same genome build [106]. The exact breakpoints often remain undetermined within the LCRs, which is expressed with uncertainty intervals in the notation [29]. The absence of a deletion in maternal blood does not exclude germline mosaicism or low-level somatic mosaicism, as in the case of the mother with the karyotype mos 46,X,del(X)(p22)/45,X/46,XX [81].

5.5. Report content

The report of a deletion should state the ISCN notation with the genome build and the minimum and maximum coordinates, the zygosity (hemizygous in males, heterozygous in females), the OMIM genes included and the distance to ANOS1, NLGN4X, ARSL and SHOX, the classification according to the ACMG/ClinGen standards for CNVs and the recommendation for maternal testing [66, 67, 106]. The report of an intragenic variant should state the gene, the MANE transcript with version (NM_001320752.2) and, if useful, the historical transcript NM_000351, the HGVS (Human Genome Variation Society) notation at DNA and protein level, the zygosity and the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) class [12, 29]. Variants of uncertain significance benefit from measurement of leucocyte STS activity and from segregation studies in males of the maternal line [29].

5.6. Postnatal algorithm

In a boy with compatible ichthyosis, the first step is STS dosage analysis (MLPA) or, if there are extracutaneous warning signs, CMA, which defines the extent [14, 29]. If dosage is normal, STS sequencing follows; if this is negative or inconclusive, leucocyte STS activity is measured [29, 30]. If activity is normal, the XLI hypothesis loses strength and FLG and the ARCI genes should be studied [29]. Once the deletion is confirmed, maternal testing defines the family risk, and targeted examination (slit lamp, testicular examination, developmental assessment) completes the characterisation [13]. In contiguous gene syndromes with Kallmann syndrome, an apparently isolated Kallmann syndrome with scaling should lead to deletion/duplication analysis and not only to sequencing [15].

5.7. Prenatal diagnosis: biochemical and genomic screening

MoM means multiples of the median; SLO, Smith-Lemli-Opitz syndrome; NIPS, non-invasive prenatal screening; hCG, human chorionic gonadotrophin. The combination of very low uE3 with a maternal deletion on NIPT has the highest predictive value, and the greatest utility lies in the male fetus with a normal ultrasound, extremely low uE3 and a family history of isolated XLI [31]. The positive predictive value of NIPT for CNVs in general is around 30%, which makes confirmation mandatory [67]. Confirmation is by CMA on amniotic fluid, by STS PCR on the newborn's blood or by maternal testing with CMA or CNV-seq [31, 117]. Historically, antenatal diagnosis was also biochemical, through enzyme deficiency in cultured amniocytes or through increased androstenetriol, 16α-hydroxy-DHEA and 16α-hydroxypregnenolone in third-trimester maternal urine [7]. When the familial variant is known, prenatal diagnosis is made by chorionic villus sampling at 10–12 weeks or by amniocentesis from 14 weeks [30].

5.8. Algorithm for low maternal oestriol

The clinical genetics reference textbook proposes a sequence for low maternal uE3 [27]. First, other causes are excluded: ultrasound to confirm viability and sex, verification that the mother is not taking dexamethasone or similar, and recalculation of the trisomy 21 risk with age, AFP and hCG, excluding uE3, with amniocentesis if the risk is high. In a viable male fetus with a normal ultrasound, STS deficiency is the most likely diagnosis; a three-generation pedigree is taken with targeted questions about ichthyosis and the schooling of affected males, and maternal blood is studied (karyotype, STS FISH, DNA). With a family history of XLI without learning problems, or without a family history but with a maternal deletion without a visible cytogenetic abnormality, management consists of reassurance, information about XLI, warning the obstetrician of the perinatal risks and discussing the implications for other relatives. Without a maternal deletion, the most likely explanation is a point variant in the mother and fetus or, less probably, a de novo deletion, possibly large, in the fetus, and amniocentesis for karyotype and STS FISH is offered. In a female fetus, which is rare, autosomal recessive congenital adrenal hyperplasia, adrenocorticotrophic hormone (ACTH) deficiency, multiple sulfatase deficiency and Smith-Lemli-Opitz syndrome are considered, the latter with a detailed anomaly scan and measurement of 7-dehydrocholesterol or DHCR7 testing on amniotic fluid [27, 32]. Undetectable oestriol also occurs in Antley-Bixler syndrome due to POR deficiency, and a 46,XY fetus with female genitalia on ultrasound points to 17-hydroxylase deficiency, lipoid adrenal hyperplasia and Smith-Lemli-Opitz syndrome [27, 123]. In pregnancies with isolated STS deficiency and no family history, the finding of 8.3% contiguous gene syndromes justifies additional molecular study of the mother and fetus by CMA [22].

6. Differential Diagnosis

The most frequent differential diagnosis is IV. In the Dutch cohort, 17% of men with a clinical diagnosis of XLI in fact had IV due to FLG variants, and mild ARCI was also mistaken for it [29]. The findings that weigh most in favour of XLI are dark brown extensor scales, involvement of the neck and absence of palmoplantar hyperlinearity; IV has finer, lighter scales, hyperlinearity, keratosis pilaris and a strong atopic association, sparing the antecubital and popliteal fossae [2, 25]. The coexistence of the two conditions, documented in several series, explains phenotypes of unexpected intensity and calls for study of both genes [29, 62, 93].

ARCI is distinguished by onset at birth with a collodion membrane or marked erythroderma, by ectropion and by autosomal recessive inheritance, which affects both sexes [19, 97]. Multiple sulfatase deficiency has ichthyosis due to loss of STS activity, but adds deficiency of the other sulfatases (mucopolysaccharidoses II, IIIA, IIID, IVA and VI, metachromatic leukodystrophy and chondrodysplasia punctata), and neurodegeneration determines the prognosis; the Saudi variant may lack ichthyosis [50]. The stippled epiphyseal calcifications of the syndromic form of XLI fall within the differential diagnosis of the chondrodysplasias punctata, where X-linked STS deficiency sits alongside CDPX2 and CHILD syndrome [104, 124]. Warfarin embryopathy, maternal systemic lupus erythematosus and maternal vitamin K deficiency produce phenocopies of CDPX1 [14, 70].

Faced with an Xp22.31 deletion found by microarray, the first distinction is between copy loss and copy gain. Loss in a boy confirms STS deficiency, even if the skin phenotype is minimal [99]; copy gain does not cause ichthyosis and its clinical significance is debated [9, 10]. With ocular findings, the coexistence of another X-linked disease from the same maternal lineage, such as RS1-related retinoschisis, should be considered before attributing macular abnormalities to XLI [94].

7. Treatments and Risk Management Strategies

7.1. Principles and sources of recommendations

There is no medicine authorised specifically for XLI, and skin treatment is symptomatic, topical and lifelong [13]. The applicable recommendations come from the guidelines for the congenital ichthyoses as a whole. The current version is the 2024 update, published in 2025 in two parts by an international multidisciplinary group, based on a systematic review and a consensus conference in June 2023; part 1 covers topical and systemic therapies (including oral retinoids, biologics and Janus kinase inhibitors), future approaches, psychosocial management, telemedicine, communication of the diagnosis, genetic counselling, prenatal diagnosis and preimplantation genetic testing, and part 2 covers complications (eye, ear, nose and throat, pruritus, pain, infections, vaccination, growth and nutrition, hair and nails, climate, physical limitations and comorbidities) and the neonatal period [100, 126]. The main text of this update was not available; the abstracts of both parts and the supplementary material of part 2 were read, which indicates, section by section, what changed relative to 2019: updates on ocular complications (one modified recommendation on topical retinoids before ectropion surgery), ear, nose and throat complications, pruritus, pain, skin infections, growth and nutrition, hair and nails, physical limitations, the neonatal period and Netherton syndrome; new sections on vaccination and comorbidities; and no update of the recommendations on vitamin D deficiency (only revision of the references) or on reactions to heat and cold [100]. The detailed recommendations cited below, with level of evidence (LoE) and grade of recommendation (GoR) according to the Scottish Intercollegiate Guidelines Network, come from the full text and supplements of the 2019 European guidelines, which the update replaced, and from the 2017 German S1 guideline [30, 33, 95]. The 2019 guidelines resulted from an expert conference of 16 countries held in Toulouse in 2016, within the ichthyosis subgroup of ERN-Skin, and the literature review found very few randomised trials, so most recommendations have a level of evidence of 3 to 4 (expert opinion) [33]. In the 2019 supplementary classification, the syndromic forms of recessive X-linked ichthyosis (OMIM 308700, 300500, 300533) are listed among the X-linked ichthyosis syndromes, alongside IFAP syndrome (MBTPS2) [33]. There is also a 2024 French national protocol for the congenital ichthyoses [127].

7.2. Topical treatment

Emollients are indicated in all ichthyoses (LoE 1, GoR B), at least twice a day and ideally after bathing (LoE 3, GoR D) [33]. The choice of agent depends on severity, location, availability in the country, formulation, reimbursement, cost and patient preference (LoE 4, GoR D), and pure occlusive ointments over large areas are not recommended in hot climates (LoE 4, GoR D) [33]. Keratolytics (urea ≥10%, alpha-hydroxy acids 5–12%, propylene glycol >20%, salicylic acid >2%) have shown superiority over emollients in removing scale in some studies, and the guideline suggests adding them when there are thick scales (LoE 1, GoR B); they are the core of treatment of XLI, a retention ichthyosis with adherent scales [13, 33]. They are applied once or twice daily, with progressive reduction according to response (LoE 1, GoR B), and should not be applied to the face, flexures or fissures, because of irritation (LoE 1, GoR B); adverse effects are pruritus, burning and irritation [33]. Low-concentration moisturising agents (urea <5%, propylene glycol <20%, dexpanthenol, macrogol 400, glycerol) and lubricants (white soft paraffin, paraffin) complete the topical range [33]. Daily lukewarm baths of at least 30 minutes, with mild soap or a soap-free wash base, followed by gentle removal of scale (sponge, microfibre cloth, pumice stone), are recommended (LoE 4); moisturising additives, colloidal preparations, sodium bicarbonate (3–6 g/L) or 0.9% saline baths may be added, and balneotherapy with thermal waters may be useful (LoE 2+, GoR C) [33]. Antiseptics should not be used routinely and iodine-based antiseptics are not recommended, because of the risk of thyroid dysfunction [33]. When there are thick scales on the scalp, an emollient or wash-off keratolytic is applied for a few hours or overnight before shampooing, with variable weekly frequency (LoE 4, GoR D), and plastic occlusion requires caution in children because of transfollicular penetration [33]. Occlusive dressings are effective in recalcitrant areas, and the German guideline gives the dark, adherent keratoses of the neck in XRI as an example [30].

Keratolytics should be avoided in newborns and young infants (LoE 3, GoR D) [33]. Salicylic acid carries a risk of systemic absorption, and the German guideline reports deposition in the stratum corneum for up to 13 days [30]. The rationale for topical cholesterol is pathophysiological: it corrects the barrier abnormality induced by cholesterol sulfate [54]. The open trial by Lykkesfeldt and Høyer (1983), with intra-individual comparison of 10% cholesterol cream versus 10% urea, showed a good response to cholesterol in 18 of 20 men and superiority over urea in 13, with no patient doing better with urea [129]. Topical tazarotene was effective in an open study of 12 patients with congenital ichthyosis and in one patient with severe XLI, and one study compared 0.05% tazarotene with 70% glycolic acid in XLI due to an extensive STS deletion [33, 130]. Urea 10% and ammonium lactate 12% do not have XLI as an approved indication in the labels consulted [13, 128].

7.3. Systemic retinoids

Acitretin

Acitretin is an oral retinoid, considered in the ichthyoses when topical treatment is insufficient (LoE 2, GoR D) and the drug of choice in this context (LoE 2, GoR D) [33]. The 2019 guideline expressly mentions its relevance for milder forms, such as severe XLI, and the German guideline considers systemic retinoids suitable for lamellar ichthyosis and XRI, as they are non-inflammatory ichthyoses [30, 33]. The only study directed at XLI included 8 men with severe disease treated for 4 months: all had marked improvement in scaling, all had hypervitaminosis A-type effects, one stopped because of pruritus (an atopic patient), there were no laboratory abnormalities, the dose of 35 mg/day gave the best balance between efficacy and adverse effects, and the benefit persisted for 4 to 6 weeks after discontinuation, which allows intermittent treatment adjusted to the seasons [131].

The main adverse effect is teratogenicity. The US label contraindicates acitretin in women who are pregnant or intend to become pregnant during treatment and for at least 3 years after discontinuation, requires reliable contraception during this period and two negative pregnancy tests before prescription, prohibits ethanol in women of childbearing potential during treatment and for 2 months afterwards (because of transesterification to etretinate, which has a long half-life) and limits dispensing to one month [35]. The European SmPC imposes the pregnancy prevention programme, with contraception from 4 weeks before until 3 years after, prescription ideally limited to 30 days, monthly pregnancy testing and testing every 1 to 3 months during the following 3 years, a ban on blood donation during treatment and for 3 years afterwards and a ban on alcohol (foods, drinks, medicines) in women of childbearing potential during treatment and for 2 months afterwards; the half-life of etretinate is about 120 days [34]. The common, reversible effects are dryness of the mucous membranes and cheilitis, lipid and hepatic abnormalities and hair loss; the long-term concern is musculoskeletal (hyperostosis, ligament ossification, reduced bone mineral density and premature epiphyseal closure described with retinoids) [33, 35]. In the psoriasis trials of the US label (n=525), 98% of patients had some adverse event and more than 75% cheilitis; there was elevation of transaminases, gamma-glutamyltransferase (GGT) or lactate dehydrogenase (LDH) in about 1 in 3 and 3.8% discontinued because of hepatic abnormalities; in 380 patients, 15% of those with pre-existing vertebral abnormalities showed progression [35]. Monitoring according to the SmPC includes liver function before treatment, every 1–2 weeks in the first 2 months and then every three months, fasting cholesterol and triglycerides before treatment, after 1 month and then every three months, blood glucose in people with diabetes, and attention to reduced night vision and mood changes [34]. The adverse effects and monitoring table of the 2019 guideline proposes a different and longer schedule: before initiation, full blood count, electrolytes, fasting glucose, urea, creatinine, liver tests (alanine aminotransferase, aspartate aminotransferase, GGT, alkaline phosphatase, bilirubin) and lipids; liver tests every 2–4 weeks in the first 2 months, every three months in the first year, every six months in the second and annually thereafter, with discontinuation if transaminases exceed 3 times the upper limit of normal; triglycerides and cholesterol monthly in the first 2 months and then at the same frequency, with discontinuation if triglycerides approach or exceed 10 mmol/L, because of the risk of pancreatitis; greater frequency if there are comorbidities or high doses; creatine phosphokinase once during follow-up; radiographs of the four limbs and lateral spine before initiation and, during follow-up, only if there are pre-existing abnormalities or symptoms; densitometry only with pre-existing abnormalities or risk factors; growth in children [33]. The same table recommends routine artificial tears and avoidance of contact lenses, avoidance of intense physical exercise (myalgia), a low-fat diet, avoidance of alcohol and other hepatotoxic agents, and no combination with tetracyclines, because of the risk of benign intracranial hypertension [33]. In children, as there are no paediatric formulations in most countries, the dose can be prepared by the pharmacist, and the capsules, which are light-sensitive, should be opened away from daylight; no growth retardation under retinoids has been described in the published series [33]. The pregnancy prevention programme described in the guideline supplement requires written informed consent, two negative pregnancy tests before initiation (the second no more than 3 days old), initiation on the 2nd or 3rd day of the next menstrual cycle, monthly visits with testing at 28-day intervals and a negative test no more than 3 days old before each renewal, and tests every 1–3 months for at least 3 years after the last dose; it prohibits breastfeeding and blood donation during treatment and for at least 3 years afterwards [33]. The same supplement lists as contraindications pregnancy or the intention to become pregnant, non-adherence to contraception, breastfeeding, hypersensitivity, severe hepatic or renal impairment, hypervitaminosis A, hyperlipidaemia and combination with tetracyclines, methotrexate, vitamin A or other retinoids, with caution in glucose or galactose malabsorption syndromes [33]. Contraindications include severe hepatic or renal impairment, chronic hyperlipidaemia, combination with tetracyclines (risk of benign intracranial hypertension) or methotrexate, other retinoids or vitamin A, and breastfeeding [34, 35].

Isotretinoin and alitretinoin

The 2019 guideline considers alitretinoin and isotretinoin, which are cleared more rapidly, preferable to acitretin in women planning pregnancy or in case of hypersensitivity to aromatic retinoids (LoE 2, GoR D) [33]. There are no adequate comparative studies with acitretin; isotretinoin requires high doses, carries a risk of intracranial hypertension, myalgia and muscle stiffness and has skeletal toxicity with more published data, and alitretinoin is associated with headache, benign intracranial hypertension and hypothyroidism; acitretin is therefore the recommended option for long-term treatment [33]. In the EU, these oral retinoids are subject to the same pregnancy prevention programme [132]. In the USA, isotretinoin is dispensed through the iPLEDGE programme [19].

Regulatory status

The 2019 guideline refers to acitretin as "EMA-approved"; the EMA page indicates that acitretin has national authorisations, and that the measures were harmonised by the 2018 referral [33, 132]. The sources consulted do not include the INFARMED SmPC or the ANVISA package leaflet, so brand names and reimbursement conditions in Portugal and Brazil are not included in this article.

7.4. Clinical trials

IGA denotes investigator's global assessment; VIIS, the visual index for ichthyosis severity. The phase 3 trial of topical isotretinoin did not meet the primary endpoint or the key secondary endpoints, with a high vehicle response; the sponsor stated that the results did not support an application to the FDA, and results by subtype (RXLI versus ARCI) are not available in the registry [134, 135]. Serious adverse events occurred in 1 of 78 patients on TMB-001 and in none of the 38 on vehicle, and most of the remainder were mild to moderate local skin reactions [134, 135]. The phase 2b trial, which had suggested benefit, was small and not powered for significance, and the discrepancy with phase 3 illustrates the risk of extrapolating from exploratory studies [136]. The studies directed at XLI are open-label, small and old, without an independent control group; the results do not allow indirect comparison between trials, and response proportions should be read alongside the vehicle response in the phase 3 trial. In the ClinicalTrials.gov search of 10 October 2026 (condition "ichthyosis", 118 records) there was no active trial directed specifically at XLI; a trial of imsidolimab (NCT04697056) was terminated with 5 patients [140]. A negative search does not prove that no studies exist.

7.5. Developments in the last 12 months and level of evidence

In the sources consulted, no regulatory process (application, opinion of the EMA Committee for Medicinal Products for Human Use (CHMP) or authorisation) specific to XLI was identified. Gene therapy has been explored in a model: retroviral transfer of STS into patients' keratinocytes restored the protein and enzyme activity, and grafts in immunodeficient mice regenerated epidermis without hyperkeratosis, in contrast to uncorrected keratinocytes [18].

7.6. Management of extracutaneous manifestations

Eye. Corneal opacities do not impair vision and require no treatment; slit-lamp examination has diagnostic and counselling value [13, 95]. Signs of ocular albinism in an extensive deletion require specialised ophthalmological assessment [13].

Testis. Testicular examination is part of the initial assessment of the boy, and cryptorchidism follows the usual urological management [13, 105]. Cryptorchidism with micropenis raises the hypothesis of hypogonadotrophic hypogonadism due to a contiguous deletion [36].

Neurodevelopment and mental health. The 2019 guideline recommends assessing quality of life and disease burden with ichthyosis-specific questionnaires or with the DLQI/CDLQI (adult and children's dermatology life quality indices) (LoE 3, GoR D), offering psychological support as early as possible and throughout life, adapted to the child, the adult and the family (LoE 4, GoR D), considering family therapy and the situation of siblings (LoE 4, GoR D), providing information on reimbursement and school and occupational support, ideally with a social worker (LoE 4, GoR D), proposing "ichthyosis schools" for therapeutic education (LoE 3, GoR D) and communicating the diagnosis to the family as soon as it is known (LoE 4, GoR D) [33]. Skin pain, scaling and female sex were the factors with the greatest weight on quality of life in the congenital ichthyoses, and the cost of moisturisers is often the main financial burden [33]. In XLI, the sources recommend screening for ADHD, ASD, depression and anxiety, treatment of ADHD and attention to mood symptoms [3, 13]. The focal epilepsy associated with the classic deletion is, in the series described, easily controlled [91, 92]. In one of the Russian cases, the seizures of the first year were controlled with valproate (Depakine®) [66].

Heart. There is no guideline with a cardiac surveillance programme specific to XLI. The 2024 European Society of Cardiology (ESC) guideline on AF does not mention XLI; it establishes that a result suggestive of AF on a screening device requires confirmation by a single-lead or continuous ECG recording of more than 30 seconds or a 12-lead ECG analysed by a physician, reports that single time-point screening in people aged 65 years or over did not increase AF detection in cluster randomised trials and that prolonged screening increases detection, with a small benefit on the combined endpoint of the STROKESTOP trial (hazard ratio, HR, 0.96; 95% CI 0.92–1.00), and identifies the selection of the population that benefits most from screening as a gap in evidence [142]. In the context of XLI, UK investigators advocate targeted cardiac screening of men and carriers, and more than 80% of the patients and carriers surveyed agreed with routine screening after diagnosis [90, 114]. A feasibility study with smartwatch ECG 3 times a week for 8 weeks in 5 adult men had data return >95%, found ventricular extrasystoles in 2 and one possible false positive, and the authors concluded that it was feasible and acceptable, but that a larger trial would be needed [143]. The prospective paediatric cohort proposes individualised assessment guided by symptoms, findings and family history [113]. An approach consistent with these sources is to ask actively about palpitations, syncope and a family history of arrhythmia at each visit, obtain an ECG in the presence of symptoms and refer symptomatic patients and adult men with risk factors to cardiology, without a validated screening interval [23, 113, 142]. In the case of cardiac arrest due to ventricular fibrillation, management was implantation of a cardioverter-defibrillator for secondary prevention, and in the case of sinus pauses with syncope, a pacemaker [66, 111]. Systemic STS inhibition by irosustat, in 10 patients with breast cancer, was associated with 2 abnormal ECGs, 1 tachycardia and 1 long QT, a pharmacological finding that supports the plausibility of the association [90].

Kallmann component. Treatment of hypogonadotrophic hypogonadism due to ANOS1 deletion follows the 2015 European consensus. Virilisation is achieved with injectable testosterone (enantate, cipionate, undecanoate) or transdermal testosterone; in paediatrics, from 12 years of age, treatment starts at a low dose, for example 50 mg of testosterone enantate per month, 10 mg of transdermal testosterone on alternate days or 40 mg of oral testosterone undecanoate per day, increasing to the adult dose over 18 to 24 months; in adults, 200 mg of testosterone enantate per month and then every 2 to 3 weeks, with measurement of trough testosterone [36]. Testosterone does not induce fertility; fertility is obtained with pulsatile GnRH or subcutaneous gonadotrophins 2 to 3 times a week, and spontaneous reversal occurs in about 10 to 20% of patients with congenital hypogonadotrophic hypogonadism [36]. Men with Kallmann syndrome due to ANOS1 may have an atypical response to treatment [20]. There is no treatment for anosmia, bimanual synkinesis or renal agenesis [36].

CDPX1 component. Management includes nasal stents or oxygen for respiratory obstruction, maxillary reconstructive surgery, a cervical collar or fusion and decompression for cervical stenosis, hearing aids and educational support; cervical spine instability is assessed by flexion-extension radiographs every 6 to 12 months until the end of growth; in the presence of cervical instability, extreme neck extension and flexion and contact sports should be avoided, and cervical imaging should be performed before general anaesthesia [14].

SHOX component. Short stature and Madelung deformity follow the approach to SHOX deficiency.

Vitamin D and growth. The 2019 guideline recommends annual measurement of 25-hydroxyvitamin D (25(OH)D) in all forms of congenital ichthyosis (LoE 2++, GoR B), or every six months if there are risk factors (pigmented skin, severity, winter and spring) (LoE 3, GoR D), 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), parathyroid hormone (PTH), calcium and phosphate are measured (LoE 3, GoR D), and densitometry and radiographs are mandatory if there are skeletal symptoms; supplementation follows the general recommendations for adults and children (LoE 4, GoR D), with maintenance to be considered given the chronicity [95]. The 2024 update did not change this section, merely revising the references [100]. After the neonatal period, growth parameters should be recorded on height and weight-for-age centile charts, with a frequency inversely proportional to age (LoE 4, GoR D); in the presence of growth delay, paediatric endocrinology and/or nutrition become involved (LoE 4, GoR D), and in adolescents attention should be paid to signs of delayed puberty, a point of added relevance in deletions that include ANOS1 [15, 95].

7.7. Pregnancy, delivery and lactation

When the male fetus is known to be affected, the obstetric team should be informed of the risks of prolonged gestation and failure to progress in labour [13, 27]. The Danish series showed vaginal delivery in 70% and concluded that intervention is justified only by other obstetric indications, which argues against a systematically interventionist approach [7]. Prenatal detection of STS deficiency has a clinical utility considered uncertain in part of the obstetric literature [24]. Carriers should be monitored for mood disorders in the puerperium [55]. Oral and topical retinoids are contraindicated in pregnancy, and acitretin is contraindicated in breastfeeding [33, 34].

7.8. Agents and situations to avoid

Topical salicylic acid before 2 years of age and over extensive areas in older children, urea ≥10% in the first year outside the palms and soles, alpha-hydroxy acids in the first years and keratolytics on inflamed skin, flexures or erosions should be avoided [30, 33]. With acitretin, tetracyclines, methotrexate, other retinoids and vitamin A are contraindicated, as is alcohol in women of childbearing potential [34, 35]. In deletions with cervical instability, contact sports and extreme cervical manoeuvres, including during anaesthesia, are avoided [14]. Warfarin inhibits ARSL and produces a phenocopy of CDPX1, which is relevant for the differential diagnosis of a child exposed in utero [14, 47].

7.9. Transition to adulthood

Transition should transfer to adult medicine the skin treatment, the monitoring of mood and attention, reproductive information for carriers and attention to cardiac rhythm, which in population data is concentrated in middle-aged men [3, 23]. For the Kallmann component, the European consensus emphasises organised transition from paediatric to adult endocrinology [36].

7.10. Guideline recommendations and divergences

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

Inheritance is X-linked recessive [1]. A carrier woman transmits the X with the deletion or variant in 50% of pregnancies: sons who inherit it are affected and daughters who inherit it are carriers; an affected man transmits it to all his daughters, who are obligate carriers, and to none of his sons [14, 29]. Daughters of an affected man and a carrier mother may be homozygous, with a phenotype similar to that of males [3]. The best time for counselling is before pregnancy [14].

Most deletions are inherited from the mother: about 85% in the syntheses and 89% (50/56) in the Chinese prenatal diagnosis cohort, with 11% de novo [17, 23]. In a series of nine prenatal cases studied by FISH, all tested mothers of fetuses with a deletion were carriers [122]. The reference textbook states that most apparently sporadic males have inherited deletions and attributes to Valdes-Flores et al. (2001) the figure of 10 of 12 mothers being carriers; the abstract of that article, which describes a Mexican family with deletion of exons 1–5, does not contain this figure [27, 62]. For the Kallmann component, about 70% of men affected through ANOS1 are simplex cases, the father is not a carrier and the mother of more than one affected son is an obligate heterozygote; maternal germline mosaicism has not been described for ANOS1 [20].

8.2. Cascade testing and carriers

Once the deletion or variant is confirmed in the proband, testing the mother is the first step, followed by sisters and maternal aunts, maternal uncles and cousins on the maternal side [13, 20]. Dosage methods (MLPA, CMA, FISH) serve for deletion carriers; STS activity also identifies carriers, because the gene escapes X inactivation [11, 56]. Information for carriers includes the risk of prolonged gestation and complicated delivery with an affected son, asymptomatic corneal opacities and the higher frequency of mood disorders in the puerperium [29, 55]. In deletions that include NLGN4X, the variant should be followed in the family, and a random X-inactivation pattern does not exclude a phenotype in a girl [16].

8.3. Prenatal diagnosis and preimplantation genetic testing

When the familial alteration is known, prenatal diagnosis is made by chorionic villus sampling between 10 and 12 weeks or by amniocentesis from 14 weeks, and preimplantation genetic testing is possible in selected cases [14, 30]. The 2019 European guideline states that genetic counselling should be offered to the patient and family by the clinical geneticist (LoE 4, GoR D), who is responsible for calculating the risk for other relatives and for offspring and for answering questions about prenatal diagnosis, predictive testing and preimplantation diagnosis, where available [33]. Germline mosaicism is very rare but possible in the X-linked ichthyoses [33]. The 2024 update of the congenital ichthyosis guidelines includes chapters on communication of the diagnosis, genetic counselling, prenatal diagnosis and preimplantation genetic testing [126]. Isolated XLI is neither life-threatening nor severely disabling, which makes a request for prenatal diagnosis or preimplantation testing an ethical question to be discussed case by case [67]. In contiguous deletions with intellectual disability or Kallmann syndrome, the discussion is different, and the extent of the familial deletion should be known before any decision [22]. Incidental prenatal findings (low uE3, maternal deletion on NIPT) should be confirmed by CMA on amniotic fluid before any decision about the pregnancy [31, 67].

8.4. Counselling of minors

Testing boys with skin signs has immediate clinical utility, because it guides testicular, ophthalmological and developmental examination [13]. The sources consulted contain no specific recommendation on carrier testing of minor girls in XLI; the decision follows the general standards for genetic counselling of minors, weighing the absence of clinically relevant manifestations in carriers during childhood [17, 90].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each study measures

Estimates from prenatal screening and genotyping (about 1 in 1,500 to 1 in 2,200 men) are higher than clinical estimates (1 in 2,000 to 1 in 6,000), because only 25–60% of male carriers reach a diagnosis of XLI and many have a mild phenotype, classified as dry skin or eczema [13, 90, 99]. The frequency of about 1 in 730 women in the UK Biobank agrees with the published estimates of 1 in 750 to 1 in 1,200 carriers [23]. The estimate of 1 in 2,200 men in the UK Biobank is lower than that of North American prenatal screening, probably because of recruitment bias towards healthier volunteers [23]. The statement that there are no racial or geographical differences, repeated in a 2025 review, has not been demonstrated for African or African-descended populations, because the Californian study did not obtain a reliable estimate in Black pregnant women [21, 145]. For counselling, the estimate of about 1 in 1,500 boys is considered reasonable by the authors of the Californian study [21].

9.2. Geography, cohorts and recurrence

In the USA and Canada, data come mainly from biochemical prenatal screening [21, 22, 24]. In Europe, there are clinical and genetic series from Denmark, Italy, Spain, the Netherlands, Germany, Austria and the United Kingdom [7, 23, 25, 29, 61, 93, 102]. In an Austrian cohort, XLI accounted for 43 of 198 patients with ichthyosis (21.7%) over 13 years [3]. In Spain, the proportion of partial deletions (25%) was higher than in other populations [61]. In North Ossetia-Alania, XLI was the second most frequent genodermatosis after IV, with similar deletions in families of different ethnic origin and distinct haplotypes, and a point variant in one Ossetian family; in Tunisia, eight patients from three families had complete STS deletion without a common haplotype [59, 60]. These data point to recurrence at a recombination hotspot and not to a founder effect. In China, NIPT has revealed maternal deletions in a large number of pregnancies, with screening and prenatal diagnosis cohorts [17, 31, 117]. Mexico has series with complete and partial deletions [18, 62].

In Portugal, the sources consulted include a family with a terminal Xp22.3 deletion, Léri-Weill dyschondrosteosis, developmental delay and ichthyosis, published by a Portuguese group, without national epidemiological data [82]. In Brazil, the textbook of genetic syndromes presents XLI in a comparative table of ichthyoses with an incidence of 1:6,000, without stating the population of origin [97]. The absence of national data in the sources consulted does not mean that such data do not exist.

9.3. Special populations

Carrier women deserve attention in pregnancy with a male fetus, in the puerperium and with regard to mental health [7, 55]. Middle-aged men concentrate the AF risk observed in the population [23, 90]. Children with extensive deletions require pubertal, skeletal, cervical and developmental surveillance [14, 15]. Women of childbearing potential on oral retinoids are subject to the pregnancy prevention programmes [35, 132].

9.4. European network and patient associations

The relevant European reference network is ERN-Skin, through the IPPK (ichthyosis and palmoplantar keratoderma) thematic group, which brings together centres such as Necker-Enfants malades (Paris), CHU de Toulouse, Erasmus MC (Rotterdam), Maastricht UMC+, Hospital Clínic and Sant Joan de Déu (Barcelona), Universitätsklinikum Münster, Bambino Gesù (Rome), the Medical University of Innsbruck and Uppsala; the network text consulted does not list Portuguese centres [37]. The Foundation for Ichthyosis & Related Skin Types (FIRST), in the USA, has a page dedicated to XLI and an expert consultation portal [96]. The Ichthyosis Support Group supports patients in the United Kingdom [98]. The 2019 guideline recommends informing patients about the associations and points to the European network of ichthyosis associations [33]. The sources consulted do not include patient associations in Portugal or Brazil.

In France, the inherited ichthyoses follow the HAS PNDS "Ichtyoses héréditaires" (2021), within the FIMARAD filière, with two reference centres (Nord, coordinated at Hôpital Necker, and Sud, coordinated in Bordeaux) and 11 competence centres; the association Ichtyose France, founded in 1991, supports patients, and the disease can be recognised as an "off-list" long-term condition, with 100% coverage [121]. The PNDS describes non-syndromic XLI as restricted to boys, with mild to moderate, dark, polygonal scales and a symptom-free interval after birth, and the syndromic form with neurological anomalies, anosmia or cryptorchidism [121].

10. Illustrative Clinical Case

10.1. Family identified through a secondary NIPT finding

Li et al. (2026) described a 35-year-old pregnant woman, gravida 2, para 1, followed in Jiangmen, China [67]. The 12-week ultrasound showed a nuchal translucency of 3.7 mm and absent nasal bone. NIPT, at 14+1 weeks, indicated a high risk of trisomy 21 and a deletion of about 2 Mb at Xp22.31. Amniocentesis at 15+6 weeks, with CMA (Affymetrix 750k), confirmed a 47,XY,+21 fetus with an Xp22.31 deletion (chrX:6455151-8141076, about 1.68 Mb), which included STS, VCX3A, HDHD1, VCX and PNPLA4; the article describes the fetal deletion as "homozygous", which in a male fetus corresponds to hemizygosity [67].

Family study showed that the 14-year-old brother had, since infancy, dry, rough, thickened and dark scales on the upper and lower limbs, with the scalp, neck and trunk spared, without corneal opacity or cryptorchidism; the ECG and sex hormones (oestradiol, luteinising hormone or LH, progesterone, follicle-stimulating hormone or FSH, and testosterone) were normal, and the boy was irritable during the consultation but declined psychiatric assessment, so ADHD was not assessed. The brother's CMA revealed the same deletion in the hemizygous state, the asymptomatic mother was a heterozygous carrier arr Xp22.31(6449836-8135568)x1, and the maternal grandmother was also a carrier [67]. The figures of the article include the pedigree with the NIPT and CMA results and, according to the legend, photographs of the brother's skin with dark brown polygonal scales, the normal ECG and the hormone profile [67].

The authors discussed the positive predictive value of NIPT for CNVs, of about 30%, the need for invasive confirmation and the ethical issues of prenatal diagnosis and preimplantation testing in a disease that is neither life-threatening nor severely disabling [67]. The case illustrates three aspects of this article: detection of XLI as a secondary finding of genomic screening, the atypical distribution of skin involvement (neck and trunk spared) and the importance of testing the mother and grandmother to trace the carrier lineage. The decision about the pregnancy was determined by the trisomy 21 and not by the deletion, and the case should not be read as an indication for routine prenatal diagnosis of isolated XLI.

10.2. Contrasting case: cardiac arrest in an adolescent

Mutlu et al. (2025) described a 17-year-old Turkish boy, with no known medical history, who collapsed at a concert with a 3-minute tonic-clonic seizure and cardiac arrest in ventricular fibrillation, with 20 minutes of resuscitation and 8 defibrillations [111]. The initial ejection fraction was 25% with normal coronary arteries and recovered to 70%; 24-hour Holter monitoring recorded 2721 polymorphic ventricular extrasystoles, which decreased as heart rate increased, and a 3-beat run of ventricular tachycardia. The exome, requested in the investigation of channelopathies, found a hemizygous deletion at Xp22.31 including exons 2 to 11 of STS. The skin had not been noticed; reverse phenotyping revealed dry, thickened and slightly scaly skin on the trunk and legs since birth, and a maternal uncle had similar skin and arrhythmias [111]. The patient received a cardioverter-defibrillator for secondary prevention and, according to the report, four sessions of intrathecal mesenchymal stem cells for hypoxic-ischaemic encephalopathy; the latter intervention does not correspond to treatment established in the guidelines. The authors presented it as the first report of cardiac arrest associated with STS deletion [111]. A single case does not establish causality or, by itself, justify universal screening, but it shows that mild ichthyosis may go unnoticed and that a family history of arrhythmia in the maternal line deserves attention.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The sources consulted do not describe reduced life expectancy in isolated XLI, and Orphanet classifies the condition as fairly mild [1]. The skin course is stable, with improvement in summer, and the daily burden of skin care and stigmatisation weigh on quality of life [2, 98, 109]. The overall prognosis is determined by the extracutaneous manifestations: ADHD in about 30–40% of boys, generally controllable focal epilepsy in 13% in a Spanish series, mood symptoms in adults and carriers, and AF in 10.5% of men with the deletion aged 40 to 69 years in the UK Biobank, versus 2.7% of controls [23, 25, 26, 109]. These figures describe the natural history without specific intervention, and there are no treatment data that modify these risks. In contiguous deletions, the prognosis depends on the genes involved: the hypogonadism of the Kallmann component is treatable and fertility is possible with gonadotrophins or pulsatile GnRH; in CDPX1 most have minimal morbidity and skeletal improvement in adulthood, except for cervical and respiratory complications; the intellectual disability and severe epilepsy of very extensive deletions limit autonomy [14, 36, 81].

11.2. Surveillance

There is no validated surveillance programme specific to XLI. The table brings together the elements from the sources, with the intervals where these exist.

12. Summary and Final Considerations

Recessive X-linked ichthyosis results from steroid sulfatase deficiency, almost always due to a recurrent deletion of about 1.5 to 1.7 Mb at Xp22.31 that removes STS and neighbouring genes, and more rarely to partial deletions, point variants or regulatory deletions. Accumulation of cholesterol sulfate in the stratum corneum retains corneocytes and produces adherent dark brown scales on the neck, trunk and extensor surfaces, which spare the flexures, palms and soles and lack palmoplantar hyperlinearity. The same deficiency in the placenta of a male fetus lowers maternal oestriol and prolongs gestation and labour, which makes prenatal screening, biochemical or by NIPT, a frequent route to diagnosis.

The true frequency, of about 1 in 1,500 to 1 in 2,200 men according to prenatal screening and genotyping, exceeds clinical estimates because many male carriers have a mild phenotype and are never diagnosed. The extracutaneous spectrum includes asymptomatic corneal opacities, cryptorchidism, ADHD, focal epilepsy of childhood, mood symptoms and, in middle-aged men, AF; in carriers, corneal opacities and puerperal mood disorders. Larger deletions add Kallmann syndrome, chondrodysplasia punctata, short stature, intellectual disability, autism or ocular albinism, and CMA defines the extent in each family.

Diagnosis is based on dosage methods (MLPA, CMA), complemented by sequencing and leucocyte STS activity, with attention to the Yq pseudogene and to the differential diagnosis with IV, which accounts for a significant proportion of clinical misdiagnoses. Skin treatment is topical, with emollients and keratolytics adjusted for age, and acitretin is reserved for severe forms, with the indication of severe congenital ichthyosis in the European SmPCs and off-label use in the USA, under a pregnancy prevention programme. The phase 3 trial of topical isotretinoin was negative. Extracutaneous management includes ophthalmological and testicular examination, neurodevelopmental and mood screening, targeted attention to cardiac rhythm without a validated screening interval and, in contiguous deletions, endocrine and skeletal follow-up. Genetic counselling focuses on the carrier mother, the obligate carrier daughters of affected men and obstetric information.

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