All causal genes in this group affect cholesterol synthesis.

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  Syndromic X-linked ichthyosis: patients present with a cutaneous phenotype similar to the non-syndromic form, but with variable associated extracutaneous symptoms that may include anosmia, hypogonadotropic hypogonadism – Kallman syndrome – and intellectual disability. It is due to large hemizygous microdeletions affecting both STS2 and contiguous genes, whose absence determines the associated clinical spectrum. Strictly, this type of ichthyosis could be considered non-syndromic since the extracutaneous symptoms are not due to STS deficiency, but by the additional deletion of contiguous genes.

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  IFAP syndrome (ichthyosis follicularis–alopecia–photophobia): characterized by generalized cutaneous affectation with erythema, follicular hyperkeratosis, palmoplantar keratoderma, alopecia and photophobia. Additionally, some patients exhibit intellectual disability, corneal opacity, renal dysplasia, cryptorchidism and skeletal malformations (BRESHECK syndrome). It is due to recessive pathogenic variants in MBTPS2.3 Of note, a phenotypically similar entity called hereditary mucoepithelial dysplasia – also called IFAP2 – exists and is due to dominant pathogenic variants in SREBF1,4 a gene found not in the X chromosome, but in chromosome 17 (Fig. 1). Both genes are transcription factors that activate the cholesterol synthesis pathway.

  
  

  Figure 1.

  Hereditary mucoepithelial dysplasia due to a pathogenic variant in SREBF1. Typical gingival erythema of the disease.

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  Chondrodysplasia punctata type 2: this disease is lethal in men and exhibits a peculiar phenotype of ichthyosis along the Blaschko lines due to X chromosome inactivation. Typical symptoms include cataracts, skeletal abnormalities like low height and rhizomelic limb shortening and punctate appearance in long bone epiphysis radiographs. It is due to dominant pathogenic variants in EBP,5 which encodes a cholesterol synthesis enzyme.

This group is characterized by patients with characteristic hair abnormalities, a clinical finding that can help with disease diagnosis. However, both the clinical signs and molecular and etiopathogenic causes are very diverse.

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  Netherton syndrome: Probably the most common syndromic ichthyosis, and the easiest one to diagnose when hair shaft alterations are identified. Although some cases describe neonatal presentation as a collodion baby, most children are born with erythroderma and a severe alteration of the cutaneous barrier causing recurrent episodes of hypernatremic dehydration and sepsis. Facial erythema is characteristic in these patients, who often exhibit intense and incoercible pruritus. In time, patients may develop a characteristic cutaneous presentation known as ichthyosis linearis circumflexa, characterized by arch-shaped or polylobulated lesions with double-edged scaling (Fig. 2). Most patients present with trichorrhexis invaginata also known as bamboo hair, a hair shaft disorder that may affect head hair as well as eyebrows and eyelashes and can be found during exploratory dermoscopy (Fig. 3). Consequently, patient hair is short and uneven, since it is fragile and breaks easily along the areas with trichorrhexis invaginata. Many patients also suffer from atopic diathesis, with skin eczematiform flares and food allergies, as well as verruciform lesions and a predisposition to human papillomavirus cutaneous infections. Netherton syndrome is caused by recessive pathogenic variants in SPINK5.6 It can be diagnosed by skin biopsy immunohistochemistry, since patients show a lack of LEKTI expression (the protein encoded by this gene, localized in the stratum corneum). Its absence prevents kallikrein inactivation, epidermal enzymes responsible for corneocyte degradation needed for physiological desquamation.

  
  

  Figure 2.

  Netherton syndrome. Poly-lobulated arcuate lesions with a double scaly border, characteristic of ichthyosis linearis circumflexa, in a patient with a pathogenic variant in the SPINK5 gene.

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  Figure 3.

  Netherton syndrome. Dermatoscopic image of the eyebrow hair showing the typical hair changes of the disease (trichorrhexis invaginata).

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  SAM syndrome (severe dermatitis–multiple allergies–metabolic wasting syndrome): A desmosomal disease whose acronym summarizes its essential clinical characteristics: severe dermatitis with ichthyosiform erythroderma, allergies and metabolic wasting leading to failure to thrive. Since SAM syndrome was described after the last consensus classification, it is not a part of it. However, we believe that its physiopathological origin and clinical signs justify the inclusion of SAM syndrome in the group of syndromic ichthyoses with hair abnormalities. Patients present symptoms since birth, often with repeated life-threatening systemic infections. Cutaneous symptoms include severe desquamating erythroderma with hypotrichosis and onychodystrophy (Fig. 4). Tooth enamel anomalies and transient hyperpigmented lesions whose histology suggest a post-inflammatory origin are not rare findings (Fig. 5). SAM syndrome is due to recessive pathogenic variants in DSG17 or dominant pathogenic variants in DSP.8 This last case may associate cardiomyopathy, since DSP is expressed in heart muscle.9

  
  

  Figure 4.

  SAM syndrome (severe dermatitis, multiple allergies and metabolic wasting). Severe ichthyosiform erythroderma and scalp hypotrichosis in a patient with a pathogenic variant in DSG1. Note the blood on the nails caused by scratching due to intense itching.

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  Figure 5.

  SAM syndrome (severe dermatitis, multiple allergies and metabolic wasting). Ichthyosiform erythroderma, onychodystrophy, and focal post-inflammatory hyperpigmentation on the dorsum of the hand and the fourth finger in a patient with a pathogenic variant in DSP.

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  Trichothiodystrophy: characterized by ichthyosis coupled with fragile hair and nails with sulfur deficiency. Ichthyosiform desquamation is usually mild, dark and relatively large, with forehead and trunk affectation (Fig. 6). Characteristically, alternating light and dark bands can be observed in the hair shaft under polarized light (tiger-tail banding). It is due to recessive pathogenic variants in AARS1,10GTF2E2,11MAARS1,10MPLKIP,12RNF113A,13 or TARS1,14 which code proteins involved in protein translation. There is a subtype which also presents photosensitivity, progressive neuropathy and accelerated ageing, caused by recessive pathogenic variants in ERCC2,15ERCC3,16GTF2H5,17 which code proteins involved in DNA repair as well as protein translation. Same as the previous cases, this group shows a striking molecular heterogeneity that hinders geno-phenotypic correlation.

  
  

  Figure 6.

  Trichothiodystrophy. Brown lamellar-like scaling on the trunk of a patient with a pathogenic variant in MPLKIP.

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The most common disease in this grous is Sjögren–Larsson syndrome, characterized by intellectual disability, spasticity and eye abnormalities (crystalline retinopathy), which is highly suggestive for diagnosis. Cutaneous involvement is not very significant and consists of discrete generalized hyperkeratosis which, in some areas, determines parallel linear lesions known as railway track lesions which can be reminiscent of lichenification in the flexures. Many patients show severe pruritus. It is due to recessive pathogenic variants in ALDH3A2,18 a fatty aldehyde dehydrogenase responsible for synthesis of fatty acids use in ceramide synthesis.

This group includes entities that do not respond to the characteristics of the previous groups.

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  KID syndrome (keratitis–ichthyosis–deafness): Characterized by keratitis, hyperkeratosis espinulosa, palmoplantar keratoderma and sensorineural deafness. It is caused by dominant pathogenic variants in GJB219 or GJB6,20 or recessive pathogenic variants in AP1B1,21 which encode gap junction proteins in charge of intercellular communication and the clathrin-coated vesicle adaptor complex, respectively. Additionally, postzygotic GJB2 variants cause keratotic lesions along the Blaschko lines that may be transmitted to the offspring as KID syndrome if it affects the gonads.22 This mosaic forms have less systemic impact since they spare sight and hearing (Fig. 7).

  
  

  Figure 7.

  KID syndrome (keratitis, ichthyosis, and deafness) in a patient with a mosaic form of the disease due to postzygotic variants in GJB2. Linear blaschkoid distribution involvement and significant plantar thickening are observed.

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  Neutral lipid storage disease: Also known as Chanarin–Dorfman disease, it presents with mild congenital ichthyosiform erythroderma, hepatosplenomegaly, myopathy, hypoacusia and cataracts.23 Histologically, vacuole accumulation is seen in most tissues (Fig. 8). It is due to recessive pathogenic variants in ABHD5,24 encoding an enzyme that synthesizes linoleic acid used in ceramide synthesis and whose absence leads to intracellular neutral lipid storage.

  
  

  Figure 8.

  Chanarin–Dorfman syndrome. Peripheral blood smear of a patient with a pathogenic variant in ABHD5, showing lipid droplets in the cytoplasm of granulocytes (Jordan anomaly).

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The main characteristics of the most infrequent syndromic ichthyoses are shown in Table 2.

Generalized alteration of the cutaneous barrier in patients with disorders of epidermal differentiation (DED) is present since birth or within the first few months of life, which helps clinical diagnosis. However, the poor phenotype–genotype correlation hinders a more precise diagnosis in many cases. Fig. 9 shows a diagnostic algorithm in which adequate anamnesis is of paramount importance.

Figure 9.

Diagnostic algorithm for congenital ichthyoses.

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Source: modified from Gutiérrez-Cerrajero C, Sprecher E, Paller AS, Akiyama M, Mazereeuw-Hautier J, Hernández-Martín A, et al. Ichthyosis. Nat Rev Dis Primers. 2023;9:2. doi: 10.1038/s41572-022-00412-3.

Blood tests, including red blood cells, hepatic and renal function, blood electrolyte levels, immunoglobulin serum levels and blood smear can help exclude syndromic forms of ichthyosis and their associated anomalies.25 For example, Netherton syndrome and desmosomal disorders both carry a risk of hypernatremic dehydration in babies.7,26 Moreover, serum immunoglobulin levels can be useful to establish differential diagnosis with hereditary immunodeficiencies, which can also present erythema and desquamation. Referring the patient to other specialists based on the clinical findings should be considered.25 Chanarin–Dorfman presents lipidic droplets in granulocytes and monocytes in blood smear (known as Jordan's anomaly)27 (Fig. 8).

Biopsies for routine histology, immunohistochemistry or, more rarely, electron microscopy may help with differential diagnosis.28 Absence of LEKTI expression (encoded by SPINK5) in immunohistochemistry can confirm a Netherton syndrome diagnosis29 and is especially useful if genetic analysis is not available.28 Light microscope analysis of the hair shaft is an accessible and non-invasive technique that adds useful information in the ichthyoses associated with hair abnormalities, such as trichorrhexis invaginate in Netherton syndrome or “tiger-tail banding” under polarized light in trichothiodystrophy.30 Although clinical diagnosis of ichthyosis is usually easy, phenotype–genotype correlation is often hard to establish. Although genetic testing using next generation sequencing is widely used in developed countries to confirm diagnosis, genetic abnormalities are not found in 15–20% of patients with DED phenotype.31–35 This can be due to undetectable or undescribed pathogenic variants, the latter being the ones that allow a broadening of the group of ichthyosis when associated with distinctive clinical findings.

DED follow patterns of monogenic Mendelian inheritance, which allows for genetic counseling, where information is provided to affected families (patients and relatives) about the molecular mechanisms and odds of transmission to potential offspring. However, perception of the risk of having an affected child changes substantially depending on the disease and a pregnancy may not be considered high-risk by couples if they already have a child with mild symptoms. In contrast, patients with severe forms or a heavy impact on quality of life may ask for genetic counseling to avoid future high-risk pregnancies.36 Regional, cultural, and socioeconomic idiosyncrasies may also influence access to genetic counseling.

Prenatal diagnosis requires obtaining embryonic tissue. Low levels of unconjugated estriol and copy number alterations in maternal serum – which detects deletions in maternal sexual chromosomes – are closely associated win an increased risk of recessive X-linked ichthyosis in male fetuses and can be used, along with other molecular techniques, for prenatal diagnosis.37,38 In any case, the method of choice for prenatal diagnosis is the genetic analysis of known pathogenic variants in the family. Pre-implantation diagnosis may be used by at-risk couples to select unaffected embryos prior to in vitro fertilization, although many countries do not consider it appropriate for ichthyosis.39

DED are genetic diseases that currently lack curative treatment. Therapy is currently aimed at alleviating symptoms to improve the patient's quality of life. Therefore, this requires treatments that not only have to be effective but also safe and well tolerated. However, the reality is that there are few studies on the long-term effects of therapies and their efficacy varies greatly across patients, even among those suffering from the same type of DED. Therefore, the chosen treatment and administration regimen depend on expert recommendations in clinical practice guidelines, information sharing with patient associations, accessibility to treatment and the personal experience of each individual patient.26,40,41

Á. Hernández-Martín is a researcher for Mayne Pharma and Celgene, a consultant/advisory board member for Sanofi, Viatris, Almirall, Galderma, and L’Oréal, and a speaker for Sanofi, Viatris, L’Oréal, Leti Pharma, Beiersdorf, and Alexion. The other authors declare no conflicts of interest.