Ichthyosis 

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Ichthyosis 

Description

  • ichthyosis is a clinical finding of dry, scaly, erythematous skin that is associated with either congenital or acquired causes(1,2,4,5)
    •  inherited ichthyosis encompasses a heterogeneous group of inherited scaling skin diseases due to specific genetic mutations affecting keratinocyte development and function(1,2,3)
    •  acquired ichthyosis can occur secondary to malignancies, autoimmune, inflammatory, metabolic, endocrine, or infectious diseases; or drug use(1,2,3)

Also Called

  • inherited ichthyosis also called
    • congenital ichthyosis
    • Mendelian disorders of cornification (MEDOC)

Types of Inherited Ichthyosis

Nonsyndromic Types of Inherited Ichthyosis

  •  nonsyndromic types of inherited ichthyosis affect only the skin and nails(1,2,3)
  • nonsyndromic inherited ichthyoses are classified into 3 types(5)
    • common ichthyosis
    • autosomal recessive congenital ichthyoses (ARCI)
    • keratinopathic ichthyoses
  • common ichthyoses include ichthyosis vulgaris and nonsyndromic recessive X-linked ichthyosis(5)
    • ichthyosis vulgaris
      •  most common ichthyosis with prevalence reported 1 in 100 to 1 in 1,000
      •  autosomal semidominant with delayed onset (manifestations occur after age 6 months)
      • most commonly caused by pathogenic variant in gene for
      • online Mendelian inheritance in man (OMIM) phenotype code in the OMIM database: Online Mendelian Inheritance in Man #146700 and #146750
    • nonsyndromic recessive X-linked ichthyosis (RXLI)
      • clinical symptoms seen in males only
      •  delayed onset (weeks to months after birth)
      •  linked to gene for steroid sulfatase (STS)
      • OMIM: OMIM #308100
  • autosomal recessive congenital ichthyosis (ARCI)(1,2,3,5)
    • includes many types of congenital ichthyosis caused by variety of genetic defects that typically present at birth with collodion (a shiny, translucent membrane that covers the skin and peels off within a few weeks)
    • all forms are more rare than common ichthyoses
    • congenital onset with neonatal symptoms
    • most ARCI present with collodion at birth
    • harlequin ichthyosis presents with thick, armor-like covering of newborn that can restrict mobility, including respiration and feeding and is associated with high mortality (OMIM #242500)
    • other types include
  • keratinopathic ichthyosis (keratopathy)
    • due to mutations in keratin genes (KRT)
    • usually autosomal dominant, but may be autosomal recessive
    • congenital onset with neonatal symptoms of extensive blistering and erosions at birth
    • types include
      • epidermolytic ichthyosis (also known as epidermolytic hyperkeratosis), (autosomal dominant OMIMs: 113800 and 113800; autosomal recessive OMIM: 113800)
      • superficial epidermolytic ichthyosis (OMIM: 146800)
      • annular epidermolytic ichthyosis (OMIMs: 607602 and 607602)
      • ichthyosis Curth-Macklin (OMIM: 146590)
      • epidermolytic nevus (no OMIM)
      • ichthyosis with confetti (OMIMs: 609165 and 609165)
  • other nonsyndromic ichthyoses (all rare)(5)
    • peeling skin syndromes (PSS) (OMIMs: 270300, 618084, 607936, 609796)
    • loricrin keratoderma (LK) (OMIM: 604117)
    • exfoliative ichthyosis (OMIM: 607936 and 617115)
    • erythrokeratodermia variabilis et progressiva (EKVP) (OMIMs: #617525, #133200,#617524, #617526, 619209, 618531)
    • keratosis linearis-ichthyosis congenita and sclerosing keratoderma syndrome (KLICK) (OMIM #601952)
    • peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome (PLACK) (OMIM #616295)

Syndromic Ichthyoses

  •  syndromic types of inherited ichthyoses are associated with cutaneous and extracutaneous findings because the affected gene encodes proteins or lipids used in multiple organs or systems(5)
  • syndromic ichthyoses are rarer than nonsyndromic ichthyosis and are classified by mode of inheritance, including(5)
    • X-linked syndromes
    • autosomal syndromes that affect hair, such as Netherton syndrome and trichothiodystrophy
    • autosomal syndromes with prominent neurologic signs, such as Refsum disease and Sjogren–Larsson syndrome
    • autosomal syndromes that affect glycosylation or have ocular or liver function anomalies
  • syndromic X-linked ichthyoses include(1,2,5)
    • recessive X-linked ichthyosis (OMIM: 308100), affecting males, and associated with cryptorchidism and corneal opacities (Kallmann syndrome)
    • ichthyosis follicularis-alopecia-photophobia syndrome (OMIM: 308205 and 619016)
    • chondrodysplasia punctata type 2 (OMIM: 302960)
    • male EBP disorder with neurological defects (OMIM: 300960)
    • congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome (OMIM: 308050)
  • autosomal ichthyotic syndromes that affect hair include(5)
    • Netherton syndrome (OMIM: 256500)
    • severe dermatitis-multiple allergies-metabolic wasting syndrome (OMIM: 615508)
    • ichthyosis-hypotrichosis syndrome (OMIM: 602400)
    • trichothiodystrophy (OMIM: 619691, 601675, 616390, 616943, 616395, 619692, 234050, 300953, 618546)
    • ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (OMIM: 607626)
  • autosomal ichthyotic syndromes with prominent neurological signs include(5)
    •  Sjogren-Larsson syndrome (fatty acid alcohol oxidoreductase deficiency) (OMIM: 270200)
    • Refsum syndrome (characterized by anosmia, early onset retinitis pigmentosa, neuropathy, deafness, ataxia) (OMIM:308100, 266500)
    • cerebral dysgenesis-neuropathy-ichthyosis palmoplantar keratoderma syndrome (OMIM: 609528)
    • mental disability-enteropathy-deafness-peripheral neuropathy-ichthyosis-keratoderma syndrome (OMIM: 609313, 242150)
    • ichthyotic keratoderma-spastic paraplegia-hypomyelination- dysmorphic facies (OMIM: 618527)
    • congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome (OMIM: 614457)
    • arthrogryposis-renal dysfunction-cholestasis syndrome (OMIM: 613404, 208085)
    • fetal Gaucher disease (OMIM: 608013)
    • multiple sulfatase deficiency (OMIM: 272200)
    • Neu-Laxova syndrome (OMIM: 256520, 616038)
  • autosomal ichthyotic disorders of glycosylation include(5)
    • deficiency of UDP-glucose ceramide glycosyltransferase (no OMIM as of 2023 May 15)
    • congenital disorder of glycosylation type 1F, type 1M and type 1Q (OMIM: 609180, 610768, 612379)
    • coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies syndrome (CHIME syndrome) (OMIM: 280000)
  • autosomal ichthyotic disorders with other associated signs include(5)
    • keratitis-ichthyosis-deafness syndrome (OMIM: 148210, 242150)
    • neutral lipid storage disease with ichthyosis (OMIM: 275630)
    • ichthyosis-prematurity syndrome (OMIM: 608649)
    • erythrokeratodermia-cardiomyopathy syndrome (OMIM: 605676)
    • hypohidrosis-electrolyte imbalance-lacrimal gland dysfunction-ichthyosis-xerostomia syndrome (HELIX syndrome) (OMIM: 617671)
    • ichthyosis-short stature-brachydactyly-microspherophakia syndrome (no OMIM as of 2023 May 15)
    • palmoplantar and perianal keratoderma/harlequin ichthyosis-like ichthyosis with thrombocytopenia (no OMIM as of 2023 May 15)

Epidemiology

Who Is Most Affected

Incidence/Prevalence

  • prevalence of inherited ichthyoses is unclear because there are many rare forms(5)
  • incidence and prevalence estimates of ichthyosis vulgaris, the most common inherited ichthyosis
  • estimated prevalence of recessive X-linked ichthyosis, the second most common type of inherited ichthyosis(5)
    • about 1 in 1,500 males in a United States cohort of 777,088 people
    • 1 in 5,034 males in a South Italian cohort of 75,653 individuals
    • 1 in 4,152 males based on hospital records of a Spanish province
    • 1 in 5,250 males based on hospital records of the Jewish population in Israel
    • 1 in 9,855 based on hospital records of a Japanese province
  • all other inherited ichthyosis are very rare with prevalence of < 1 in 100,000(5)
  • overall, acquired ichthyosis is rare(5)
    • prevalence may be high in certain conditions
    • in patients with HIV/AIDS, prevalence is about 30%
    • in patients with diabetes, prevalence is about 22%
    • in human T-cell lymphotropic virus type 1 (HTLV-1) infection, prevalence is about 50%

Associated Conditions

  •  atopic dermatitis may be associated with ichthyosis vulgaris(2,3)

Etiology and Pathogenesis

Inherited Ichthyoses

Nonsyndromic Ichthyoses
  • nonsyndromic ichthyoses affect only the skin and nails(5)
  • ichthyosis vulgaris (most common inherited ichthyosis)(1,2,3)
    • autosomal semidominant inheritance
    • most commonly affected gene is FLG, which leads to deficient or impaired in filaggrin which is needed to aggregate keratin filaments and act as moisturizing factor for skin hydration
    • other causal genes
      • CASP14 which is involved in enzymatic processes of filament aggregation
      • ASPRV1, which is also involved in enzymatic processes of filament aggregation
  • X-linked recessive ichthyosis(2,5)
    • second most common type of inherited ichthyosis
    • occurs due to deletion of steroid sulfatase (STS) gene, which is needed for an enzyme in the cholesterol synthesis pathway
    • STS is localized to region of X-chromosome that escapes X-inactivation
    • cholesterol is a component of the extracellular space of the epidermis
  • many genes have been identified as associated with various autosomal recessive congenital ichthyoses (ARCI)
    • harlequin ichthyosis – associated with mutations in ABCA12 gene
    • lamellar ichthyosis/congenital ichthyosiform erythroderma – genes include transglutaminase 1 deficiency (TGM1), lipoxygenase (ALOX12B, ALOXE3), ABCA12, NIPAL4, CYP4F22, loc12p11.2-q13.1, CERS3, PNPLA1, SDR9C7, and SULT2B1
    • noncongenital with late or delayed onset – genes include LIPN and CASP14
    • self-improving congenital ichthyosis – genes include TGM1, ALOX12B, ALOXE3
    • bathing suit ichthyosis – gene TGM1
    • Reference – Management of congenital ichthyoses: European guidelines of care, part one (Br J Dermatol 2019 Feb;180(2):272)
  • keratinopathic ichthyosis (KPI)
    • primarily includes autosomal dominant forms
      • epidermolytic ichthyosis – genes KRT1/KRT10
      • superficial epidermolytic ichthyosis – gene KRT2
    • variants include
      • annular epidermolytic ichthyosis – autosomal dominant, genes KRT1/KRT10
      • ichthyosis Hystrix Curth-Macklin – autosomal dominant, gene KRT1
      • autosomal recessive epidermolytic ichthyosis – gene KRT10
      • congenital reticular ichthyosiform erythroderma – autosomal dominant, genes KRT10/KRT1
      • epidermolytic nevi – postzygotic mosaicism inheritance, genes KRT1/KRT10
    • Reference – Management of congenital ichthyoses: European guidelines of care, part one (Br J Dermatol 2019 Feb;180(2):272)
  • other nonsyndromic ichthyoses (with inheritance and affected genes) include
    • loricrin keratoderma – autosomal dominant, gene LOR
    • erythrokeratodermia variabilis et progressiva – may be autosomal dominant or recessive, genes include GJB3, GJB4, GJA1, KDSR, KRT83
    • peeling skin syndrome (PSS) – autosomal recessive, genes include CDSN, TGM5, CHST8, CSTA, SERPINB8
    • keratosis linearis-ichthyosis congenita keratoderma (KLICK) – autosomal recessive, gene POMP
    • Reference – Management of congenital ichthyoses: European guidelines of care, part one (Br J Dermatol 2019 Feb;180(2):272)
Syndromic Ichthyoses
  • syndromic ichthyosis have cutaneous and extracutaneous manifestations(5)
  • X-chromosomal ichthyosis syndromes (with inheritance and affected gene)
    • X-linked recessive ichthyosis syndromic forms – STS
    • ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome – X-linked recessive, MPBTPS2
    • chondrodysplasia punctata type 2 (also known as Conradi-Hunermann-Happle syndrome) – X-linked dominant, EBP
    • congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome – X-linked dominant, NSDHL
    • Reference – Management of congenital ichthyoses: European guidelines of care, part one (Br J Dermatol 2019 Feb;180(2):272)
  • autosomal recessive ichthyosis syndromes with prominent hair abnormalities (and affected gene[s])
    • Netherton syndrome – SPINK5
    • HIS ichthyosis hypotrichosis syndrome – ST14
    • trichothiodystrophy (TTD) – ERCC2/XPD, ERCC3/XPB, GTF2H5/TTDA
    • trichothiodystrophy (TTD, nonphotosensitive forms) – MPLKIP (C7Orf11) / TTDN1, RNF113A, GTF2E2
    • Sabinas brittle hair syndrome
    • Reference – Management of congenital ichthyoses: European guidelines of care, part one (Br J Dermatol 2019 Feb;180(2):272)
  • autosomal recessive ichthyosis syndromes with prominent neurologic signs (and affected gene[s])
    • Sjogren-Larsson syndrome – ALDH3A2
    • Refsum syndrome – PHYH / PEX7
    • intellectual disability-enteropathy-deafness-neuropathology-ichthyosis-keratodermia (MEDNIK) syndrome – AP1S1
    • congenital disorder of glycosylation type 1f (CDG1F) – MPDU1
    • CHIME syndrome – PIGL, SRD5A3
    • Reference – Management of congenital ichthyoses: European guidelines of care, part one (Br J Dermatol 2019 Feb;180(2):272)
  • autosomal recessive ichthyosis syndromes with fatal disease course (and affected gene[s])
    • Gaucher syndrome type 2 – GBA
    • multiple sulfatase deficiency – SUMF1
    • congenital disorder of glycosylation type Im (CDG-IM) – DOLK
    • cerebral dysgenesis-neuropathy-ichthyosis-palmoplantar keratoderma (CEDNIK) – SNAP29
    • arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome – VPS33B
    • Reference – Management of congenital ichthyoses: European guidelines of care, part one (Br J Dermatol 2019 Feb;180(2):272)
  • other syndromic ichthyoses (with inheritance and affected gene[s])
    • keratitis ichthyosis deafness (KID) syndrome – autosomal dominant, GJB2 (GJB6)
    • neutral lipid storage disease with ichthyosis – autosomal recessive, ABHD5
    • ichthyosis prematurity syndrome – autosomal recessive, SLC27A4
    • erythroderma congenital with palmoplantar keratoderma, hypotrichosis and hyper-IgE (SAM syndrome) – autosomal recessive, DSG1
    • ichthyosis-hypotrichosis-sclerosing cholangitis syndrome – autosomal recessive, CLDN1
    • hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia (HELIX) syndrome – autosomal recessive, CLDN10
    • Reference – Management of congenital ichthyoses: European guidelines of care, part one (Br J Dermatol 2019 Feb;180(2):272)
  • inherited ichthyoses are disorders of cornification that follow Mendelian patterns of inheritance(5)
    • the ichthyoses encompass a heterogeneous group of genetic disorders
    • each ichthyosis is caused by a mutation in a specific gene involved in the synthesis or metabolic function of keratinocyte proteins or lipids that are needed to maintain the stratum corneum
  • defects in biosynthesis, metabolism, and transport of the proteins and lipids of the skin lead to disruption of the normal epithelial function of skin(5)
    • increased transepidermal water loss leads to xerosis and scaling
    • protection from external insults and injuries to the skin may be limited, leading to inflammation or infection
  • > 50 different genetic mutations have been identified as underlying various inherited ichthyoses(5)
    • pathogenic variants in the filaggrin gene (FLG) needed for aggregation of keratin filaments, genes that encode keratin proteins (for example, KRT1, KRT2, and KRT10) and genes involved in processing proteins (for example, CASP14) or the metabolism of lipids (for example, ALDH3A2) are among the most commonly affected genes
    • genes in the X chromosome are also linked to ichthyoses and result in X-linked conditions
    • inheritance may be autosomal dominant, autosomal semi-dominant, autosomal recessive, X-linked, or mosaic depending on genetic mutation identified
  • there is wide variation in phenotype-genotype correlations leading to clinical heterogeneity in symptoms and presentations among various ichthyoses(5)

Acquired Ichthyoses

History and Physical

Clinical Presentation

Ichthyosis Vulgaris

  • Ichthyosis vulgaris – Ichthyosis vulgaris-involvement of lower leg.Copyright© 2014, EBSCO Information Services.
  • Ichthyosis vulgaris – Ichthyosis vulgaris-hyperlinear palms.Copyright© 2014, EBSCO Information Services.
  • Ichthyosis vulgaris – Ichthyosis vulgaris.Copyright© 2014, EBSCO Information Services.
  • Ichthyosis vulgaris – Ichthyosis vulgaris- fine branny scale.Copyright© 2014, EBSCO Information Services.
  • ichthyosis vulgaris, associated with(1,2,3,5)
    • delayed onset, with symptoms starting about 2-6 months after birth
    • signs of generalized xerosis and light scaling
    • scaling on the legs and hyperlinear palmoplantar markings on the hands and feet are highly characteristic
    • flexural surfaces (antecubital or popliteal fossae) and the face are usually not involved
    • scaling in patients with darker skin tends to be more pigmented than the rest of the skin
    • pruritus is common
    • hypohidrosis possible
    • no associated erythema of the skin is identified
    • nonscarring alopecia may be seen
    • symptoms may improve in summer
    • 50% develop atopic dermatitis, while 20% may develop asthma or allergic rhinitis
  • an image of ichthyosis in black or brown skin can be found in Mukwende M, Tamony P, Turner M. Mind the Gap: A handbook of clinical signs in Black and Brown skin. St George’s, University of London; 2020

Recessive X-Linked Ichthyosis

  • X-linked ichthyosis – X-linked ichthyosis-fine pale adherent scale in neonate.Copyright© 2014, EBSCO Information Services.
  • X-linked ichthyosis – X-linked ichthyosis-marked involvement of back.Copyright© 2014, EBSCO Information Services.
  • X-linked ichthyosis – X-linked ichthyosis- dark scales on leg.Copyright© 2014, EBSCO Information Services.
  • X-linked ichthyosis – X-linked ichthyosis-dark scale on abdomen.Copyright© 2014, EBSCO Information Services.
  • X-linked ichthyosis – X-linked ichthyosis-fine pale adherent scale in neonate.Copyright© 2014, EBSCO Information Services.
  •  recessive X-linked ichthyosis (RXLI) may be nonsyndromic (more common) or syndromic(5)
  • nonsyndromic RXLI is associated with(1,2,3)
    • manifestations seen only in males
    • large, rhomboid scaling covering the entire skin by 2-6 months after birth
    • symptoms most frequently seen on the scalp and neck
    • antecubital and popliteal regions, the face, palms of hands, and soles of feet typically spared
    •  no accentuated palmoplantar markings
    • pruritus is common
    •  no scarring alopecia
    • hypohidrosis possible
  • syndromic presentations may be associated with
    •  cryptorchidism and/or subclinical corneal opacities(3)
    • anosmia and delayed development (Kallmann syndrome)(5)

Autosomal Recessive Congenital Ichthyoses (ARCI)

  • Collodion baby – Collodion baby-self healing type; child left with normal skin.Copyright© 2014, EBSCO Information Services.
  • Ichthyosis in collodion baby – Collodion baby with development of lamellar ichthyosis.Copyright© 2014, EBSCO Information Services.
  • Ectropion in ichthyosis – Collodion baby with severe ectropion.Copyright© 2014, EBSCO Information Services.
  • Lamellar ichthyosis – Lamellar ichthyosis – large dark plates of scale.Copyright© 2014, EBSCO Information Services.
  • Harlequin ichthyosis – Harlequin ichthyosis.Copyright© 2014, EBSCO Information Services.
  • autosomal recessive congenital ichthyoses (ARCI)(1,2,3)
    • there are many types of ARCI, including
      • lamellar ichthyoses
      • harlequin ichthyosis
      • congenital ichthyosiform erythroderma
      • bathing suit ichthyosis
      • self-healing collodion baby
  • ARCI typically present in neonate with collodion
    •  collodion is shiny membrane covering entire skin that cracks after few days and peels off after few weeks
    •  after healing of collodion, generalized scaling with keratosis usually develops, sometimes with underlying erythema
  • scaling that develops after collodion may be lamellar characterized by large, plate-like scales
  • other symptoms of ARCI(5)
    • ARCI may be associated with scarring alopecia and ectropion
    • pruritus is common
    • may be associated with skin infection, failure to thrive, and a higher risk of mortality
  • harlequin ichthyosis
    • very rare
    •  presents with the newborn encased in armor-like skin with large, diamond-shaped scales (like a “harlequin” costume) that can limit mobility, including respiration and feeding, and is associated with high mortality
  • syndromic ARCI are rare, but include neutral lipid storage disease with ichthyosis(5)
    • also called Chanarin-Dorfman disease
    • characterized by hepatosplenomegaly, myopathy, hearing loss, and cataracts
  • self-improving congenital ichthyosis (SICI)
    • brachydactyly, ear kinking, ALOXE3 variant, and ALOX12B variant each reported to be more common in patients with SICI compared to other forms of ARCI, whereas TGM1 variant was not found in any patient with SICI and ectropion was more common in patients who did not self-improve
      •  based on prospective cohort study
      • 78 children and adults (median age 15 years, 63% female) with ARCI in network for ichthyoses and related keratinization disorders (NIRK) registry were assessed
        • lamellar ichthyosis in 55%, SICI in 23%, congenital ichthyosiform erythroderma in 13%, bathing suit ichthyosis in 5%, and harlequin ichthyosis in 4%
        • consanguinity of parents in 16.7%
      • 26.9% were born prematurely
      • genetic analysis performed in 68 patients
      • comparing patients with SICI vs. patients without SICI
        • collodion membrane at birth in 80% vs. 82.5%
        • brachydactyly of fourth and fifth fingers in 55.6% vs. 25%
        • kinking ear in 47.1% vs. 22.2%
        • ectropion in 25% vs. 42.3%
        • subjective itch in 90.9% vs. 71.7%
        • hypohidrosis or anhidrosis in 82.4% vs. 91.4%
        • vitamin D insufficiency (< 30 ng/mL) in 90% vs. 96.1%
        • ALOXE3 variant in 50% vs. 3.8%
        • ALOX12B variant in 37.5% vs. 9.6%
        • PNPLA1 variant in 6.3% vs. 7.7%
        • CYP4F22 variant in 6.3% vs. 5.8%
        • TGM1 variant in 0% vs. 36.5%
      • Reference – J Eur Acad Dermatol Venereol 2022 Apr;36(4):582

Keratinopathic Ichthyosis

  • Bullous ichthyosis in newborn – Bullae at birth in neonate with bullous ichthyosis.Copyright© 2014, EBSCO Information Services.
  • Bullous ichthyosis with erythema – Bullous ichthyosis at birth-erythema and blistering.Copyright© 2014, EBSCO Information Services.
  • Bullous ichthyosis – Bullous ichthyosis.Copyright© 2014, EBSCO Information Services.
  • Bullous ichthyosis in infant – Bullous ichthyosis at one week beginning to dry and thicken up.Copyright© 2014, EBSCO Information Services.
  • Resolving bullous ichthyosis – Resolving bullous ichthyosis.Copyright© 2014, EBSCO Information Services.
  • Keratoderma of bullous ichthyosis in child – Bullous ichthyosis-thick warty skin.Copyright© 2014, EBSCO Information Services.
  • Palmar keratoderma of bullous ichthyosis – Bullous ichthyosis-marked palmar keratoderma.Copyright© 2014, EBSCO Information Services.
  • Plantar keratoderma of ichthyosis – Bullous ichthyosis-marked plantar keratoderma.Copyright© 2014, EBSCO Information Services.
  • Keratoderma of ichthyosis in older patient – Bullous ichthyosis-thick warty skin.Copyright© 2014, EBSCO Information Services.
  • keratinopathic ichthyosis, including epidermolytic ichthyosis (also known as epidermolytic hyperkeratosis)(1,2,3)
    •  characterized by blistering and skin erosions seen at birth (differential diagnosis includes epidermolysis bullosa)
    • blisters and erosions resolve and are replaced by hyperkeratosis after few months
      •  generalized scaling with numerous annular, polycyclic, and erythematous scaly plaques
      •  scaling typically seen on trunk and extremities, over joints
      •  may have hypohidrosis
      • pruritus is common
    • may be associated with skin fragility and increased likelihood to result in skin erosions after minor trauma
    • may be associated with skin infections
  • other types include(5)
    • ichthyosis with confetti, also called congenital reticular ichthyosiform erythroderma, which is associated with development of multiple white (“confetti”) lesions at ages 3-10 years
    • epidermolytic nevus, characterized by hyperpigmented keratotic epidermal nevi that may appear as curvilinear streaks

Syndromic Ichthyosis

Syndromic Presentations
  • syndromic ichthyosis is characterized by manifestations of ichthyosis and signs or symptoms in extracutaneous organ systems(5)
  • syndromic ichthyosis is rare, but tends to present at birth or early childhood with ichthyosis or collodion membrane, as well as other signs, such as(5)
    • prematurity
    • hair abnormalities (as in Netherton syndrome or trichothiodystrophy)
    • neurologic signs, such as hypotonia, intellectual disability (as in Sjogren-Larsson syndrome), spasticity, motor and sensory neuropathy, seizures, and/or cerebellar ataxia
    • eye abnormalities, such as retinitis pigmentosa (as in Refsum disease), and coloboma
  • some types of syndromic ichthyosis are associated with lethality, as in fetal Gaucher disease, deficiency of UDP-glucose ceramide glycosyltransferase, and chondrodysplasia punctata type 2(5)
Sjogren-Larsson Syndrome (SLS)
  • Sjogren-Larsson Syndrome (SLS) is an autosomal recessive, metabolic disorder that is caused by biallelic pathogenic variants in the ALDH3A2 gene that encodes for the enzyme fatty aldehyde dehydrogenase (FALDH)
    • the deficiency causes an accumulation of fatty aldehydes and lipids in organs leading to characteristic skin (ichthyosis, melanosis, and pruritus), eye (decreased visual acuity and photophobia), and brain (intellectual disability and spastic diplegia) manifestations
    • SLS is more common in Europe and the Middle East, but it is a rare disease with an unknown worldwide prevalence
  • clinical features vary widely and depend upon the age of presentation, such as
    • infancy: preterm birth and generalized erythroderma in the flexural areas, neck, and lower abdomen (often sparing the face) or ichthyosis without neurologic or ocular findings
    • age 1-2 years: generalized ichthyosiform hyperkeratosis develops presenting as a ridge or lichenified pattern, thickened skin with fine scale or keratoderma with hyperpigmented desquamation, and cognitive and motor delays with or without other neurologic findings or ocular abnormalities
    • ≥ 3 years old: ichthyosiform hyperkeratosis, spasticity, intellectual disability, speech and language issues, seizures, impaired visual acuity, and photophobia
Netherton Syndrome
  • Netherton syndrome (NS) is a rare, autosomal recessive congenital disorder
    • characterized by ichthyosis, trichorrhexis invaginata or other hair shaft abnormalities (“bamboo hair”) and atopic diathesis
    • ichthyoses may be either congenital ichthyosiform erythroderma or ichthyosis linearis circumflexa
      • congenital ichthyosiform erythroderma presents as generalized erythroderma and desquamation at birth
      • ichthyosis linearis circumflexa, seen in about 50%, presents in older children and adults as pruritic, erythematous scaly plaques
    • atopic conditions include food allergies, hay fever, and/or asthma
    • hair is reported to be typically lusterless, dry, sparse, and/or brittle
  • reported to affect 1 in 100,000-200,000 live births
  • presentation
    • infants frequently present with severe erythroderma and may be susceptible to sepsis, hypernatremic dehydration, delayed growth, immune abnormalities, and enteropathy
    • symptoms may wax and wane throughout life
    • older children with ichthyosis linearis circumflexa develop linear and serpiginous plaques with double-edged scaling
    • other signs/symptoms that are reported to be common in individuals with NS (not all may be present) include
      • acanthosis nigricans
      • asthma
      • congenital nonbullous ichthyosiform erythroderma
      • eczema
      • fine, brittle hair
  • diagnosis confirmed with germ-line SPINK5 mutation
  • References – Cureus 2018 Jul 30;10(7):e3070full-text, Genetic and Rare Diseases Information Center Netherton syndrome 2016 Apr, BMJ Case Rep 2017 May 28;2017full-text
  • case report of Netherton syndrome can be found in JAMA Dermatol 2022 Nov 1;158(11):1315

Acquired Ichthyosis

  • acquired ichthyosis typically presents in adults with underlying conditions
    • presents with diffuse scaling
    • scaling may vary from light scaling to hyperpigmented thick scaling
    • scaling is symmetrically distributed
    • may mimic ichthyosis vulgaris, severe xerosis, or severe eczema
    • family history is negative for ichthyosis and atopic conditions
    • Reference – J Eur Acad Dermatol Venereol 2023 Jan;37(1):47

Diagnosis

Making the Diagnosis

  • diagnosis of inherited ichthyosis is based upon family history and clinical presentation at birth or in children, including(1)
    •  timing of onset, and character and severity of scaling
    •  involvement of other organ systems
    •  other skin findings (such as alopecia or palmoplantar involvement)
  •  specific types can be confirmed by genetic analysis, if needed for diagnostic uncertainty or genetic counseling, particularly for Netherton syndrome, Sjogren-Larsson syndrome, keratinopathic ichthyosis, and harlequin ichthyosis(1,3)
  • diagnosis of acquired ichthyosis is based upon clinical presentation and identification of an underlying cause
    • acquired ichthyosis is characterized by light scaling to hyperpigmented thick scaling and may mimic severe xerosis or eczema

Differential Diagnosis

  • Dermatomyositis – Facial rash in dermatomyositis. A ‘butterfly rash’ in a child is more likely to be dermatomyositis than lupus.Copyright© 2014, EBSCO Information Services.
  • Atopic dermatitis – Erythroderma in an infant.Copyright© 2014, EBSCO Information Services.
  • hypothyroidism
  • sarcoidosis
  • leprosy
  • HIV infection
  • lupus erythematosus
  • dermatomyositis
  • immunodeficiency syndromes
  • for delayed or adult onset ichthyosis, rule out acquired ichthyosis, which may be due to
    • Hodgkin lymphoma (HL)
    • non-Hodgkin lymphoma
    • mycosis fungoides
    • multiple myeloma
    •  diabetes
    •  HIV/AIDS
    • renal failure
  • for suspected acquired ichthyosis, also rule out common skin conditions
  • case presentation of probable splice site variant in SPINK5 resulting in Netherton syndrome misdiagnosed as Hyper IgE syndrome in early infancy can be found in Turk J Pediatr 2019;61(4):604PDF

Testing Overview

  • lab testing may be needed for syndromic presentations to assess specific anomalies and rule out differential diagnoses(5)
    • blood cell count and blood smear
    • electrolytes
    • liver and renal function tests
    • immunoglobulin serum levels may help rule out the differential diagnosis of hereditary immunodeficiencies
  • skin biopsy may be used to rule out differential diagnoses and support diagnosis of ichthyosis(1,3,5)
    • most histology is suggestive of ichthyosis rather than having specific findings
    •  ichthyosis vulgaris is characterized by reduced or absent granular layer on hematoxylin and eosin (H and E) stain, and lack of filaggrin on immunohistochemical staining
    •  keratopathic ichthyosis characterized by pale keratinocytes and keratohyalin granules
    • retained nuclei with granular inclusions suggest loricrin keratoderma
    •  ultrastructural analysis by electron microscopy can identify some specific findings, such as keratohyalin defects in ichthyosis vulgaris, or corneodesmosomes in recessive X-linked ichthyosis
    • negative immunostaining for LEKTI (encoded by SPINK5) can pinpoint diagnosis of Netherton syndrome
  • microscopic exam of hair anomalies may identify specific abnormalities, including(5)
    • trichorrhexis invaginata in Netherton syndrome
    • “tiger tail” appearance in trichothiodystrophy
  • genetic analysis can determine variants and specific types, but testing may not be covered by health insurance and can be costly(1,5)
    • genotyping by multiplex ligation-dependent probe amplification or whole exome sequencing can provide specific genetic diagnosis in > 80% of cases
    • specific genetic variants associated with specific inherited ichthyoses include
      • FLG variants that affect filaggrin expression and underlie most ichthyosis vulgaris and the rare ichthyoses of peeling skin syndrome
      • STS variants, which affect a sulfatase involved in converting cholesterol sulfate into cholesterol, and are seen in recessive X-linked ichthyosis (RXLI)
      • ABCA12 variants, which affect an enzyme needed for ceramides and underlie many forms of autosomal recessive congenital ichthyoses, including harlequin ichthyosis
      • SPINK5 variant which is responsible for Netherton syndrome and affects serine protease inhibitors
    • genotyping may provide prognostic information and guide genetic counselling and prenatal diagnosis
  • severity scoring
    • validated severity scoring scales can be useful to follow patients’ clinical courses and to increase the reliability of clinical trials (JAMA Dermatol 2022 Apr 1;158(4):354)
    • severity scoring methods include
      • Congenital Ichthyosis Severity Index – validated, clinically-based tool to rate hyperkeratosis, erythema, and alopecia on 5- and 6-point Likert scales (Pediatr Dermatol 2010 Mar;27(2):148)
      •  Bodemer ichthyosis score – comprehensive score assessing degree and extent of scale, erythema, pruritus, skin pain, palmoplantar keratoderma, fissures, hand retraction, foot retraction, movement impairment, ectropion, and eclabium (Br J Dermatol 2011 Nov;165(5):1087)
      • Visual Index for Ichthyosis Severity – validated index that rates lamellar- or keratoderma-type scales on 4 different body sites (J Invest Dermatol 2017 Sep;137(9):1834)
      • Ichthyosis Area Severity Index (IASI) – nonvalidated measure of erythema, scaling, transepidermal water loss, and pruritus at 4 sites (head and neck, upper limbs, trunk, and lower limbs) with total scoring of 0-48 (J Allergy Clin Immunol 2017 Jan;139(1):152full-text)
      • Ichthyosis Scoring System- validated tool rating scale and erythema on 10 body regions that can be used for research studies (JAMA Dermatol 2022 Apr 1;158(4):359full-text)

Management

Management Overview

  • acquired ichthyosis is managed by treatment of the underlying cause
  • management of congenital ichthyosis is based on reducing symptoms and complications(1,4)
    • there are no curative treatments currently available for inherited ichthyosis
    • there is limited evidence for efficacy of most treatments
  •  for newborns with severe collodion membrane or erythroderma due to congenital ichthyosis, use supportive care in the intensive care unit (ICU) to stabilize temperature, hydration, and monitor or treat for infections(4,5)
  • advise general measures of skin care for all patients, including
    •  regular bathing to soak skin
    •  mechanical desquamation of scales with pumice, sponge, or microfiber cloth
    • psychological support and education
    •  otorhinolaryngology consult for external ear cleaning
    • ophthalmology consult for ectropion
    • multidisciplinary support with involvement of psychologists, dermatologists, specialist nurses, and therapists for patients, parents, caregivers, and other family members as needed
  • first-line treatments for all patients include topical emollients and keratolytics
    • topical emollients and keratolytics may be sufficient treatment to manage patients with common ichthyosis (ichthyosis vulgaris and nonsyndromic recessive X-linked ichthyosis)
    • advise use of topical emollients ≥ 2 times daily after bathing
    • options include petrolatum (petroleum jelly), paraffin, urea-based, propylene glycol, lactic acid, and salicylic acid; in newborns, petrolatum is preferred since other emollients can be systemically absorbed and cause toxicity
  • consider topical retinoids for patients with severe scaling, digital contractures or ectropion; options include
    • tazarotene 0.05% or 0.1% gel or cream once daily
    • tretinoin 0.025%-0.1% cream once daily
    • adapalene 0.1% or 0.3% gel once daily
  • for newborns with harlequin ichthyosis, Netherton syndrome, or other ichthyosis with severe collodion membrane or erythroderma and for more severe symptoms unresponsive to topical emollients/keratolytics and retinoids, consider systemic retinoids; options include
    • acitretin 0.5-1 mg/kg/day orally for children and adults used off-label for treatment of ichthyosis in the United States (typical dose 10-25 mg/day; maximum dose 75 mg/day)
    • isotretinoin 0.5-1 mg/kg/day orally for children and adults used off-label for treatment of ichthyosis in the United States
    • alitretinoin (oral alitretinoin not available in the United States)
    • etretinate (not available in the United States or Europe)
  • there is limited and inconsistent evidence for immunosuppressants for congenital ichthyosis
  •  consider genetic counseling for prenatal diagnostics(4)

Counseling, Psychosocial Management, and Education

Topical Emollients and Keratolytics

  • emollients are used to moisturize the skin in patients with ichthyosis and reduce pruritus, while keratolytics are used to decrease scaling and skin thickness(5)
  • there is insufficient evidence to support superiority of any specific emollient or keratolytic for inherited ichthyosis (Br J Dermatol 2019 Feb;180(2):272 and J Am Acad Dermatol 2013 Oct;69(4):544)
  • commonly used emollients and keratolytics(2,4,5)
    • petrolatum (petroleum jelly) or paraffin is an inexpensive emollient, but may be too occlusive and may block sweating for some patients
    • urea is a humectant and keratolytic
      • less greasy than petrolatum and paraffin
      • urea ≥ 10% is not advised for infants < 1 year old due to risk of absorption
    •  propylene glycol (up to 15%), used as emollient and keratolytic
    •  lactic acid (up to 10%) can be used as a keratolytic
    • salicylic acid (up to 10%) can be used as a keratolytic
      • do not use in children < 2 years old, and limit use to localized areas in older children due to risks for systemic absorption
      • in adults, risk of systemic absorption increased with use on > 20% of the body or underlying hepatic or renal dysfunction
  • European expert guideline of care on management of congenital ichthyoses recommendations

Medications

Retinoids

Topical Retinoids
  • topical retinoids are often used to try to reduce scales and roughness of the skin in patients with congenital ichthyosis, although efficacy is based on observational studies and extrapolation from other uses of retinoids(5)
  • Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group consensus recommendations for topical retinoids
    • topical retinoids can improve scaling in patients with some types of ichthyosis (PeDRA Level II, Grade B)
    • data based on case reports in lamellar ichthyosis, other autosomal recessive congenital ichthyoses, recessive X-linked ichthyosis, epidermolytic ichthyosis, and erythrokeratodermia variabilis
    • topical retinoids are useful for managing scale, digital contractures, and ectropion (PeDRA Level III, Grade C)
    • no comparative efficacy data available
    • systemic lab monitoring is not recommended with topical retinoids (PeDRA Level II, Grade B)
    • Reference – Pediatr Dermatol 2021 Jan;38(1):164full-text
  • European expert guideline of care on management of congenital ichthyoses recommendations
  • topical retinoid options include
    • tazarotene (available as 0.05% or 0.1% gel or cream): apply topically once daily
    • tretinoin (available as 0.025%, 0.5%, and 0.1% gel or cream): apply topically once daily
    • adapalene (available as 0.1% or 0.3% gel or cream): apply topically once daily
    • Reference – Pediatr Dermatol 2021 Jan;38(1):164full-text
  • adverse effects include irritation, pruritus, erythema, and photosensitivity; there may be a risk of absorption with tazarotene but no systemic adverse effects reported with widespread use (Pediatr Dermatol 2021 Jan;38(1):164full-text)
  • no randomized trials evaluating topical retinoids for ichthyosis, excluding ichthyosis vulgaris, found in systematic review (J Am Acad Dermatol 2013 Oct;69(4):544)
Systemic Retinoids
  • systemic retinoids appear to improve scaling and although evidence is limited, they are commonly used for certain types of ichthyosis, such as Sjogren-Larsson syndrome, lamellar ichthyosis, harlequin ichthyosis, and some types of congenital ichthyosiform erythroderma(5)
  • other types of ichthyosis may not benefit from systemic retinoids, such as Netherton syndrome, some types of epidermolytic ichthyosis, or other conditions with disorders with increased skin fragility, peeling skin, atopic diathesis, or excessive desquamation (Pediatr Dermatol 2021 Jan;38(1):164)
  • European expert guideline of care on management of congenital ichthyoses recommendations
  • Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group consensus recommendations for systemic retinoids
    • for neonates with harlequin ichthyosis and impaired breathing or threatened viability of distal extremities, systemic retinoids may be beneficial (PeDRA Level III, Grade C)
    • for neonates with milder phenotypes of harlequin ichthyosis, systemic retinoids may not be required (PeDRA Level III, Grade C)
    • consider isotretinoin as the first-line option of systemic retinoids for patients of reproductive potential (PeDRA Level I, Grade A)
    • optimal dose of systemic retinoids is the lowest dose that achieves and maintains desired therapeutic effects with acceptable mucocutaneous and systemic toxicities (PeDRA Level I, Grade A)
    • counsel patients about long-term toxicities as systemic retinoid therapy is often long term (PeDRA Level I, Grade A)
    • for pre-pubertal children on acitretin, consider switching to isotretinoin before puberty if at risk of pregnancy due to prolonged half-life of acitretin (up to 3 years) (PeDRA Level III, Grade C)
    • beneficial effects of retinoids in ichthyosis are recognized to be dose‐dependent
    • Reference – Pediatr Dermatol 2021 Jan;38(1):164full-text
  • systemic retinoid options include(1,5)
    • acitretin (Soriatane) used off-label for treatment of ichthyosis in the United States
      • dosing: 0.5-1 mg/kg/day orally for children and adults (typical dose 10-25 mg/day; maximum dose 75 mg/day)
      • boxed warning for embryo-fetal toxicity
        • available through Education and Pregnancy Prevention for Acitretin (EPPA) Program
        • avoid pregnancy while taking medication and for 3 years after discontinuing medication
        • pregnancy tests are required prior to initiation (2 tests), every month during therapy, and every 3 months after discontinuation for at least 3 years
      • contraindicated in patients with severely impaired liver or kidney function and in patients with chronic abnormal elevation in serum lipids; also contraindicated in combination with either methotrexate or tetracyclines
    • isotretinoin (Accutane) used off-label for treatment of ichthyosis in the United States
      • dosing: 0.5-1 mg/kg/day orally for children and adults
      • boxed warning for embryo-fetal toxicity
        • only available through Risk Evaluation and Mitigation Strategy (iPLEDGE)
        • contraception counseling must be provided to all patients who can get pregnant prior to and during treatment
        • scheduled pregnancy testing and documentation of negative pregnancy required prior to each prescription (≤ 30-day supply for each prescription)
    • alitretinoin (oral alitretinoin not available in the United States)
    • etretinate (not available in the United States or Europe)
    • Reference – Br J Dermatol 2019 Feb;180(2):272
  • adverse effects of oral retinoids(5)
    • mucocutaneous effects may include cheilitis, nasal dryness, xerosis, hair loss, and conjunctival irritation
    • skeletal toxicities reported in children include premature epiphyseal closure, calcifications of tendons and ligaments, osteophytes, diffuse idiopathic skeletal hyperostosis (DISH), and potential changes to bone density and growth
    • retinal dysfunction, night blindness, and dry eyes
    • lipid abnormalities and hepatotoxicity
    • fetal teratogenicity
  • Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group consensus recommendations for monitoring on systemic retinoids
    • obtain comprehensive family and personal medical history for risk factors for skeletal toxicity
    • for children < 18 years old, obtain annual growth assessment (height, weight, body mass index [BMI], and growth curve)
    • ask about musculoskeletal symptoms and follow‐up symptoms with imaging
    • ask about diet (including sufficient vitamin D intake and no additional vitamin A sources)
    • for children < 18 years old, once reached full growth (ages 16‐18 years) and in adults who are likely to continue long-term oral retinoid, obtain baseline skeletal x-rays of the lateral cervical and thoracic spine, lateral view of the calcanei to include Achilles tendon, hips, and symptomatic areas; and bone density evaluation (for example, DEXA scan)
    • if on long-term retinoid therapy, repeat x-ray bone evaluation every 3‐5 years or if symptomatic
    • for long‐term oral retinoid therapy, advise evaluation by ophthalmology 4‐6 months after start of systemic retinoid therapy, with routine follow‐up every 6‐12 months
    • perform baseline serum lipid panels and liver function tests and, if in an acceptable range, repeat testing in 1‐2 months after starting treatment; if testing is within the acceptable range, repeat testing can be done every 6‐12 months
    • for long-term retinoid therapy, patients with persistent, clinically significant elevations in serum lipids may continue treatment with effective lipid management
    • monitor patients for development of psychiatric symptoms
    • consider co-managing patients with history of depression, anxiety, and other affective disorders with a mental health provider
    • Reference – Pediatr Dermatol 2021 Jan;38(1):164full-text

Immunosuppressants

  • topical corticosteroid
    • European expert guideline of care on management of congenital ichthyoses recommend limited use of topical steroids for eczematous lesions in patients with Netherton syndrome (Expert Consensus Grade D, Level 3)
    • long-term use should be avoided due to risks of absorption and skin atrophy
    • Reference – Br J Dermatol 2019 Mar;180(3):484
  • topical calcineurin inhibitors
    • European expert guideline of care on management of congenital ichthyoses recommends use of topical calcineurin inhibitors tacrolimus 0.03% or 0.1% ointment or pimecrolimus 1% cream (both used off-label for treatment of ichthyosis in the United States) for short-term treatment of flares on limited regions in patients with Netherton syndrome (Expert Consensus Grade D, Level 3)
    • systemic absorption may occur and serum or plasma drug levels should be monitored if used for more than short-term treatment
    • Reference – Br J Dermatol 2019 Mar;180(3):484
  • European expert guideline of care on management of congenital ichthyoses recommends against use of infliximab due to lack of evidence of efficacy (Expert Consensus Grade D, Level 3) (Br J Dermatol 2019 Feb;180(2):272)
  • interleukin (IL) inhibitors
  • evidence of efficacy for immunosuppressants
    • secukinumab may not reduce severity of erythema, pruritus, or scaling in adults with congenital ichthyosis (level 2 [mid-level] evidence)
      •  based on small randomized trial
      • 20 adults (mean aged 35 years, range 22-48) with epidermolytic ichthyosis, Netherton syndrome, lamellar ichthyosis, or congenital ichthyosiform erythroderma randomized to secukinumab 300 mg every 4 weeks vs. placebo for 16 weeks with open label follow-up for 36 weeks
      • primary outcome was Ichthyosis Area Severity Index (IASI), a nonvalidated measure of erythema, scaling, transepidermal water loss and pruritus, scored on total scale 0-48 (subscores include IASI-erythema [IASI-E] and IASI-scaling [IASI-S])
      • other outcomes included Visual Index for Ichthyosis Severity (VIIS), a validated index of scaling with total scoring of 0-32
      • comparing secukinumab vs. placebo at 16 weeks of follow-up (blinded trial) (no significant difference in any comparison of scores)
        • mean IASI 31 vs. 32
        • mean IASI-E 15.6 vs. 15
        • mean IASI-S 15.7 vs. 16.9
        • mean VIIS 19.4 vs. 21
      • comparing secukinumab vs. placebo at 32 weeks of follow-up (not blinded)
        • mean IASI 28.3 vs. 30 (no significant difference)
        • mean IASI-E 13.5 vs. 14.8 (p = 0.04)
        • mean IASI-S 14.9 vs. 15.5 (no significant difference)
        • mean VIIS 17.4 vs. 21.3 (p = 0.01)
      • at 52 weeks, secukinumab associated with significant improvement in VIIS
      • Reference – Arch Dermatol Res 2023 Mar;315(2):305
    • case reports for dupilumab for Netherton syndrome
      • dupilumab 600 mg subcutaneously initially then 300 mg subcutaneously every 2 weeks reported to improve symptoms of Netherton syndrome at 2 months in 32-year-old woman in case report (JAMA Dermatol 2020 Mar 1;156(3):350)
      • dupilumab 600 mg subcutaneously at week 0, then 300 mg every 2 weeks reported to reduce itching, erythema, and scaling in 20-year-old patient with Netherton syndrome (J Dermatol 2022 Jan;49(1):165)
      • dupilumab 600 mg subcutaneously at week 0, then 300 mg every 2 weeks then weekly reported associated with some initial improvement, then deterioration in symptoms after 6 months of treatment in 41-year-old patient with Netherton syndrome (Dermatology 2023;239(1):72full-text)
    • anakinra (IL-1 inhibitor) reported to initially improve symptoms in patients but effectiveness reported to diminish after several months in 4 patients with Netherton syndrome in case series (Dermatology 2023;239(1):72full-text)
  • IV immunoglobulin (IVIG)

Other Medications

  • oral vitamin D
    • vitamin D deficiency has been associated with congenital ichthyosis
    • optimal serum vitamin D concentration is unknown
    • European expert guideline of care on management of congenital ichthyoses recommendations
    • Reference – Br J Dermatol 2019 Feb;180(2):272
    • vitamin D may be as effective as acitretin in patients with autosomal recessive congenital ichthyosis (ARCI) or epidermolytic ichthyosis, although both reported to have only modest effects (level 2 [mid-level] evidence)
      •  based on small randomized trial
      • 27 children (aged 3-19 years) with congenital non-syndromic ichthyosis (most patients had autosomal recessive congenital ichthyosis or epidermolytic ichthyosis [ichthyosis vulgaris and X-linked recessive ichthyosis were excluded]) were randomized to vitamin D 2,000 units/day orally vs. acitretin 0.5 mg/kg/day (not exceeding 25 mg/day) orally for 24 weeks
      • vitamin D 2,000 units/day associated with statistically significant improvements in disease severity compared to baseline at 12 weeks, but not at 24 weeks
      • acitretin associated with statistically significant improvements in disease severity compared to baseline at 24 weeks
      • no significant difference in outcomes comparing vitamin D vs. acitretin
      • Reference – J Dtsch Dermatol Ges 2022 Mar;20(3):297
  • topical calcipotriene (Dovonex; also known as calcipotriol) used off-label for treatment of ichthyosis in the United States
    • synthetic vitamin D derivative
    • off-label dosing used in studies: calcipotriene 0.05% topically twice daily (maximum of 100 g/week) (J Am Acad Dermatol 2013 Oct;69(4):544)
    • calcipotriene associated with reduced scaling in ichthyosis (level 2 [mid-level] evidence)
      •  based on small randomized trial
      •  27 patients with ichthyosis vulgaris, X-linked ichthyosis or congenital ichthyosis randomized to calcipotriene 50 mcg/g twice daily (≤ 100 g/week) vs. placebo for 12 weeks
      •  calcipotriene associated with reduced scaling, but increased skin irritation
      •  Reference – Arch Dermatol 1995 May;131(5):556
      •  no additional randomized trials of calcipotriene for ichthyosis, excluding ichthyosis vulgaris, found in systematic review (J Am Acad Dermatol 2013 Oct;69(4):544)
  • topical N-acetylcysteine (NAC)

Prenatal Genetic Counseling

  • identification of the specific genetic mutations underpinning various inherited ichthyoses allows for prenatal diagnosis and counselling in families at risk(5)
    • molecular genetic testing can be used to assess known genetic variants in a family
    • embryonic tissue and/or imaging may be used for screening in pregnant patients
    • patients may choose in vitro fertilization techniques that allow for preimplantation evaluation of embryos before transfer to the uterus

Complications

  • complications may vary depending on type and severity of congenital ichthyosis(1,4,5)
  • heat intolerance from failure to sweat is common to many types of inherited ichthyosis(1,4,5)
  • skin infections, including bacterial and fungal (usually tinea or candidal) infections, may be frequent in patients with Netherton syndrome, epidermolytic ichthyosis, and keratitis-ichthyosis-deafness (KID) syndrome(2,4,5)
    • in severe conditions, recurrent sepsis may occur
    • mortality from sepsis has been reported
  • ocular and auditory complications may be frequent(1,4,5)
    •  ectropion (turning outward of lower eyelid) is common in many types of inherited ichthyosis
    • other findings may include scaling of the eyelids, conjunctivitis, and eyelash anomalies
    • corneal damage can occur
    • excessive accumulation of desquamated material in the outer ear canal can lead to pain and impaired hearing
  •  psychological issues and decreased quality of life due to symptoms is common in more severe forms of inherited ichthyosis(2,4)
  • growth delay and nutritional deficiency(1,4,5)
    • may be associated with severe forms, especially Netherton syndrome
    • may be related to an increased resting energy expenditure due to epidermal turnover, chronic skin inflammation, and cutaneous protein loss
    • vitamin D deficiency has been observed
  •  decreased range of motion of joints and decreased tactile sensation of extremities(2,4)

Prognosis

  • inherited ichthyoses are a heterogeneous group of conditions and prognosis will vary with specific type of ichthyosis(2)
    • common ichthyosis typically follows a mild course(5)
    •  clinical course of ichthyosis vulgaris may vary with climate and humidity(2)
    •  collodion associated with 10%-20% mortality(4)
  • acquired ichthyosis tends to improve once the inciting conditions is resolved (J Eur Acad Dermatol Venereol 2023 Jan;37(1):47)

Prevention and Screening

Prevention

  • not applicable

Screening

  •  genetic counseling and screening may be appropriate(4)

Guidelines and Resources

Guidelines

International Guidelines

United States Guidelines

  • Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group consensus recommendations on use of retinoids in ichthyosis and other disorders of cornification in children and adolescents can be found in Pediatr Dermatol 2021 Jan;38(1):164full-text

United Kingdom Guidelines

European Guidelines

Central and South American Guidelines

Review Articles

Patient Information

References

General References Used

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

  1. Schmuth M, Martinz V, Janecke AR, et al. Inherited ichthyoses/generalized Mendelian disorders of cornification. Eur J Hum Genet. 2013 Feb;21(2):123-33full-text, commentary can be found in Eur J Hum Genet 2014 Apr;22(4):444full-text.
  2. Traupe H, Fischer J, Oji V. Nonsyndromic types of ichthyoses – an update. J Dtsch Dermatol Ges. 2014 Feb;12(2):109-21full-text.
  3. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010 Oct;63(4):607-41.
  4. Oji V, Traupe H. Ichthyosis: clinical manifestations and practical treatment options. Am J Clin Dermatol. 2009;10(6):351-64.
  5. Gutiérrez-Cerrajero C, Sprecher E, Paller AS, et al. Ichthyosis. Nat Rev Dis Primers. 2023 Jan 19;9(1):2.

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