View source for X-linked ichthyosis

{{Infobox medical condition (new)
| name            = X-linked ichthyosis
| synonyms        = Steroid sulfatase deficiency, X-linked recessive ichthyosis<ref name="Bolognia">{{Cite book |last=Rapini, Ronald P. |title=Dermatology: 2-Volume Set |last2=Bolognia, Jean L. |last3=Jorizzo, Joseph L. |publisher=Mosby |year=2007 |isbn=978-1-4160-2999-1 |location=St. Louis}}</ref>
| image           = File:X-linked recessive.svg
| caption         = X-linked recessive inheritance: Affected boys may inherit a deletion or mutation of the ''STS'' gene from their mothers
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}}'''X-linked ichthyosis''' (abbreviated ''XLI'') is a [[skin]] condition caused by the [[genetic disorder|hereditary deficiency]] of the [[steroid sulfatase]] (STS) enzyme that affects 1 in 2000 to 1 in 6000 males.<ref name="PedDerm">{{Cite book |last=Carlo Gelmetti |title=Pediatric Dermatology and Dermatopathology: A Concise Atlas |last2=Caputo, Ruggero |publisher=T&F STM |year=2002 |isbn=978-1-84184-120-5 |page=160}}</ref>  XLI manifests with dry, scaly skin<ref>{{OMIM|308100|ICHTHYOSIS, X-LINKED}}</ref> and is due to deletions<ref name="Ballabio">{{Cite journal |vauthors=Ballabio A, Parenti G, Carrozzo R, etal |year=1987 |title=Isolation and characterization of a steroid sulfatase cDNA clone: genomic deletions in patients with X-chromosome-linked ichthyosis |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue=13 |pages=4519–23 |bibcode=1987PNAS...84.4519B |doi=10.1073/pnas.84.13.4519 |pmc=305121 |pmid=3474618 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Bonifas JM, Morley BJ, Oakey RE, Kan YW, Epstein EH |date=December 1987 |title=Cloning of a cDNA for steroid sulfatase: frequent occurrence of gene deletions in patients with recessive X chromosome-linked ichthyosis |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue=24 |pages=9248–51 |bibcode=1987PNAS...84.9248B |doi=10.1073/pnas.84.24.9248 |pmc=299730 |pmid=3480541 |doi-access=free}}</ref> or mutations<ref>{{Cite journal |vauthors=Basler E, Grompe M, Parenti G, Yates J, Ballabio A |date=March 1992 |title=Identification of point mutations in the steroid sulfatase gene of three patients with X-linked ichthyosis |journal=Am. J. Hum. Genet. |volume=50 |issue=3 |pages=483–91 |pmc=1684279 |pmid=1539590}}</ref> in the ''STS'' gene.  XLI can also occur in the context of larger deletions causing [[contiguous gene syndromes]].<ref name="Ballabio" /> Treatment is largely aimed at alleviating the skin symptoms.<ref name="emed">{{EMedicine|derm|191|Ichthyosis, X-Linked}}: Treatment Section</ref> The term is from the [[Ancient Greek]] 'ichthys' meaning 'fish'.

== Signs and symptoms ==
[[File:Boy with X linked Ichthyosis rotated.JPG|thumb|X linked ichthyosis]]

The major symptoms of XLI include scaling of the skin, particularly on the neck, trunk, and lower extremities.  The extensor surfaces are typically the most severely affected areas.  The >4&nbsp;mm diameter scales adhere to the underlying skin and can be dark brown or gray in color.  Symptoms may subside during the summer.<ref name=PedDerm/>

=== Associated medical conditions ===
Aside from the skin scaling, XLI is not typically associated with other major medical problems.<ref>{{Cite journal |vauthors=DiGiovanna JJ, Robinson-Bostom L |year=2003 |title=Ichthyosis: etiology, diagnosis, and management |journal=Am J Clin Dermatol |volume=4 |issue=2 |pages=81–95 |doi=10.2165/00128071-200304020-00002 |pmid=12553849 |s2cid=243176269}}</ref> [[Atrial fibrillation]] or [[atrial flutter]] may affect up to 1 in 10 males with XLI.<ref>{{Cite journal |last=Brcic |first=Lucija |last2=Underwood |first2=Jack FG |last3=Kendall |first3=Kimberley M. |last4=Caseras |first4=Xavier |last5=Kirov |first5=George |last6=Davies |first6=William |year=2020 |title=Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank |journal=Journal of Medical Genetics |volume=57 |issue=10 |pages=692–698 |doi=10.1136/jmedgenet-2019-106676 |pmc=7525778 |pmid=32139392}}</ref> Heart rhythm abnormalities in individuals with XLI tend to co-occur with disorders of the [[gastrointestinal tract]], and are likely to result from [[steroid sulfatase]] deficiency.<ref>Wren G, Baker E, Underwood JFG, Humby T, Thompson AR, Kirov G, Escott-Price V, Davies W (2022) Characterising heart rhythm abnormalities associated with Xp22.31 deletion Journal of Medical Genetics PMID 36379544 doi:10.1136/jmg-2022-108862 URL:https://jmg.bmj.com/content/early/2022/11/15/jmg-2022-108862.long</ref> Cardiac [[arrhythmia]] in XLI may be related to abnormal development of the [[interventricular septum]] or [[interatrial septum]].<ref>Wren G, Davies W (2024) Cardiac arrhythmia in individuals with steroid sulfatase deficiency (X-linked ichthyosis): candidate anatomical and biochemical pathways Essays in Biochemistry PMID 38571328 doi:10.1042/EBC20230098 URL:https://portlandpress.com/essaysbiochem/article/doi/10.1042/EBC20230098/234273/Cardiac-arrhythmia-in-individuals-with-steroid</ref> Corneal opacities may be present but do not affect vision. [[Cryptorchidism]] is reported in some individuals.<ref name=PedDerm/> Individuals with XLI appear at increased risk of neurodevelopmental disorders such as [[autism]] and [[attention deficit hyperactivity disorder]] and some affected individuals exhibit mood problems <ref>Chatterjee S, Humby T, Davies W (2016) Behavioural and psychiatric phenotypes in men and boys with X-linked ichthyosis: evidence from a worldwide online survey. PLoS One 11(10):e0164417 PMID 27711218 doi:10.1371/journal.pone.0164417 URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164417</ref> Mood problems in XLI appear to be most influenced by stigma or bullying associated with the skin condition, and by difficulties with treating the skin condition.<ref>Wren G, Humby T, Thompson AR, Davies W (2022) Mood symptoms, neurodevelopmental traits, and their contributory factors in X-linked ichthyosis, ichthyosis vulgaris and psoriasis. Clinical and Experimental Dermatology PMID 35104372 doi:10.111/ced.15116 URL:https://doi.org/10.1111/ced.15116</ref> XLI is associated with mild-moderate impairments in [[memory]] which appear to be independent of effects on mood.<ref>Wren G, Flanagan J, Underwood J, Thompson A, Humby T, Davies W (2024) Memory, mood and associated neuroanatomy in individuals with steroid sulphatase deficiency (X-linked ichthyosis). Genes Brain and Behavior doi:10.1111/gbb.12893 URL:https://onlinelibrary.wiley.com/doi/10.1111/gbb.12893</ref> Blood-clotting abnormalities may occur more frequently in males with XLI and female carriers.<ref>Brcic L, Wren GH, Underwood JFG, Kirov G, Davies W (2022) Comorbid medical issues in X-linked ichthyosis. JID Innovations 2(3):100109 PMID 35330591 doi:10.1016/j.xjidi.2022.100109 URL: https://www.jidinnovations.org/article/S2667-0267(22)00016-9/fulltext</ref> Individuals with XLI can exhibit [[intellectual disability]], although this is thought to be due to deletions encompassing neighboring genes (e.g. [[VCX]]) in addition to ''STS''.<ref>{{Cite journal |vauthors=Van Esch H, Hollanders K, Badisco L, etal |year=2005 |title=Deletion of VCX-A due to NAHR plays a major role in the occurrence of mental retardation in patients with X-linked ichthyosis |journal=Hum. Mol. Genet. |volume=14 |issue=13 |pages=1795–803 |doi=10.1093/hmg/ddi186 |pmid=15888481 |doi-access=free}}</ref> The skin and medical conditions associated with XLI are likely to be due to perturbed [[basement membrane]] function and abnormal interactions with the [[extracellular matrix]].<ref>Wren GH, Davies W (2022) X-linked ichthyosis: New insights into a multi-system disorder ''Skin Health and Disease'' PMID 36479267 doi:10.1002/ski2.179 URL:https://onlinelibrary.wiley.com/doi/10.1002/ski2.179</ref> Knockdown of STS gene expression in human skin cell cultures affects pathways associated with skin function, brain and heart development, and blood-clotting that may be relevant for explaining the skin condition and increased likelihood of ADHD/autism, cardiac arrhythmias and disorders of [[hemostasis]] in XLI<ref>McGeoghan F, Camera E, Maiellaro M, Menon M, Huang M, Dewan P, Ziaj S, Caley MP, Donaldson M, Enright AJ, O'Toole EA (2023) RNA sequencing and lipidomics uncovers novel pathomechanisms in recessive X-linked ichthyosis Frontiers in Molecular Biosciences 10:1176802 PMID 37363400 doi:10.3389/fmolb.2023.1176802 URL:https://www.frontiersin.org/articles/10.3389/fmolb.2023.1176802/full</ref>

Female carriers generally do not experience any of these problems but can have difficulty during childbirth, as the STS expressed in the placenta plays a role in normal labor.<ref>{{Cite journal |vauthors=Bradshaw KD, Carr BR |year=1986 |title=Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deficiency and X-linked ichthyosis |journal=Obstet Gynecol Surv |volume=41 |issue=7 |pages=401–13 |pmid=3531932}}</ref> Female carriers may also be at slightly increased risk of developing mental health problems following childbirth <ref>Cavenagh A, Chatterjee S, Davies W (2019) Behavioural and psychiatric phenotypes in female carriers of genetic mutations associated with X-linked ichthyosis. PLoS One 14(2):e0212330 PMID 30768640 doi:10.1371/journal.pone.0212330 URL:https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212330</ref> For these reasons carriers should ensure their [[obstetrician]] is aware of the condition.{{citation needed|date=October 2020}}

== Genetics ==
[[File:IchthyosisXlinked2.JPG|thumb|left|X linked ichthyosis - this boy has an infant brother and maternal uncle with the same condition]]
The ''STS'' gene is located on the X chromosome at band Xp22.3.  Thus, the syndrome is an [[genetic disorder|X-linked condition]], and it affects males and females differently.  The 23rd pair of chromosomes is typically termed the "sex chromosomes".  Females have two X chromosomes and males have one X and one Y chromosome.  Therefore, in normal individuals, males carry a single copy of the ''STS'' gene and females carry two copies.  This gene partially escapes [[X-inactivation]] and females normally express higher amounts of the STS enzyme than males.<ref>{{Cite journal |vauthors=Lykkesfeldt G, Lykkesfeldt AE, Skakkebaek NE |year=1984 |title=Steroid sulphatase in man: a non inactivated X-locus with partial gene dosage compensation |journal=Hum. Genet. |volume=65 |issue=4 |pages=355–7 |doi=10.1007/BF00291559 |pmid=6582028 |s2cid=2625156}}</ref>

XLI can occur through new deletions or mutations of the ''STS'' gene but is more commonly inherited from a carrier mother.<ref name="Valdes">{{Cite journal |vauthors=Valdes-Flores M, Kofman-Alfaro SH, Jimenez-Vaca AL, Cuevas-Covarrubias SA |date=August 2001 |title=Carrier identification by FISH analysis in isolated cases of X-linked ichthyosis |journal=Am. J. Med. Genet. |volume=102 |issue=2 |pages=146–8 |doi=10.1002/ajmg.1450 |pmid=11477606}}</ref>  A [[hemizygous]] deletion or mutation of the ''STS'' gene in a male results in complete absence of enzyme activity, while a female carrier of a mutation or deletion is [[heterozygous]] and still has a normal copy of the ''STS'' gene.  Female carriers of an ''STS'' deletion or mutation still express the STS enzyme, although with decreased enzyme activity.<ref name=Cuevas/>

For this reason, XLI most commonly affects males, although individuals with numeric abnormalities of the sex chromosomes (45,X and 47,XXY) who also carry ''STS'' deletions or mutations would be exceptions to this rule.{{citation needed|date=October 2020}}

In addition, a female could be affected if she were the offspring of an affected male and a carrier female and inherited a deletion or mutation of the ''STS'' gene on both X chromosomes.{{cn|date=November 2024}}

=== Genetic counseling issues ===
Since the majority of cases appear to occur through transmission of an ''STS'' deletion from a carrier mother,<ref name=Valdes/> enzyme testing or DNA testing should be performed in the mother of any newly diagnosed simplex case (i.e. the first case in a family).  In the case of an extended family with many affected individuals, carrier status can often be assigned based on pedigree analysis.
* Males with XLI will transmit the X chromosome harboring the ''STS'' deletion or mutation to each of his female offspring, who will therefore be an [[X-linked recessive|obligate carrier]].  However, all male offspring will be unaffected, since they receive their father's Y chromosome.{{cn|date=November 2024}}
* Female carriers of an ''STS'' deletion or mutation have a 50% chance with each pregnancy of transmitting it to an offspring.  Thus, each male offspring has a 50% chance of being affected by XLI, while each female offspring has a 50% chance of being a carrier for this condition.  Any individual that inherits the mother's normal copy of the ''STS'' gene will be unaffected and will have an extremely low chance of having a child affected with this condition.{{cn|date=November 2024}}

Due to random segregation of the chromosomes during [[gametogenesis]], each pregnancy will be subject to the same probabilities, regardless of the number of previously affected or unaffected offspring. The above recurrence risks are based on the assumption that an affected male or carrier female will have children with an unaffected or non-carrier individual.  The risks of having affected offspring would clearly increase in the case of a union between a male with XLI and a carrier female.{{cn|date=November 2024}}

===Physiology/biochemistry===
[[File:DHEA sulfate.png|thumb|DHEA sulfate]]
The [[Steroid sulfatase|STS]] enzyme (EC 3.1.6.2), also referred to as Arylsulfatase C, is expressed throughout the body, with highest expression in the skin, liver, lymph nodes, and placenta, and lower expression in breast tissue and brain<ref>{{Cite journal |vauthors=Selcer KW, Difrancesca HM, Chandra AB, Li PK |year=2007 |title=Immunohistochemical analysis of steroid sulfatase in human tissues |journal=J. Steroid Biochem. Mol. Biol. |volume=105 |issue=1–5 |pages=115–23 |doi=10.1016/j.jsbmb.2006.12.105 |pmid=17604157 |s2cid=22124602}}</ref>  STS catalyzes the hydrolysis of sulfated steroids, such as [[estrone sulfate]] and [[dehydroepiandrosterone sulfate]] (DHEAS), to non-sulfated steroids estradiol and androstenediol, respectively.<ref>{{Cite journal |vauthors=Reed MJ, Purohit A, Woo LW, Newman SP, Potter BV |date=April 2005 |title=Steroid sulfatase: molecular biology, regulation, and inhibition |journal=Endocr. Rev. |volume=26 |issue=2 |pages=171–202 |doi=10.1210/er.2004-0003 |pmid=15561802 |doi-access=free}}</ref>  Prenatally, the enzyme is involved in placental [[estrogen]] production.<ref>{{Cite journal |vauthors=Jöbsis AC, De Groot WP, Tigges AJ, etal |year=1980 |title=X-linked ichthyosis and X-linked placental sulfatase deficiency: a disease entity. Histochemical observations |journal=Am. J. Pathol. |volume=99 |issue=2 |pages=279–89 |pmc=1903491 |pmid=6929654}}</ref>  The enzyme is also involved in adrenal steroid production as well as conversion of sulfated steroids in other tissues.{{citation needed|date=October 2020}}

There seems to be a particularly important role for the enzyme in skin.  Deficiency of the enzyme leads to the characteristic dry and scaly skin seen in ichthyosis.  Recent research indicates that the skin abnormalities seen in XLI may be due to accumulation of [[cholesterol sulfate]] in the outer epidermis, leading to abnormal barrier function and corneocyte retention.<ref>{{Cite journal |vauthors=Elias PM, Crumrine D, Rassner U, etal |year=2004 |title=Basis for abnormal desquamation and permeability barrier dysfunction in RXLI |journal=J. Invest. Dermatol. |volume=122 |issue=2 |pages=314–9 |doi=10.1046/j.1523-1747.2003.22258.x |pmid=15009711 |doi-access=free}}</ref>

== Diagnosis ==
XLI can be suspected based on clinical findings, although symptoms can take varying amounts of time to become evident, from a few hours after birth, up to a year in milder cases.  The diagnosis is usually made by a [[dermatologist]], who also typically formulates the treatment plan (see below).  STS enzyme deficiency is confirmed using a clinically available biochemical assay.  Carrier detection can be performed in mothers of affected sons using this test (see Genetics, below).<ref name="Cuevas">{{Cite journal |vauthors=Cuevas-Covarrubias SA, Kofman-Alfaro S, Orozco Orozco E, Diaz-Zagoya JC |year=1995 |title=The biochemical identification of carrier state in mothers of sporadic cases of X-linked recessive ichthyosis |journal=Genet. Couns. |volume=6 |issue=2 |pages=103–7 |pmid=7546451}}</ref>  Molecular testing for DNA deletions or mutations is also offered, and can be particularly useful in the evaluation of individuals with associated medical conditions (see below).  [[Prenatal diagnosis]] is possible using either biochemical or molecular tests.  However, the use of prenatal diagnosis for genetic conditions that are considered to be generally benign raises serious ethical considerations and requires detailed genetic counseling.{{citation needed|date=October 2020}}

==Treatment==
Because XLI is caused by a gene mutation or deletion, there is no "cure."  One of the aims of treatment is to reduce scaling by removing the excess, flaky scales, and keep the skin hydrated.  This can be achieved using a variety of topical creams.<ref name=PedDerm/><ref name=emed/> Other treatments involve
* Keratolytic agents such as Ammonium lactate (Lac-Hydrin) are used to facilitate the release of retained corneocytes.{{cn|date=November 2024}}
* oral isotretinoin{{cn|date=November 2024}}
* acitretin<ref>{{Cite journal |last=Bruckner-Tuderman |first=Leena |last2=Sigg |first2=Christian |last3=Geiger |first3=Jean-Marie |last4=Gilardi |first4=Stefano |date=1988-04-01 |title=Acitretin in the Symptomatic Therapy for Severe Recessive X-linked Ichthyosis |url=https://doi.org/10.1001/archderm.1988.01670040031017 |journal=Archives of Dermatology |volume=124 |issue=4 |pages=529–532 |doi=10.1001/archderm.1988.01670040031017 |issn=0003-987X |pmid=2965549|url-access=subscription }}</ref>
* The topical receptor-selective retinoid tazarotene <ref>{{Cite journal |vauthors=Cotellessa C, Cuevas-Covarrubias SA, Valeri P, Fargnoli MC, Peris K |year=2005 |title=Topical tazarotene 0.05% versus glycolic acid 70% treatment in X-linked ichthyosis due to extensive deletion of the STS gene |journal=Acta Derm. Venereol. |volume=85 |issue=4 |pages=346–8 |doi=10.1080/00015550510026613 |pmid=16191859 |doi-access=free}}</ref>

Research is ongoing with regard to the use of gene therapy to treat XLI.<ref>{{Cite journal |vauthors=Freiberg RA, Choate KA, Deng H, Alperin ES, Shapiro LJ, Khavari PA |year=1997 |title=A model of corrective gene transfer in X-linked ichthyosis |url=http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9175741 |journal=Hum. Mol. Genet. |volume=6 |issue=6 |pages=927–33 |doi=10.1093/hmg/6.6.927 |pmid=9175741 |doi-access=free}}</ref> Timber Pharmaceuticals is planning on conducting a phase 3 trial of its investigational topical isotretinoin product in the second quarter of 2022 for the treatment of congential ichthyosis.<ref>{{Cite web |title=Press Releases |url=https://www.timberpharma.com/news-releases |access-date=2022-04-03 |website=Timber |language=en}}</ref>

== History ==
In the 1960s, recessive x-linked ichthyosis was distinguished clinically from other ichthyoses.<ref name="Fitz2">Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. {{ISBN|0-07-138076-0}}.</ref>{{rp|486}}<ref name="Andrews">James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. {{ISBN|0-7216-2921-0}}.</ref>{{rp|561}}

== See also ==
* [[Ichthyosis]]
* [[Carvajal syndrome]]

==References==
{{Reflist}}

== External links ==
{{Medical resources
|  DiseasesDB      = 29136
|  ICD10           = {{ICD10|Q|80|1|q|80}}
|  ICD9            = {{ICD9|757.1}}
|  ICDO            =
|  OMIM            = 308100
|  MedlinePlus     =
|  eMedicineSubj   = derm
|  eMedicineTopic  = 191
|  MeshID          = D016114
|  Orphanet        = 461
}}

{{Congenital malformations and deformations of integument}}
{{X-linked disorders}}
{{Defects of steroid metabolism}}

[[Category:Genodermatoses]]
[[Category:Cholesterol and steroid metabolism disorders]]
[[Category:Rare diseases]]