Comorbid Medical Issues in X-Linked Ichthyosis

Brcic, Lucija; Wren, Georgina; Underwood, Jack; Kirov, George; Davies, William

doi:10.1016/j.xjidi.2022.100109

Cited by 5 publications

(8 citation statements)

References 15 publications

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“…Systemic inhibition of the STS enzyme in a cohort of 10 patients with early breast cancer prescreened to exclude a history of cardiac arrhythmia resulted in three grade 2 adverse events (two related to abnormal ECG and one to tachycardia) and one grade 1 adverse event (prolonged QT) 33. The STS enzyme affects cardiac valve function34 and fibrotic pathways,8 15 35 and regulates androgen and oestrogen production and the balance between sulfated and non-sulfated steroids such as dehydroepiandrosterone sulfate (DHEAS) and DHEA 36. DHEA(S) levels correlate with AF risk in older men in some studies,12 and levels of these hormones (and the DHEA:DHEAS ratio) increase upon acute psychosocial stress, with the increase in levels correlating with the stress-induced increase in heart rate 37…”

Section: Discussionmentioning

confidence: 99%

“…Twenty-five per cent to 60% of males carrying such variants are diagnosed with X linked ichthyosis (XLI (MIM: 308100)), a dermatological condition characterised by skin scaling and resulting from absence of the steroid sulfatase (STS) enzyme 3. In males, typically sized XLI deletions of 1.5–1.7 Mb are associated with extracutaneous symptoms including: corneal opacities,3 testicular maldescent,3 focal epilepsy,4 atopic disorders (asthma, eczema and allergic rhinitis),5–7 aberrant haemostasis and fibrosis,8 and increased neurodevelopmental and mood diagnoses/traits9; larger deletions (>2.5 Mb) can be associated with more severe developmental issues. Heterozygous female carriers can also show high neurodevelopmental and mood traits, and around 60% experience delayed or prolonged labour during childbirth, but these individuals do not usually exhibit the physical (skin, eye and neurological) phenotypes seen in males 10…”

Section: Introductionmentioning

confidence: 99%

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Characterising heart rhythm abnormalities associated with Xp22.31 deletion

et al. 2022

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BackgroundGenetic deletions at Xp22.31 are associated with the skin condition X linked ichthyosis (XLI), and with a substantially increased risk of atrial fibrillation/flutter (AF), in males. AF is associated with elevated thrombosis, heart failure, stroke and dementia risk.MethodsThrough: (a) examining deletion carriers with a diagnosis of AF in UK Biobank, (b) undertaking an online survey regarding abnormal heart rhythms (AHRs) in men/boys with XLI and female carriers of XLI-associated deletions and (c) screening for association between common genetic variants within Xp22.31 and idiopathic AF-related conditions in UK Biobank, we have investigated how AHRs manifest in deletion carriers, and have identified associated risk factors/comorbidities and candidate gene(s). Finally, we examined attitudes towards heart screening in deletion carriers.ResultsWe show that AHRs may affect up to 35% of deletion carriers (compared with <20% of age-matched non-carriers), show no consistent pattern of onset but may be precipitated by stress, and typically resolve quickly and respond well to intervention. Gastrointestinal (GI) conditions and asthma/anaemia were the most strongly associated comorbidities in male and female deletion carriers with AHR, respectively. Genetic analysis indicated significant enrichment of common AF risk variants aroundSTS(7 065 298–7 272 682 bp in GRCh37/hg19 genome build) in males, and of common GI disorder and asthma/anaemia risk variants aroundPNPLA4(7 866 804–7 895 780 bp) in males and females, respectively. Deletion carriers were overwhelmingly in favour of cardiac screening implementation.ConclusionOur data suggest AHRs are frequently associated with Xp22.31 deletion, and highlight subgroups of deletion carriers that may be prioritised for screening. Examining cardiac function further in deletion carriers, and in model systems lacking steroid sulfatase, may clarify AF pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterising heart rhythm abnormalities associated with Xp22.31 deletion

et al. 2022

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“…Dupuytren's contracture, in which one or more fingers become permanently flexed, typically onsets in middleage due to fibrosis of the palmar fascia. 83 In UKBB, we identified diagnosis in 3.5% of male deletion carriers (compared to 0.6% in non-carriers), 84 and the DECIPHER T A B L E 1 Lines of evidence supporting the role of altered laminin and basement membrane function in X-linked ichthyosis (XLI) extracutaneous phenotypes…”

Section: Dupuytren's Contracturementioning

confidence: 94%

“…Dupuytren's contracture, in which one or more fingers become permanently flexed, typically onsets in middle‐age due to fibrosis of the palmar fascia. 83 In UKBB, we identified diagnosis in 3.5% of male deletion carriers (compared to 0.6% in non‐carriers), 84 and the DECIPHER database describes one patient with a pathogenic point mutation within STS and contracture of the 5th finger. 15…”

Section: Newly‐identified Medical Comorbiditiesmentioning

confidence: 99%

“…Work in UKBB also identified a specific bleeding‐related phenotype (‘hemorrhage or hematoma complicating a procedure’) as being more common (3.5%) in deletion‐carrying males than male non‐carriers (0.5%). 84 This finding could reflect the fact that deletion carriers undergo more, or more invasive, procedures than non‐carriers and/or that deletion carriers are more likely to be prescribed retinoid‐derived pharmacotherapy with adverse effects on blood‐clotting. 85 Alternatively, and perhaps more likely given that no deletion carriers reported being prescribed such medications, it could have a biological explanation.…”

Section: Newly‐identified Medical Comorbiditiesmentioning

confidence: 99%

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X‐linked ichthyosis: New insights into a multi‐system disorder

Wren

Davies

2022

Skin Health and Disease

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Background X‐linked ichthyosis (XLI) is a rare genetic condition almostexclusively affecting males; it is characterised by abnormal desquamation and retentionhyperkeratosis, and presents with polygonal brown scales. Most cases resultfrom genetic deletions within Xp22.31 spanning the STS (steroid sulfatase)gene, with the remaining cases resulting from STS‐specific mutations. For manyyears it has been recognised that individuals with XLI are at increased risk ofcryptorchidism and corneal opacities. Methods We discuss emerging evidence that such individuals are alsomore likely to be affected by a range of neurodevelopmental and psychiatrictraits, by cardiac arrhythmias, and by rare fibrotic and bleeding‐relatedconditions. We consider candidate mechanisms that may confer elevatedlikelihood of these individual conditions, and propose a novel commonbiological risk pathway. Results Understanding the prevalence, nature and co‐occurrence ofcomorbidities associated with XLI is critical for ensuring early identificationof symptoms and for providing the most effective genetic counselling andmultidisciplinary care for affected individuals. Conclusion Future work in males with XLI, and in new preclinical andcellular model systems, should further clarify underlying pathophysiologicalmechanisms amenable to therapeutic intervention.

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Cardiac arrhythmia in individuals with steroid sulfatase deficiency (X-linked ichthyosis): candidate anatomical and biochemical pathways

Wren,

Davies

2024

Essays in Biochemistry

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Circulating steroids, including sex hormones, can affect cardiac development and function. In mammals, steroid sulfatase (STS) is the enzyme solely responsible for cleaving sulfate groups from various steroid molecules, thereby altering their activity and water solubility. Recent studies have indicated that Xp22.31 genetic deletions encompassing STS (associated with the rare dermatological condition X-linked ichthyosis), and common variants within the STS gene, are associated with a markedly elevated risk of cardiac arrhythmias, notably atrial fibrillation/flutter. Here, we consider emerging basic science and clinical findings which implicate structural heart abnormalities (notably septal defects) as a mediator of this heightened risk, and propose candidate cellular and biochemical mechanisms. Finally, we consider how the biological link between STS activity and heart structure/function might be investigated further and the clinical implications of work in this area.

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Comorbid Medical Issues in X-Linked Ichthyosis

Cited by 5 publications

References 15 publications

Characterising heart rhythm abnormalities associated with Xp22.31 deletion

Characterising heart rhythm abnormalities associated with Xp22.31 deletion

X‐linked ichthyosis: New insights into a multi‐system disorder

Cardiac arrhythmia in individuals with steroid sulfatase deficiency (X-linked ichthyosis): candidate anatomical and biochemical pathways

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