Informing guidelines for managing X-linked ichthyosis: expert commentary

Updated international guidelines for the management of congenital ichthyoses, including X-linked ichthyosis (XLI), have recently been developed and published by a taskforce of clinicians, academics and advocates from patient support groups and charities. Dr William Davies, whose research was used to support the new guidelines, discusses why screening for psychological and medical comorbidities in individuals diagnosed with XLI will reduce the likelihood of chronic health conditions within this patient population and alleviate associated healthcare burdens.   

X-linked ichthyosis (XLI) is a rare dermatological condition caused by the absence, or profound attenuation, of activity of the enzyme steroid sulfatase (STS).¹ This enzyme cleaves sulfate groups from a variety of steroids, and its absence in the skin results in the accumulation of cholesterol sulfate, which in turn leads to abnormal desquamation, altered skin permeability and retention hyperkeratosis.¹ The condition is typically caused by Xp22.31 microdeletions encompassing the STS gene and, being X-linked, almost exclusively affects males.¹

XLI can be managed relatively effectively through the rigorous application of topical emollients, moisturisers and keratolytics, but currently it has no cure.¹ Historically, XLI has been associated with an increased risk of cryptorchidism in early life, and of corneal opacity manifest from adolescence onwards.

Newly identified comorbidities in XLI

Emerging data have highlighted multiple additional comorbidities.² Early case reports describe individuals lacking functional STS and presenting with ichthyosis and cognitive, psychiatric or neurological symptoms. More recent, and more comprehensive, case series^3–6 and online survey data⁷ have suggested that 30–40% of males with XLI meet diagnostic criteria for one or more neurodevelopmental conditions, including attention deficit hyperactivity disorder (ADHD) – particularly the inattentive subtype – as well as autism spectrum conditions, dyspraxia and epilepsy.

Generally, individuals diagnosed with XLI demonstrate IQs within the typical range, although there may be relatively subtle effects on some aspects of cognition such as fluid reasoning⁸ and memory.⁹

Larger genetic deletions tend to be associated with more severe neurodevelopmental phenotypes. Carriers of such deletions are more likely to co-present with learning disability.^3-6

The prevalence of mood disorders and associated traits, including depression, anxiety and irritability, is also substantially higher in males diagnosed with XLI than in males from the general population.^9–11 Moreover, female Xp22.31 deletion carriers are at elevated risk of neurodevelopmental and mood conditions compared with sex-matched non-carriers.¹²

Using the UK Biobank resource of around half a million middle-aged participants,¹³ we unexpectedly discovered that males with deletions including STS were at significantly greater risk of being diagnosed with atrial fibrillation or atrial flutter than male non-carriers.⁸ Follow-up work in the XLI patient population suggested that heart rhythm abnormalities more generally are likely to affect 25–35% of males with XLI, that these abnormalities are most commonly precipitated by stress, and that they present disproportionately with comorbid gastrointestinal conditions.¹⁴

The biological basis for the increased arrhythmia risk in XLI is currently unclear, although it may be related to the presence of septal defects.¹⁵ As with brain-related conditions, female deletion carriers are at elevated risk of cardiac abnormalities compared with sex-matched non-carriers.¹⁴

Work in animal models,^16,17 and human molecular genetic analyses,¹⁴ have suggested that the psychological, cognitive and cardiac phenotypes in patients with XLI have a biological basis and are not simply a response to living with a dermatological condition, or a side effect of dermatological treatments. Additionally, these studies have implicated STS loss specifically as being causal for such phenotypes rather than loss of contiguous genes.

Comorbidities and early screening in XLI

Although it is important to appreciate population neurodiversity and its many positive impacts, it must also be recognised that neurodevelopmental and mood disorders can extensively disrupt family dynamics, impact educational and employment opportunities, impair social function, disturb sleep and cognitive function, predispose to suboptimal decision-making – resulting in physical injury, criminal behaviour and substance misuse, for example – and adversely affect general quality of life.^18–21

Heart rhythm abnormalities confer risk of numerous serious health conditions with long-term consequences, including heart failure, cardiac arrest, stroke and cognitive decline and dementia.²² Combined, the sequelae of these conditions place a considerable burden on affected individuals, as well as on their loved ones, carers and healthcare systems.

The early identification of psychological and cardiac issues in individuals lacking STS, and subsequent symptom monitoring and intervention where required, will mitigate the likelihood of persistent health issues. Interventions might include a combination of pharmacotherapy, surgery, behaviour management strategies, lifestyle advice or educational and social adjustments.^23,24

Given the population prevalence of Xp22.31 deletions,⁸ and rates of comorbidities and their downstream consequences,²⁵ we estimate that around 300,000 deletion-carrying males worldwide – and an even larger number of female carriers – may currently be at risk of long-term adverse health, educational and social problems.

The 2024 international guidelines of care for the management of congenital ichthyoses, recently published in the British Journal of Dermatology,²⁶ now explicitly advise clinicians diagnosing XLI (predominantly dermatologists) to screen for psychological and cardiac issues and to refer onwards to specialists for further investigation as appropriate.

Key psychological and neurological symptoms for diagnosing clinicians to be aware of include distractibility, disorganisation, impulsive decision-making, coordination difficulties, hyperactivity, difficulties establishing and maintaining friendships, seizures, irritability and depressive or anxious traits.

Key symptoms of arrhythmias that may warrant further analysis include palpitations, chest pain, breathlessness, dizziness or fainting, extreme anxiety or fatigue. Where feasible, cascade testing, whereby family members who could potentially carry the XLI-associated genetic variant are also screened for psychological, neurological and cardiac symptoms, should also be undertaken.²²

The use of wearable technologies over the next few years may also facilitate the detection of abnormal heart rhythms, including in asymptomatic individuals. Pilot data have indicated the feasibility of using smartwatches in the XLI population to this effect.²⁷

Future work and clinical considerations

The biological and environmental mechanisms mediating neurological, psychiatric and cardiac disorder risk in XLI require further investigation in clinical samples and in animal and cellular models. Such studies should detect optimal intervention points for therapy.

As the proposed screening procedures in XLI are rolled out more widely, an analysis of their impact in terms of benefits and costs will be required. Finally, it will be important to recognise and avoid potential issues associated with treating multimorbidity in the XLI population. For example, stimulant medications frequently administered to treat ADHD may exacerbate cardiac arrhythmias and worsen health outcomes in vulnerable subgroups.²⁸

In conclusion, XLI is increasingly recognised as a multisystem disorder with significant psychological and cardiac comorbidities. Early screening for these conditions, now formally recommended in international guidelines, is critical to improving long-term outcomes for affected individuals.

Continued research into the underlying mechanisms and careful monitoring of emerging management strategies will be essential to optimise care and reduce the wider health and social impact of this condition.

Author

Dr William Davies FHEA MBiochem PhD
Schools of Medicine and Psychology, Cardiff University, UK

References

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