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Harlequin ichthyosis
This condition affects the skin's protective barrier, leading to serious complications from birth. It is one of the most severe forms of ichthyosis, a group of disorders causing dry, scaly skin, and requires intensive medical care.
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Overview
Harlequin ichthyosis is a profound genetic skin disorder, present from birth. Affected infants are born with very thick, hard skin that forms large, diamond-shaped plates separated by deep cracks. This severe presentation is due to a significant problem with the development of the outermost layer of the skin, known as the epidermis [PMID:33678070].
This condition is part of a larger group of disorders called ichthyoses, which are characterised by dry, scaly, or thickened skin. Harlequin ichthyosis is considered the most severe form within this group. The unusual skin acts as a poor barrier, making affected babies highly vulnerable to infection, dehydration, and problems regulating body temperature.
Symptoms & clinical features
Babies with Harlequin ichthyosis are born with distinctive and severe skin symptoms. The skin is extremely thick, rigid, and appears as large, shiny plates resembling armour, often with deep red fissures (cracks) between them [PMID:33678070]. These fissures can increase the risk of infection.
The rigidity of the skin can restrict movement, particularly around the mouth and eyes. This can lead to eyelids being turned outwards (ectropion) and lips being pulled back (eclabium), making feeding difficult. The tight skin can also restrict breathing movements, sometimes requiring respiratory support. Other features can include flattened ears and nose, and sometimes problems with hands and feet, such as swollen digits. The condition requires immediate and intensive medical care from birth.
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Affected organs
The primary organ affected by Harlequin ichthyosis is the skin. The abnormalities in skin development lead to a compromised skin barrier, which typically protects the body from the environment. This impaired barrier function has widespread effects on other body systems.
Babies with Harlequin ichthyosis are at high risk of severe dehydration due to excessive water loss through the skin, and they are also vulnerable to hypothermia (low body temperature) because of impaired temperature regulation. The deep cracks in the skin can serve as entry points for bacteria, leading to serious infections. The rigid skin can also affect the eyes, mouth, and respiratory system, potentially causing feeding and breathing difficulties.
Risks & severity
Harlequin ichthyosis is a severe condition that poses significant risks, particularly in the newborn period. The compromised skin barrier leads to a high risk of life-threatening complications such as severe infection, dehydration, and respiratory distress [PMID:33678070]. Without intensive medical care, the mortality rate in the neonatal period is historically very high.
However, with advances in neonatal care, including humidified incubators, aggressive moisturising, and antibiotics, more infants are surviving beyond the newborn period. Those who survive often develop a form of severe erythrodermic ichthyosis, characterised by widespread red, scaly skin throughout life. This requires ongoing specialist dermatological care to manage skin integrity, prevent complications, and maintain quality of life.
Genetic causes
Harlequin ichthyosis is caused by pathogenic variants (sometimes called mutations) in the *ABCA12* gene [PMID:16172605]. This gene provides instructions for making a protein called ATP-binding cassette transporter A12. This protein is crucial for the normal development of the skin's outermost layer, the epidermis.
The ABCA12 protein is thought to play a role in transporting lipids (fats) across cell membranes, which are essential for forming the skin's protective barrier. When the *ABCA12* gene has pathogenic variants, the protein either does not work correctly or is not produced at all. This disruption means that lipids cannot be properly transported, leading to the severe skin thickening and cracking characteristic of Harlequin ichthyosis.
- ABCA12 ATP binding cassette subfamily A member 12The ABCA12 gene provides instructions for an ATP-binding cassette (ABC) transporter protein crucial for lipid transport in skin cells and normal skin development.
Inheritance pattern
Harlequin ichthyosis follows an autosomal recessive inheritance pattern. This means that an individual must inherit two pathogenic variants, one from each parent, to develop the condition.
Parents who each carry one pathogenic variant in the *ABCA12* gene are typically unaffected themselves, as they have one working copy of the gene. They are known as carriers. For each child born to two carriers, there is a 25% chance the child will inherit two pathogenic variants and develop Harlequin ichthyosis, a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two working copies of the gene and be neither affected nor a carrier. Genetic counselling can provide more detailed information for families.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
The diagnosis of Harlequin ichthyosis is usually made at birth based on the distinctive clinical appearance of the skin. Genetic testing is then used to confirm the diagnosis by identifying pathogenic variants in the *ABCA12* gene. This testing can be carried out through the NHS Genomic Medicine Service (GMS).
If Harlequin ichthyosis is suspected, a referral to a clinical genetics service is typically made. Genetic testing for this condition, and other forms of ichthyosis, is available through specific NHS R-codes, ensuring access to appropriate diagnostic pathways. Prenatal diagnosis may also be possible in subsequent pregnancies for families with a known genetic cause of Harlequin ichthyosis.
Management & lifestyle
The management of Harlequin ichthyosis begins immediately at birth and focuses on intensive supportive care. This often involves admission to a neonatal intensive care unit (NICU). Key aspects of care include maintaining skin hydration through frequent application of emollients and use of humidified environments, preventing infection with meticulous skin care and antibiotics as needed, and managing temperature regulation.
Long-term management for individuals who survive the neonatal period involves ongoing specialist dermatological care. This typically includes regular use of moisturisers and other topical treatments to manage skin dryness and scaling. Oral retinoids may be considered in some cases, under specialist guidance. A multidisciplinary approach involving dermatologists, geneticists, ophthalmologists, and other specialists is often needed to address the various health challenges associated with the condition.
UK care pathway
In the UK, suspected cases of Harlequin ichthyosis would typically enter the NHS Genomic Medicine Service (GMS) pathway. Initial clinical assessment by neonatologists or paediatricians would lead to a referral to a clinical genetics service. Genetic testing, covered by specific NHS R-codes, helps confirm the diagnosis and identify the underlying genetic cause. Genetic counsellors are available to provide support, explain inheritance patterns, and discuss implications for the wider family.
Frequently asked questions
Is Harlequin ichthyosis common?
No, Harlequin ichthyosis is a very rare condition. The exact prevalence is not well established, but it is considered one of the rarest forms of ichthyosis.
Can Harlequin ichthyosis be detected before birth?
For families with a known genetic cause of Harlequin ichthyosis, prenatal diagnosis is possible in subsequent pregnancies. This involves genetic testing of the foetus, often through amniocentesis or chorionic villus sampling.
What is the life expectancy for someone with Harlequin ichthyosis?
Historically, Harlequin ichthyosis was often fatal in the newborn period. However, with advances in neonatal intensive care, more infants are surviving. Those who survive beyond infancy often require lifelong specialist medical care to manage their skin and associated health issues.
Are there different levels of severity for Harlequin ichthyosis?
Harlequin ichthyosis is considered the most severe form of ichthyosis and presents with a characteristic and extreme clinical picture at birth. While the initial presentation is consistently severe, the long-term outcomes and the nature of ongoing skin issues can vary among individuals who survive the neonatal period.
How does Harlequin ichthyosis affect daily life?
Individuals living with Harlequin ichthyosis require ongoing, often intensive, skin care. This includes frequent moisturising and careful management to prevent infections. The condition can also affect comfort, mobility, and appearance, requiring significant adaptation and support throughout life.
References
- Akiyama M, Choate K, Hernández-Martín Á. Nonsyndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy. The British journal of dermatology. 2025. PMID: 40308026
- Hotz A, Kopp J, Bourrat E. Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients. Genes. 2021. PMID: 33435499
- Elkhatib AM, Omar M. Ichthyosis Fetalis. 2026. PMID: 32809327
- Akhdari N, Ouladsiad M, Aboussad A. Harlequin ichthyosis. Skinmed. 2010. PMID: 21413658
- Takeichi T, Akiyama M. Inherited ichthyosis: Non-syndromic forms. The Journal of dermatology. 2016. PMID: 26945532
- Akhtar S, Anwaar A, Haq IU. Harlequin Ichthyosis: A Case Report. Clinical case reports. 2025. PMID: 40667495
- Alanzi A, Alatefi D, Alkabazi M. Early Neonatal Death in Harlequin Ichthyosis: A Case Report and Literature Review. Clinical case reports. 2025. PMID: 41113302
- Milstone LM, Choate KA. Improving outcomes for harlequin ichthyosis. Journal of the American Academy of Dermatology. 2013. PMID: 24124810