Slipping Through the Cracks: An Analysis of Harlequin Ichthyosis
Summary of Disease
Harlequin ichthyosis (HI) is regarded as the most severe and frequently fatal form of recessive congenital ichthyosis–a heterogenous group of keratinization disorders characterized by abnormal skin scaling over the whole body.1 It is also commonly known as: Harlequin baby syndrome, HI, Icthyosis Congenita and Harlequin Fetus Type.2 HI affects 1 in 300,000 people all around the world.2 Individuals who are affected by this disorder are born with hard, thick skin covering most of their bodies. It severely affects the presentation of facial features, leading to distortion of the lips, eyelids, ears and nostrils.2 In the past, infants born with this condition would rarely survive more than a few days after birth due to defects in the body’s lipid transport, enzyme activity and cell differentiation.2 Altered enzyme activity greatly impacts the signalling processes within skin cells, leading to flattened nuclei within these cells, thereby making lipid (fat) transport much more difficult.2 However, immense progress has been made in treatment protocols for HI, paving the way for people affected by this condition to live well into their teens and twenties.2 In order to improve the knowledge surrounding treatment for the disorder, the etiology and pathology of HI must be understood thoroughly.
Symptoms & Etiology
This rare genetic disorder can be clearly observed as the skin dries out to form hard-diamond shaped plaques separated by fissures, or deep cracks. 3These skin abnormalities affect the shape of the eyelids, nose, mouth and ears and limit movement of arms or legs.3 Restricted movement of the chest is also commonly associated with HI, which can lead to difficulties breathing and ultimately, respiratory failure.3 Through improved genetic sequencing methods, it has been found that mutations in the ABCA12 gene are responsible for the presentation of this disorder (Figure 1).4 In the body, the ABCA12 gene provides instructions for making a protein that is essential for the normal development of skin cells by playing a major role in transport of lipids (fats) in the epidermis (the outermost layer of skin).4 Mutations in the gene causing loss of function of the ABCA12 protein disrupt the normal development of the epidermis, resulting in the hard scales observed in the presentation of HI.4 As the skin abnormalities associated with HI disrupt the skin's protective barrier, this makes it very difficult for infants to control water loss, regulate body temperature and fight infections.4 Despite physical characteristics of the disorder posing a serious threat to infant’s vitality, mental and intellectual developments are not expected to be affected by the disorder.4 These prominent physical markers help doctors perform accurate and consistent diagnosis of HI.
Figure 1: ABCA12 Gene Involved in the Onset of Harlequin Ichthyosis
Adapted from the Journal of Investigative Dermatology4
Diagnosis
In addition to the distinct physical characteristics, infants affected by HI often undergo genetic testing to precisely determine the type of ichthyosis present. There is a tendency for babies affected by the disorder to be born prematurely.5 Successful prenatal diagnosis of ichthyosis in the fetus of a pregnant woman whose previous liveborn child was affected by harlequin ichthyosis has proven to provide valuable information regarding the disorder.5 Through early diagnosis healthcare professionals can better prepare therapies prior to delivery. Analysis of ultrasonographically guided fetoscopic skin biopsies showed premature hyperkeratosis marked around hair follicles and sweat ducts, forming plugs of hyperkeratotic debris.5 This cell morphology shows a large contrast to that of healthy epidermal cells (Figure 2).3 Due to the autosomal recessive nature of HI, there is a 25% chance that a child will be born with HI if the parents have already had a child with the disorder.3
Figure 2: Epidermal cells of an individual affected by HI seen in diagram A and wild-type epidermal cells seen in diagram B
Adapted from the Journal of Clinical Investigation3
Treatment and Prognosis
Due to the severe physical threats posed by the disorder to an infant's health, it was previously rare that the newborn would survive past two days post-birth. However, with intensive medical support and improved treatment, the average life expectancy has lengthened with several affected individuals living into childhood and adolescence.6 The increasing number of surviving patients is largely due to the wider availability of neonatal intensive care that demands a multidisciplinary approach. Affected infants are at heightened risk of poor nutrition, difficulty with breathing, and systemic infections. Immediate treatment may include: intubation, which involves placing a tube into the infant’s airway to ensure they are receiving oxygen; application of topical retinoids and debridement of constriction areas of skin to allow for adequate chest expansion; and diligent cleaning, moisturizing, and dressing of the skin to reduce the risk of infection. For severe cases, the use of oral retinoids has shown benefit outweighing their known risks. Oral retinoids are medications used to decrease inflammation in the skin.7 Antibiotic treatment is administered to prevent infection when the thick plate-like skin splits and peels off.7 As a result of the intensive nature of the disorder, most infants will need one-on-one nursing care for the first several weeks of life.7 Surviving children often display dry, reddened skin which may be covered by large thin scales and sparse hair, and physical development is often delayed due to the large caloric needs for skin function.7 Progression in scientific knowledge of the disorder and treatment protocols are remarkable and as technology continues to improve, this will allow for more research to be performed in regards to the treatment of HI.
Current Research
A recent study using a 3D model of the disorder to reveal potential targets for therapeutic medication and treatment. Experimental procedures such as RNA sequencing and CRISPR/Cas9 were conducted to define the effects of ABCA12 gene malfunction.8 This study identified dysregulated skin development, lipid metabolism and inflammation.8 It was found that cytokines IL-36α and IL-36γ were upregulated in skin affected by HI, while the innate immune inhibitor IL-37 was significantly downregulated.8 Cytokines serve an important function in the immunoregulatory system acting as signaling molecules involved in inflammation and immunity.8 By identifying the biochemical and physiological pathways that are disrupted due to HI, new targets for therapeutic treatment were identified, allowing for progress to be made in the treatment of HI.
Support Groups
While for many a diagnosis of Harlequin Ichthyosis can bring about a feeling of fear, several global and local organizations are dedicated to offering support and resources to those affected by this rare disease. The mission of the First Skin Foundation is to improve the quality of life of affected individuals along with their families and seek cures for those affected by ichthyosis and related skin types.9 They are a global leader in advocacy for ichthyosis and provide research grants, educational materials, special patient-centered meetings and conferences for education on ichthyosis.9 They can help individuals affected by HI find a doctor near them, give information for newly diagnosed individuals and skin management tips.9 The Ichthyosis Support Group in the UK aims to preserve and protect the health of people affected by ichthyosis, advance education of the medical profession on this subject, and promote research into the management of ichthyosis.10 It is crucial to continue supporting research investigating the management of Harlequin Ichthyosis in order to ensure that individuals affected by the disorder have the best possible chance at a long life.
Maria Puscas
Works Cited:
Akiyama M. Harlequin ichthyosis and other autosomal recessive congenital ichthyoses: The underlying genetic defects and pathomechanisms. Journal of Dermatological Science.https://www.sciencedirect.com/science/article/pii/S0923181106000090?casa_token=8yYaTM-6sGsAAAAA%3AedjoH-PxultJYpJ6-iJcRnRFP8JiCIHDvxrE_4leGiGXO1TKS6pRNWmdAkTnOLPFeSacuDMVqsc. Published February 14, 2006. Accessed November 28, 2020.
Kelsell PD, Norgett EE, Unsworth H, et al. Mutations in ABCA12 Underlie the Severe Congenital Skin Disease Harlequin Ichthyosis. The American Journal of Human Genetics. https://www.sciencedirect.com/science/article/pii/S0002929707607265. Published January 9, 2008. Accessed November 28, 2020.
Hovnanian A. Harlequin ichthyosis unmasked: a defect of lipid transport. The Journal of Clinical Investigation. https://www.jci.org/articles/view/25736. Published July 1, 2005. Accessed November 28, 2020.
Thomas AC, Cullup T, Norgett EE, et al. ABCA12 Is the Major Harlequin Ichthyosis Gene. Journal of Investigative Dermatology. https://www.sciencedirect.com/science/article/pii/S0022202X15326865. Published December 8, 2015. Accessed November 28, 2020.
Elias S, Mazur M, Sabbagha R, Esterly NB, Simpson JL. Prenatal diagnosis of harlequin ichthyosis. Wiley Online Library. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1399-0004.1980.tb00147.x. Published April 23, 2008. Accessed November 28, 2020.
Shefali Rajpopat MRCP. Harlequin Ichthyosis. Archives of Dermatology. https://jamanetwork.com/journals/jamadermatology/article-abstract/423924. Published June 20, 2011. Accessed November 28, 2020.
Ahmed H, O'Toole EA. Recent Advances in the Genetics and Management of Harlequin Ichthyosis. Wiley Online Library. https://onlinelibrary.wiley.com/doi/full/10.1111/pde.12383?casa_token=PH5BCrSk-3UAAAAA%3AhsMl4S1Syrp6K7YeFneE-w5xPZyCz363GdJICtVj66L8d6uoMT4vaqLQ1XB6peF5XBMLGZL4XauNBbSh. Published June 12, 2014. Accessed November 28, 2020.
Enjalbert F, Dewan P, Caley MP, et al. 3D model of harlequin ichthyosis reveals inflammatory therapeutic targets. The Journal of Clinical Investigation. https://www.jci.org/articles/view/132987. Published September 1, 2020. Accessed November 28, 2020.
Foundation for Ichthyosis and Related Skin Types FIRST. FIRST - Foundation for Ichthyosis & Related Skin Types, Inc. First Skin Foundation. http://www.firstskinfoundation.org/. Published 1989. Accessed November 28, 2020.
Ichthyosis Support Group . What We Do. Ichthyosis Support Group - People who care about ichthyosis. https://www.ichthyosis.org.uk/what-we-do. Published 1997. Accessed November 28, 2020.
Cite This Article:
Puscas M., Lees K., Charron B., Chharawala V., Lombo L., Kozak A., Ananthakrishnan O. The Genetic Profiling of the Autism Spectrum Disorder. Illustrated by A. So. Rare Disease Review. April 2021. DOI:10.13140/RG.2.2.24554.85445.
