Harlequin Ichthyosis: Genetic Causes, Daily Impact, and the Need for Research

Why does Harper need 3+ showers a day? The answer lies in the biology of one of the rarest skin conditions: Harlequin Ichthyosis (HI). HI is one of the most significant types of autosomal recessive congenital ichthyoses, which are skin disorders that result in dry, thickened patches. A mutation in the ABAC12 gene causes HI and occurs in approximately one in 3,000,000 births.1 The ABAC12 gene codes for the ABAC12 protein, which is responsible for transporting fats and lipids to the epidermis2, the outermost layer of our skin. The loss of this protein means that the body cannot transport the fats where they are supposed to go, resulting in the skin presenting as thick, hard patches of skin separated by cracks, along with other symptoms like dehydration and increased risks of infections.1 Due to this dysfunction in the skin barrier, lotioning and skin care are essential for treating skin dehydration in HI.2 Showering is crucial for removing the dry scales and skin and helping with the cracks that appear, providing comfort and easing the symptoms of HI, like feelings of itchiness and tightness.3 Although we know the gene responsible for HI, HI remains a complex condition to manage due to differences in the exact mutation in the gene and how these mutations present themselves. Understanding more about the effects and mechanisms of this condition will increase treatment and survival rates in the future. The limited literature on HI means physicians may sometimes use treatments known for other related skin disorders2, which shows the lack of research regarding rare diseases, which may hinder proper treatments. The difficulty in finding a cure for HI comes from the fact that it is a genetic condition; the mutation in the ABAC12 gene may result in various downstream cascading effects.4 Future research may discover treatments through gene therapies that can restore the proper functioning of ABAC12. Current treatments allow for the management of HI’s chronic symptoms. The available resources to manage symptoms often depend on factors such as location and socioeconomic status, and there are also factors at play that many may not be aware of. Firstly, education plays an essential role in effectively managing HI. Healthcare professionals should inform parents of long-term, out-of-hospital management and when to seek medical assistance. This includes education on skin care routines, signs of complications, and the importance of treatment adherence, like steps to prevent infections. This knowledge allows for a comprehensive understanding of the conditions of HI, which empowers families to make informed decisions that lead to better health outcomes. Beyond skincare, individuals with HI also require more minerals and calories due to the rapid turnover of skin cells at the surface, so one should adjust the diet to meet increased nutritional demands.5 Secondly, it is essential to consider the impact of the social stigma of rare diseases and the monetary costs of HI for the parents. Respectful education and advocacy for rare diseases can shift the public perception of rare diseases, fostering greater awareness and creating a supportive environment for those with rare diseases. Treatment requires time and effort, and marginalized communities with less access to affordable care and treatment for HI struggle to maintain difficult symptoms. Thirdly, while translational research seeks to develop a range of treatments for HI patients around the world, often they are inaccessible due to the cost of newly developed skincare treatments or the limited availability of tools and education regarding medical procedures.2 HI remains difficult as is, and is harder still in developing nations, as DNA sequencing is required to confirm the disease fully, which may not be available. Angie and Harper’s advocacy about awareness and living with the disease ties strongly into the necessity for advocacy for research into HI. With every step forward in raising awareness for HI, we also step towards finding new therapies for rare diseases. Ultimately, it is through education, advocacy, and empathy that a rare disease can be transformed from an experience of isolation to one of empowerment and triumph. 1. Shrestha AB, Biswas P, Shrestha S, et al. Harlequin ichthyosis: A case report and literature review. Clin Case Rep. 2022;10(12):e6709. doi:10.1002/ccr3.6709 2. Tsivilika M, Kavvadas D, Karachrysafi S, Sioga A, Papamitsou T. Management of Harlequin Ichthyosis: A Brief Review of the Recent Literature. Child Basel Switz. 2022;9(6):893. doi:10.3390/children9060893 3. Foundation for Ichthyosis & Skin Related Types. Bathing and Exfoliation. Accessed May 4, 2025. https://www.firstskinfoundation.org/bathing-exfoliation 4. Thomas AC, Cullup T, Norgett EE, et al. ABCA12 is the major harlequin ichthyosis gene. J Invest Dermatol. 2006;126(11):2408-2413. doi:10.1038/sj.jid.5700455 5. Foundation for Ichthyosis & Skin Related Types. Nutrition. Accessed May 11, 2025. https://www.firstskinfoundation.org/nutrition