Brief Summary of Disease
The birth of a newborn child is a monumental event for parents. The sudden cry of a newborn indicates a sign of life. The next few seconds that follow, however, will change the lives of some parents. The estimated prevalence of harlequin ichthyosis (HI) is 1 in 300,000. 1 HI, more commonly known as harlequin fetus, is a very rare genetic skin disease that is transmitted via autosomal recessive inheritance.1 Babies born with HI present with a distinct appearance such as thick, plate-like skin separated by cracks, which can disfigure facial features.2 The eyes, mouth, and ears are commonly affected due to the tightening of the skin. Further complications include difficulty with breathing and eating, dehydration, infection, thermoregulation, and can eventually lead to death.2,3
Etiology and Pathology
This disorder is caused by a mutation in the ABCA12 gene.2 This gene makes proteins which play an essential role in the normal development of skin cells. The protein helps transport molecules, mainly lipids (fat), in the outermost layer of the skin, known as the epidermis. 4 The lipids in the epidermis help prevent water loss. 4 Since the mutation causes a change in the lipid transportation mechanism, the skin is unable to efficiently form as a protective barrier. As a result, the skin becomes thick, and mobility is compromised.
As a result of the skin losing its ability to act as a protective layer and becomes thickened, hyperkeratosis can occur.5 Neonates are also more prone to infections, such as sepsis, dehydration and thermoregulation is compromised.6 Babies that survive past infancy develop skin changes that come from the same family of genetic skin disorders, known as non-bullous congenital ichthyosiform erythroderma (NBCIE).7 As a result, the skin becomes red and is usually itchy or painful.8 The tightening of the skin commonly affects the eyes and ears resulting in vision problems, such as developing cataracts, and deafness may also occur.7 Respiratory problems are the most common in the early stages of HI due to the constriction of the skin, and can eventually lead to respiratory failure and death. In some cases of HI, children experienced a delay in motor skill and other developmental milestones.7
The primary means of diagnosis is through clinical appearance after birth, but several prenatal tests can also be used to diagnose HI. Routine ultrasounds may show signs of HI, such as the eversion of the lips and eyelids, leading to a probable diagnosis of HI. However, a challenge that exists when testing for HI is that the physical manifestation of the disease may not be expressed until later stages of development.1,9 Therefore, early ultrasound scans may not show any signs of HI. Another way to diagnosis HI is by testing for the mutation of the ABCA12 gene via a DNA-based analysis. Women who have had a history of pregnancies with harlequin babies are advised to have prenatal testing.1 Amniocentesis can be performed to screen for the affected gene and is often used when there are abnormal ultrasound findings or advanced maternal age.1,10 Chorionic villus sampling is another technique that is used to diagnose HI.1
For the individuals that survive the neonatal period, they will have to live the rest of their lives with a chronic skin disease. Normal lipid transporters help secrete enzymes and proteins that are required for skin shedding.9 Since their regular function is impaired, patients with HI are unable to properly shed their skin, extensive management is required. As neonatal care has greatly improved, many babies born with HI can receive treatment and supportive care early on. A team of dermatologists and other specialists work together to optimize survival in the infancy stage.9 After a baby has been born with HI, they are sent to the neonatal intensive care unit to prevent complications. Antibiotics are used to help fight infections in the early stages.2 Individuals with delayed fine and gross motor skills may require occupational or speech-language therapy.7
Throughout the rest of their lives, those affected with HI will have to keep their skin moist as much as possible by applying skin softening creams.2 By keeping the skin moisturized, this will help prevent cracking and reduce the risk of infections. There are formulas that help repair the skin barrier by moisturizing and may include cholesterol, moisturizers with petrolatum (Vaseline) and mild keratolytic therapies to remove excess skin.2 Recent treatments include oral retinoids that have shown positive changes such as softening of the skin and improving limb mobility.9 While treatments are advancing and show positive results, speech-language therapy, support from medical professionals, use of creams and a balanced diet has proved to be a necessity in providing a healthy, independent life for those with HI.9
While the detection of HI cannot always be seen early on, screening for the disease may help parents that are recessive for the gene. Parents who are carriers for the disorder have a 25% chance of transmitting the disease per pregnancy. Corrective gene therapy may be a possibility for some couples. However, there are risks of further genetic mutations when taking this path.9 As always, further research to understand the pathways of diseases is paramount. If the mutation in the ABCA12 gene is found at different locations, then this may create an opportunity for different treatments.9 As technology advances, new therapies may arise that will reduce the constant need for emollients in diseases like HI.9
The treatments and understanding of HI have greatly improved since the first description of HI in 1750 by Reverend Oliver Hart.10 In 2005, researchers were able to trace the cause of HI to a mutation in the ABCA12 gene.10 Advancements in intensive neonatal care have positively impacted both short and long-term outcomes.9 However, therapy for ichthyosis, such as HI, are still lacking. Dr. Paller and others researchers are looking for more safe and effective treatment to deal with the symptoms of these skin disorders by trying to understand the disease on a molecular level.10 Dr. Paller and fellow ichthyoses researchers have analyzed the linkages between TH17 and IL-23 pathways, which are involved in inflammation and epidermal pathologies. Their findings suggest that the immune profile of ichthyosis is similar to psoriasis, and psoriasis treatments may be used for patients affected by ichthyosis.10 Priority Setting Partnership (PSP) is a method of qualitative research that has been used to determine the prioritization of therapy uncertainties of congenital ichthyosis. By establishing a prioritization list of the current treatments for ichthyosis, researchers and funding bodies will be able to determine what is important to patients with ichthyosis.11
The Foundation for Ichthyosis and Related Skin Types (FIRST)
FIRST has helped connect patients and families affected by this disease and other related skin diseases. They are the world’s leading patient advocacy organization for those affected by ichthyosis. FIRST also provides a support network, education, resources to medical professionals and other services.
Ichthyosis Support Group
Ichthyosis Support Group is another organization that works to create a network of patients and families affected by HI, and is committed to raising awareness for greater research for this condition. As the timeline for research and treatments expands and advances, so will the lives of those affected by HI.
1. Rathore S, David LS, Beck MM, Bindra MS, Arunachal G. Harlequin ichthyosis: Prenatal diagnosis of a rare yet severe genetic dermatosis. J Clin Diagn Res. 2015;9(11):QD04-QD06. doi:10.7860/JCDR/2015/15250.6705.
2. National Organization for Rare Disorders. Ichthyosis, harlequin type. https://rarediseases.org/rare-diseases/ichthyosis-harlequin-type/
3. Glick JB, Craiglow BG, Choate KA, Kato H, Fleming RE, Siegfried E, & Glick SA. Improved management of harlequin ichthyosis with advances in neonatal intensive care. Am Aced Pediatrics. 2017;139(1) doi:10.1542/peds.2016-1003
4. U.S. National Library of Medicine. ABCA12 gene. https://ghr.nlm.nih.gov/gene/ABCA12#conditions
5. Sheth, JJ, Bhavsar R, Patel D, Joshi A, & Sheth FJ. Harlequin ichthyosis due to novel splice site mutation in the ABCA12 gene: Postnatal to prenatal diagnosis. Int. J. Dermatol. 2018;57(4), 428-433. doi:10.1111/ijd.13923
6. U.S. National Library of Medicine. Harlequin ichthyosis. https://ghr.nlm.nih.gov/condition/harlequin-ichthyosis#diagnosis
7. Rajpopat, S et al. Harlequin ichthyosis: a review of clinical and molecular findings in 45 cases. Arch Dermatol. 2011;147(6), 681-686. doi:10.1001/archdermatol.2011.9
8. Orphanet. Congenital non-bullous ichthyosiform erythyroderma. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=79394
9. Ahmed H., & O'Toole E. A. Recent advances in the genetics and management of harlequin ichthyosis. Pediatr Dermatol. 2014;31(5), 539-546. doi:10.1111/pde.12383
10. Paller, A et al. An IL-17-dominant immune profile is shared across the major orphan forms of ichthyosis. J Allergy Clin Immunol. 2017;139(1), 152-165. doi.org/10.1016/j.jaci.2016.07.019
11. Hernández‐Martín A., et al. Prioritization of therapy uncertainties in congenital ichthyosis: results from a Priority Setting Partnership. Br J Dermatol. 2015;173(5), 1280-1283.
Cite This Article:
Nop S., Chan G., Lewis K., Ho J. Harlequin Ichthyosis. Illustrated by J Tamura. Rare Disease Review. November 2019.