Literature Review
Literature Review – October 2025
Researchers Propose New Names, Advance Understanding of Risks
Amy Paller, MD
Northwestern University FIRST MSAB Chair
Riddhi Patel
Predoctoral Fellow at Northwestern University
A proposal for a new pathogenesis-guided classification for inherited epidermal differentiation disorders
Nonsyndromic epidermal differentiation disorders: New classification and nomenclature based on disease-associated genes leading to targeted therapy. Akiyama M, Choate K, Hernandez-Martin A, et al. Br J Dermatol. Published online May 1, 2025. doi:10.1093/bjd/ljaf154
Syndromic epidermal differentiation disorders: New classification towards pathogenesis-based therapy. Paller AS, Teng J, Mazereeuw-Hautier J, et al. Br J Dermatol. Published online April 4, 2025. doi:10.1093/bjd/ljaf123
Palmoplantar epidermal differentiation disorders: a new classification towards pathogenesis-based therapy. Sprecher E, Ishida-Yamamoto A, Schwartz J, et al. Br J Dermatol. Published online March 19, 2025. doi:10.1093/bjd/ljaf054
Four landmark articles have been published this year in the British Journal of Dermatology, in which top experts in ichthyosis from around the world propose a new way to name the various forms of ichthyosis and related skin types. The group working on the new classification system, called the Reclassifying Epidermal Differentiation Disorders Initiative (REDDI), included 15 expert physician-scientists and two affected individuals. Over more than two years, the team met virtually and in person to achieve these landmark papers.
The new names are meant to be more accurate in their grouping than the old names of “disorders of cornification” or “disorders of keratinization” for the entire group. In addition, the new names get rid of terms that have been hurtful to people with ichthyosis, like “vulgar” in ichthyosis vulgaris, “harlequin” referring to a clown, “hystrix” meaning porcupine, or even “ichthyosis” itself which means fish.
The new naming system discards the names of people whose names tell us nothing about the skin problem (for example, Netherton syndrome). Historically, these conditions also used names based on what the skin looked like, which led to confusing or outdated terms.
The new classification follows trends in naming of genetic issues by including the underlying gene that is affected. It also groups the disorders based on function, with the goal to find new treatments based on understanding the gene affected and how that gene change causes disease in the skin.
The authors replace the word “ichthyosis” with “epidermal differentiation disorder” or EDD, which truly encompasses all of the different types. There are three main categories:
- Nonsyndromic epidermal differentiation disorders (nEDDs) affecting just the skin, hair, nails, and/or sweat glands
- Syndromic epidermal differentiation disorders (sEDDs) affecting the skin and its structure plus at least one other body system (most often the nervous system or eyes)
- Palmoplantar epidermal differentiation disorders (pEDDs) affecting mainly the palms and soles
These names will be more scientific to help doctors understand what causes the disease at a molecular and functional level. By classifying these conditions by the gene that is affected, doctors will be better able to counsel families about prognosis and develop more precise treatments.
The articles include an introduction to this new concept and one article on each of the three different subtypes. Each article has detailed tables with old names and new names, key features and detailed descriptions of each of the almost 150 subtypes now listed, and many photographic images to help practitioners recognize these EDDs and plan the best treatment. As such, these articles will be the new encyclopedia for ichthyosis and other similar disorders.
We recommend that you tell your doctor to keep each of these handy as a reference in their clinics. Clearly, the old names will be around for a while as each person has a form with a label that becomes part of one’s identity. The same is true for FIRST itself as an organization.
But during the next decade, these names will likely transition, as getting a test that tells the gene causing EDDs becomes the norm, and new individuals born with EDDs are told the new names rather than “ichthyosis”. The FIRST-associated registry has long offered free testing to find genes for FIRST members – and all are encouraged to take advantage of this offer, which simply involves providing consent to registry personnel and sending a sample of saliva. Taken together, this is an opportunity to be part of a transition that focuses on what causes the skin scaling, thickening, and redness and that will accelerate discoveries towards treatment and cure.
Bullying in children with congenital ichthyosis
Review: Most of the rare forms of ichthyosis have scaling and often red skin from birth that involve the whole body and are easy to see. In addition, affected children often show behaviors that make them seem different, such as scratching and reluctance to join in sports because of issues with sweating. These differences make children with ichthyosis at increased risk of bullying. Indeed, bullying is a frequent concern for both affected individuals and their families as discussed at support meetings. However, research on the subject has been lacking. This study, performed at Northwestern and the Ann and Robert H. Lurie Children’s Hospital of Chicago, surveyed children with ichthyosis and their caregivers about the children’s bullying experiences. FIRST members actively participated in this survey.
Forty-nine caregivers and children completed the survey, which asked questions about bullying, stigma, and quality of life. There was also an open-ended question in which caregivers and children could include other comments about their experiences. Thirty-three percent of the children with ichthyosis who completed the survey had experienced moderate bullying. This is higher than the 15-19% in the general United States high school population between 2021 and 2023. Of all affected body parts, only facial involvement was associated with significantly increased bullying, as reported by children. Bullying was done by other children in 80.7% of cases, but could be from adults, such as teachers or even strangers. Children experienced bullying by being excluded, called names, and asked rude questions. Children reported feeling sad, embarrassed, worried about the future, and “less human.”
Caregivers suggested strategies to manage negative attention, including encouraging the child to avoid thinking about ichthyosis as shameful or a secret. They also suggested avoiding appearance-based comments at home and instead focusing on action-based and character-based comments. Strategies to address and reduce bullying in children with ichthyosis proposed in this study were increasing awareness and education related to ichthyosis in the school setting to build a strong support network. Screening for bullying during health appointments was encouraged for early identification of bullying and to identify if the child worried about feeling different. Children’s books featuring characters with visible differences can act as anti-bullying tools for families and are listed online through the FIRST website (firstskinfoundation.org/bullying).
The importance of cardiac screening in X-linked ichthyosis – a plea
Reference: Davies W. Clin Exp Dermatol. Published online May 16, 2025. doi:10.1093/ced/llaf221
Review: This author from Cardiff University in the United Kingdom looked at a dataset of almost half a million participants from the UK and found that adults with X-linked ichthyosis had a four times increased risk of atrial fibrillation/flutter, in which the upper chambers of the heart have a fast or irregular beat. When the author then surveyed boys and men with X-linked ichthyosis and adult females who were carriers of the mutation, they found a higher prevalence of parent- and self-reported heart rhythm abnormalities. The cause of increased heart rhythm abnormality risk is unclear and still needs further investigation. This paper recommends that asking about cardiac problems should be part of the routine clinic visit. If palpitations, chest pain, breathlessness, extreme anxiety, dizziness or fainting, and fatigue are frequent or continuous, affected individuals should be evaluated by a cardiologist.
Increased risk of anxiety and coping strategies in patients with selected genodermatoses with cornification disruption
Reference: Fryze M, Mlak R, Kulbaka A, Wertheim-Tysarowska K, Matosiuk D, Pietrzak A. Sci Rep. 2025;15(1):14013. Published 2025 Apr 23. doi:10.1038/s41598-025-98535-6
Review: This study from the Medical University of Lublin in Poland compared anxiety levels between adults with ichthyosis or palmoplantar keratoderma with unaffected adults using surveys and tools that assessed emotional state and personality traits. High or moderate levels of trait anxiety were four times more common in those with ichthyosis or palmoplantar keratoderma when compared to the unaffected group. The authors highlighted the importance of stress-coping strategies in these individuals, noting that avoidance as a coping mechanism (trying to distance oneself from problems and avoiding social interactions) was a common and ineffective strategy. Doctors need to pay attention to the patient’s mental health state and refer to professional psychological/psychiatric therapy to improve their ability to cope, which has an impact on one’s quality of life.
Congenital ichthyosis is associated with cutaneous infections in a case-control study of 2260 patients.
Reference: Curtis KL, Zeldin S, Lipner SR. Clin Exp Dermatol. 2025;50(2):429-431. doi:10.1093/ced/llae382
Review: This study review from Weill Cornell Medicine used the All of Us Database through the National Institutes of Health to analyze the risk of developing skin infections in 226 people with congenital ichthyosis and 2034 unaffected controls. The study found a fivefold increase in the risk of developing fungal nail infection, a threefold risk of body fungal infection, and a twofold increase in the risk of a fungal foot infection in individuals with congenital ichthyosis. Participants with congenital ichthyosis also had a threefold increased risk of warts. Skin infections such as fungal infections and warts, which show localized scaling and thickened skin, may be hard to identify in patients with congenital ichthyosis because of the associated scaling and thickening of skin. The authors suggest that a poor skin barrier in ichthyosis could increase the potential penetration of the fungi and viruses that cause fungal infection and warts, respectively, and recommend that fungal infection be considered in those who do not respond to ichthyosis treatments.
Biologics in congenital ichthyosis: are they effective?
Reference: Mazereeuw-Hautier J, Granier Tournier C, Hernandez-Martin A, … Paller AS. Br J Dermatol. 2025;192(2):327-334. doi:10.1093/bjd/ljae420
Review: During the last decade, numerous medications called biologics have become available to treat two common red, scaling skin disorders, eczema and psoriasis. Based on studies from skin biopsies and tape strips of people with ichthyosis, including many members of FIRST, evidence emerged that there may be shifts in the immune system of skin that could be treated by these biologics. Indeed, at least 30 papers have shown the benefit of a biologic for a patient with ichthyosis. However, it is common that only those with positive results are reported. In this multicenter international study, the authors analyzed change in ichthyosis severity in patients with congenital ichthyosis who were treated with at least one biologic for 3 months. More than half of the 98 patients treated with a biologic (average age 20 years) had a form that was associated with very red skin (Netherton syndrome or congenital ichthyosiform erythroderma (CIE)) and severe or very severe disease. Overall, 45 patients (46%) responded to treatment to some extent; however, only 18 (18%) had a moderate to excellent response and all had forms with very red skin. There was no one biologic drug or clinical sign with improvement (that is, skin redness, scaling, or itch) that seemed superior to others. None of the patients with lamellar ichthyosis or epidermolytic ichthyosis had a good response to biologics. The main takeaway of this study is that biologics may lead to improvement in a subset of patients with ichthyosis, particularly in those with redder skin. Further studies are needed to evaluate the effects of biologics in specific forms of congenital ichthyosis.
Literature Review – April 2025
Tofacitinib ameliorates skin inflammation in a patient with severe autosomal recessive congenital ichthyosis
Kennedy Gallagher, predoctoral fellow at Northwestern University
Reference: Yu-Chen Lin, Yi-Kai Hong, Wilson Jr F Aala, Kiyotaka Hitomi, Masashi Akiyama, John A McGrath, Chao-Kai Hsu
Clinical and Experimental Dermatology, Volume 49, Issue 8, August 2024, Pages 887–892, https://doi.org/10.1093/ced/llae080
Review: Autosomal recessive congenital ichthyosis (ARCI) is a group of scaling disorders that causes dry, scaly skin and abnormal water loss through the skin barrier. Current treatments for this condition are limited and largely not effective. This report highlights the case of a 27-year-old man with ARCI, caused by change in a gene called TGM1, which produces a protein called transglutaminase 1. Transglutaminase 1 is critical in making the skin barrier.
Many people with ARCI have been treated with targeted biologic medications, such as dupilumab, secukinumab, and ustekinumab, that treat eczema or psoriasis. These agents are very specific in their targeting of inflammation – and they have not worked for those with ARCI due to gene changes in TGM1 (often called lamellar ichthyosis). The inflammatory pathways that these medications target require activating Janus kinase (JAK), suggesting that inhibiting JAKs might offer a new treatment approach.
The patient was prescribed a JAK inhibitor called tofacitinib (11 mg daily) for 26 weeks. Within the first month, his skin showed significant improvements, including reduced skin redness, cracking, and itching. His overall quality of life improved. His skin water loss rate decreased at 10 weeks but increased again in the weeks that followed.
This study suggests that oral tofacitinib could be a promising treatment option for patients with ARCI, but it should be noted that: i) this is a single case report and failures of use of a JAK inhibitor are not typically reported; ii) this is a costly medication that is not approved for ARCI; and iii) this group of medications – and particularly tofacitinib – has a boxed warning from the Food and Drug Administration because of severe possible side effects that include malignancy, infections, clots, and cardiovascular disease. Nevertheless, newer JAK inhibitors are available that have not shown these issues to date, suggesting the possibility that they could be trialed in the future.
Accumulation of ether phospholipids in induced pluripotent stem cells and oligodendrocyte-lineage cells established from patients with Sjogren-Larsson syndrome.
Katie Hummel, predoctoral fellow at Northwestern University
Reference: Yamaguchi Y; Okuno H; Tokuoka S; Kita Y; Sanosaka T; Kohyama J; Kurosawa
K; Sakai N; Miya F; Takahashi T; Kosaki K; Okano H
Congenital Anomalies. 65(1):e12587, 2025 Jan-Dec.
Review: Sjogren-Larsson Syndrome (SLS) is a rare genetic condition that leads to dry, scaly skin and neurologic issues. It is caused by changes in a gene called ALDH3A2, which is responsible for producing an enzyme called fatty aldehyde dehydrogenase (FALDH). This enzyme helps to break down certain fats in the body. When this enzyme does not work properly, these fats can build up, causing these health problems.
Not much is known about how fat metabolism works in SLS, but previous research on a deceased 65-year-old patient showed an unusual buildup of certain fats in the brain. To learn more, researchers created a disease model using nerve cells taken from two patients with SLS. From these cells, the scientists made “stem cells” by treating the cells with chemicals that made them able to become any cell type in the body.
The study found that these stem cells from both of the patients with SLS had almost no activity for the involved enzyme, FALDH. When the scientists looked at the fats in brain-like cells derived from the stem cells, they found the same type of fat buildup seen in the brain of the deceased patient. This suggests that the stem cell model can be used to better understand how SLS affects the brain and could be helpful for future research examining if a new treatment could help with the neurologic issues.
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