Literature Review - October 2025

Researchers Propose New Names, Advance Understanding of Risks

                                     Amy Paller, MD  &  Riddhi Patel
Northwestern University FIRST MSAB Chair & Predoctoral Fellow at Northwestern University

A proposal for a new pathogenesis-guided classification for inherited epidermal differentiation disorders

Reference:  Hernández-Martín Á, Paller AS, Sprecher E, et al. Br J Dermatol. Published online March 28, 2025. doi:10.1093/bjd/ljaf065

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 Historically, these conditions also used names based on what the skin looked like, which led to confusing or outdated terms.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

Some of the new names are shorter (like FLG-nEDD, formerly ichthyosis vulgaris), while other names will be longer or harder to remember. Other ones that affect many in FIRST with their new names are: STS-sEDD (X-linked ichthyosis); TGM1-nEDD (most with lamellar ichthyosis); ALOX12B-nEDD (most common form of CIE); ABCA12-nEDD (harlequin ichthyosis); KRT9-pEDD (epidermolytic palmoplantar keratoderma).

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.

Reference:  Rustad AM, Soltani H, Yang LJ, …Paller AS. Pediatr Dermatol. 2025;42(3):499-505. doi:10.1111/pde.15920
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.

Literature Review - April 2023

Safety, tolerability, and efficacy of a novel topical isotretinoin formulation for the treatment of X-linked or lamellar congenital ichthyosis: Results from a phase 2a proof-of-concept study

Paller AS, Browning J, Parish LC, Bunick CG, Rome Z, Bhatia N., J Am Acad Dermatol. 2022;87(5):1189-1191. doi:10.1016/j.jaad.2022.02.060

Review: Oral retinoids have more risk for adverse side effects than topical retinoids due to systemic absorption. This study tested the tolerability, safety and efficacy of topical isotretinoin in patients with lamellar or X-linked recessive ichthyosis. Isotretinoin has been available as an oral medication for many years. A topical formulation is not available for patients at this time.

In the first 8 weeks of the study, patients applied either a low (0.1%) or high (0.2%) concentration of the medication to one area of skin, and ointment without the medication to another similar area of the skin. In the last 4 weeks, both areas of the skin received medication. Patients did not demonstrate abnormalities of routine lab tests or evidence of absorption of isotretinoin. Skin side effects included irritation and itching, which was rated mild to moderate in most cases. At the end of the study, more patients using the 0.1% concentration than the 0.2% concentration had improvement of scaling.

Summary: This study of topical isotretinoin ointment provides preliminary evidence suggesting this medication can reduce scaling for patients with lamellar and X-linked ichthyosis, although skin irritation may limit use. Additional studies in a larger group of patients are needed.

Literature Review – October 2022

John Browning, MD

Secukinumab significantly reduces inflammation but only mildly improves scaling in four cases of Autosomal Recessive Congenital Ichthyosis.

Journal: Clinical and Experimental Dermatology

Publication Type and Date: Case Series. 2022 Aug 12. doi: 10.1111/ced.15373. Online ahead of print.

Reference: Subramani D, Sardana G, Kothari R, Gupta A.

Review: Autosomal recessive congenital ichthyosis parentheses (ARCI), consisting of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI), harlequin ichthyosis, and pleomorphic ichthyosis, is difficult to manage. In this article the authors share about their experience using secukinumab and treating three patients with ARCI. They were inspired to do this because of recent reports demonstrating elevation of IL-17 related cytokines in individuals with ARCI and reports of successful use of used to secukinumab in patients with CIE and Netherton syndrome. Secukinumab is a biologic that inhibits IL-17 and is FDA-approved as a treatment for psoriasis. The authors found that two siblings with CIE demonstrated dramatic improvement with secukinumab whereas the patient with LI only observed a modest improvement in scaling. They hypothesize that the improved results with the CIE patients are due to the presence of greater inflammation and elevated cytokine levels in CIE compared with LI.

Summary: Off-label use of secukinumab may be beneficial in treating CIE. More research is needed to evaluate optimal dosing, safety monitoring, and use in other forms of ichthyosis.

Management of Harlequin Ichthyosis: A Brief Review of the Recent Literature.

Journal: Children (Basel).

Publication Type and Date: Review. 2022 Jun 15;9(6):893

Reference: Tsivilika M, Kavvadas D, Karachrysafi S, Sioga A, Papamitsou T.

Review: Harlequin ichthyosis (HI) is a severe and extremely rare form of congenital ichthyosis. HI occurs mostly from mutations in the ABCA12 gene. There are three distinct types of HI, based mostly on skin abnormalities. Lipid dysregulation and severe desquamation lead to skin fractures and fissures due to significant lack of connective substance.

Admission to a NICU for newborns with HI is highly recommended as mortality is high, with average survival rate being 55%. HI’s highest mortality rates were reported in the first three months of life due to respiratory failure or sepsis in 75% of cases. Affected neonates should be maintained in an incubator with additional humidity and constant monitoring of the kidneys and liver. Electrolytes, daily weight, and urine output should be monitored regularly. It is also crucial to prevent infection during this period.

Necrosis of neonatal digits is common and the application of a topical retinoid such as tazarotene cream 0.1% can help in prevention. If joint constriction or eclabium interferes with normal oral feeding then a nasogastric or oropharyngeal tube maybe placed for feeding. Once sucking and swallowing functions return then normal feeding can be resumed. Vitamin D levels should be monitored and possible supplementation may be necessary for management.

Ophthalmic ointment should be applied around the eyelid margin. Although surgical intervention has been reported for ectropion in the infantile period, there is no evidence that early surgery decreases the possibility for ectropion later in life. Systemic retinoid use is somewhat controversial and should only be considered under close guidance. Surgery can be difficult in this population due to vascular access and airway security issues. Surgical release of limb contraction may be necessary, especially in cases of compartment syndrome.

Parent cooperation is critical so as to avoid serious predicaments.

Summary: It is important for neonates with HI to be treated by physicians aware of the guidelines in managing the various and numerous issues that arise early in life so as to avoid further complications. Management requires a multidisciplinary team of experts in order to minimize risks and promote healthy outcomes.

Distinct skin microbiome community structures in congenital ichthyosis.

Journal: British Journal of Dermatology

Publication Type and Date: Original Investigation, 2022 May.

Reference: Tham KC, Lefferdink R, Duan K, Lim SS, Wong XFCC, Ibler E, Wu B, Abu-Zayed H, Rangel SM, Del Duca E, Chowdhury M, Chima M, Kim HJ, Lee B, Guttman-Yassky E, Paller AS, Common JEA.

Review: Although most forms of ichthyosis share a Th 17 cell immune signature, it is unknown and little research has been done in exploring the microbiota of ichthyosis. In this study, the authors analyzed the skin microbiome of participants with loss-of-function mutations in ALOX12B (CIE), CYP4F22 (CIE), NIPAL4 (CIE), PNPLA1 (CIE), TGM1 (LI), KRT10 (EI), and SPINK5 (NS). It was found that a dysbiosis of the skin microbiome occurred in all of these conditions, with higher abundance of staphylococci and corynebacterium, but lower abundance of C.. acnes. Microbiome analysis also showed increased abundance of M. sloofiae and Trichophyton species, implicating fungal species as part of the dysbiosis. The authors speculate that in the future biotherapeutics could play a part of the treatment strategy for ichthyosis.

Summary: The microbiome of ichthyosis skin is different from non-ichthyosis skin It is important to be aware of some of the specific differences so that anticipation of potential infections can be achieved. Use of topical probiotics might play a role in mitigating microbiome dysbiosis in the future.

Literature Review - August 2022

Robert A. Silverman, MD

“Big Data” Exposes Issues Linked to X-linked Ichthyosis

 Reference: Brcic L, Wren GH, Underwood, FG, et al: Comorbid medical issues in X-linked ichthyosis. JID innovations 2022;2:100109

Review: X-linked ichthyosis occurs primarily in males, although mothers of these boys who carry the abnormal gene deletion on the X (female) chromosome can also show signs and symptoms of dry skin and more. The gene codes for a protein enzyme, steroid sulfatase (STS), that is important for skin integrity and many other important functions of other organs in the body. “Comorbidity” is the word that describes these other medical issues.

Different deletions in the same STS gene can cause different associated comorbidities. Boys may be born with undescended testicles, asymptomatic eye issues called corneal opacities, and neurodevelopmental or mood disorders. Young pregnant women who carry abnormalities in some of their genes have lower placental estrogen hormone that can result in longer gestations beyond term and delayed or prolonged labor. They also have milder dry skin and milder mood disorders.

Ichthyosis investigators in England analyzed a large United Kingdom databank containing medical information on over 500,000 middle-aged individuals from the general population. They uncovered new associated medical conditions in small numbers of affected adults that include heart problems, increased bleeding disorders such as nose bleeds, and placental hematomas in pregnant women. They also discovered an increased risk of palmar fascial fibromatosis also known as Dupuytren contracture. Exactly how the abnormal STS gene is related to these observations is not completely understood.

Patients with X-linked ichthyosis should know about newly discovered comorbidities and inform their primary care physician to be on the lookout for them.

Don’t Forget Your Vitamin D

Reference: Bakshi S, Mahajan R, Karim A, et al: Oral vitamin D versus acitretin in congenital non-syndromic ichthyosis: double blinded, randomized controlled trial. 

Review: Vitamin D is very important for day-to-day maintenance of your skin. It regulates cellular proliferation, differentiation, barrier function and immune function – all processes that are affected in patients with most, if not all, forms of ichthyosis. Because there is such a rapid production or turnover of skin cells in ichthyosis, it should not be surprising that vitamin D levels are frequently reduced.

There has been an interest in studying the role of vitamin D in ichthyosis for many years. Researchers performed a controlled, evidence-based evaluation of vitamin D administration in presumably non-vitamin D deficient children with ichthyosis and compared their findings to a similar group of children who were given acitretin, a retinoid that has been used for years for treating ichthyosis. They measured their results with several important validated scales, Visual Index for Ichthyosis Severity (VIIS), the Ichthyosis Area Severity Index (IASI) and the Ichthyosis Quality of Life Indes-32 (IQoL-32). They also measured the effects of vitamin D on important cellular pathways in the laboratory and looked for adverse events in the trials.

Subjects that were vitamin D deficient before the study were “normalized” with 60,000 IU vit D given eight weeks before the study began. For the 24-week study, subjects were given either vit D (2,000 iu/day) and an acitretin placebo or low-dose acitretin (.5mg/kg/day) and a vit D placebo.

While both groups improved in clinical parameters, there were no statistically significant differences in improvement between the vit D group when compared to the acitretin group. No serious adverse events occurred in any subject. In the lab, mRNA expression for IL-17 and the retinoid receptor gamma were both significantly reduced. The authors suggested that vitamin D and acitretin both work by the same mechanisms.  They interpret these results as vitamin D is as good as acitretin for patients with ichthyosis.

Careful analysis of the study methods could uncover biases that led to these conclusions. Even though the results were mixed, vitamin D is very important and one should consider supplementation for all forms of “red” ichthyosis to keep levels in the normal range.

Interviews Assess Weight of Ichthyosis Caregiving

Reference: Daae E, Feragen KB, Sitek JC, von der Lippe C:  It’s more than just lubrication of the skin: parents’ experiences of caring for a child with ichthyosis.  Health Psychol and Behav Med 2022;10:335-356.

Review: Researchers from Norway have highlighted and confirmed the troubles, challenges and devastating effects that having a child with ichthyosis has on one’s personal and family life. They sought to understand from the parents perspective, the issues that parents confront on a daily basis in order to provide information that would provide other clinicians and researchers, data to help parents manage stress and lead to better health outcomes for their children with ichthyosis. 

The authors used semi-structured interviews, predetermined open-ended questions, and participant-led explorations to gather their findings. Participants in the study came from the Norweigan national database of rare disorders and included parents of children and adults with ichthyosis. There were a total of 19 parents and 19 children who participated in the study (48% of parents and 11% of adults in the total population of the patients with ichthyosis in the rare disease database.  Interviews were by telephone which may have hampered the effects of nonverbal and visual cues on data collection but may have improved honest collection because of the sense of anonymity this technique provided.

Results were not surprising. There were four main themes: The reactions of new parents and others to the differences in their child’s skin; experiences with health-care services; the difficulties of skin care; and, the impact on relationships. Parents of newborns felt afraid, alone, helpless and in denial. The lack of knowledge of health-care professionals, the lack of guidance and poor communication only served to magnify these distressing feelings. Touching, itching, pain, financial and time burdens were universally mentioned. Overwhelming emotions frequently resulted in poor communication about their worries in even every-day situations.

I recommend that this article be made available to all parents with a child who has ichthyosis and should be provided to, and read by, all of their health care providers to enhance their understanding of the effects of this condition.

Literature Review - January 2022

Leslie Potter Lawley, MD

Kerrie Satcher, MD
 

Prenatal diagnosis of a rare variant of harlequin ichthyosis with literature review

Journal: BMC Medical Imaging

Publication Type and Date: Case report and review of the literature, March 2021

Reference: Zhou Y, Liang L, Wang L, Zhang.

Review:

Harlequin ichthyosis (HI) is a rare ichthyosis that presents as large, plate-like scales covering the whole body, along with turned out lips (eclabium), turned out eyelids (ectropion) and flattened ears. There is rarely effective treatment for HI and mortality of affected patients is high. The authors report two cases of HI diagnosed with ultrasound during the third trimester. In case one, a 31-week ultrasound revealed thickening of the skin, ectropion, short nose bone, flat nose, open mouth and persistent flexion of the fingers and toes. In case two, a 30-week ultrasound, performed because of decreased fetal movements, showed similar findings.

The authors of this article reviewed the published literature over the past 20 years and found 10 cases of HI diagnosed through ultrasound. Three were identified during the second trimester and seven during the third trimester. Both 2D and 3D ultrasound used together best identify the features of HI. The characteristic features of HI on ultrasound will be apparent later in pregnancy and many pregnant women do not have an ultrasound during this latter part of gestation, when these features are evident.

Summary:

Fetal characteristics of HI appreciated on ultrasound include ectropion, abnormal double auricles, flattened nasal ridge, persistent open mouth, limb contractures and decreased movement. Additionally, the authors comment that particles floating in the amniotic fluid can be seen. Both 2D and 3D ultrasound performed together later in pregnancy are most likely to identify these features.

Collodion babies: A 15-year retrospective multicenter study in The Netherlands- Evaluation of severity scores to predict the underlying disease.

Journal: Journal of the American Academy of Dermatology

Publication Type and Date: Research letter, April 2021

Reference: Cuperus E, Bolling M, Graaf M, et al.

Review:

Collodion baby can be the initial presentation in many different types of ichthyoses. A previous study by Rubio-Gomez et al proposed a clinical scoring system based on 15 characteristics of collodion. This previous study suggested extensive collodion was more associated with non-syndromic ichthyosis. The four major forms of non-syndromic ichthyosis include ichthyosis vulgaris, recessive X-linked ichthyosis, kertinopathic ichthyosis and autosomal recessive congenital ichthyosis.

The authors used the same collodion severity scoring system to evaluate 23 babies at three academic sites in the Netherlands. Genetic studies were completed on all babies and they were grouped into non-syndromic ichthyosis, syndromic ichthyosis, and self-healing collodion baby/unspecified congenital ichthyosis. The authors found no significant difference in the scores of the syndromic and non-syndromic ichthyosis groups. Although, the authors did find a trend toward lower severity scores in the syndromic ichthyosis group.

Summary:

A scoring system has been proposed as a way to measure severity of collodion and predict the underlying ichthyosis type. This scoring system has not been proven to reliably predict type of ichthyosis, although, lower scores have been seen in syndromic ichthyosis and higher scores in non-syndromic ichthyosis. It is possible that the small number of study patients contributed to the inability to assess the validity of the scoring system.

The Genomic and Phenotypic Landscape of Ichthyosis: An Analysis of 1000 Kindreds.

Journal: Journal of the American Medical Association Dermatology

Publication Type and Date:  Original investigation, December 2021

Reference: Sun Q, Burgren N, Cheraghlou S, et al.

Review:

Over a 10 year period, the authors recruited  1000 patients from all over the world with ichthyosis to be a part of the study. Patients completed a questionnaire, genetic testing on blood or saliva, and standardized clinical photographs. Pathogenic variants of genetic material were identified in 869 participants. The authors identified 266 unique disease associated variants in 32 genes.

35% of patients with a genetic diagnosis completed the questionnaire. Itching, decreased sweating, skin pain, eye problems, skin odor and infections were the most commonly reported features.

• Collodion membrane at birth, skin odor, hearing problems, eye problems and alopecia were associated with patients who had TGM1 variant.
• Collodion membrane at birth was associated with patients who had ALOX12B variant.
• Skin pain, skin odor and skin infections were associated with patients who had KRT10 variant.
• Collodion membrane at birth and skin odor were associated with patients who had FLG variant.
• Collodion membrane at birth, skin pain, skin odor, skin infections, and hypohidrosis were associated with patients with STS variant.

Summary:

This study helps us expand the genetic causes of ichthyosis, along with the clinical features of different types of ichthyoses. The authors report specific clinical features of ichthyosis which are significantly associated with particular genetic causes. This can help doctors with diagnosis, and guide treatment plans for patients moving forward.

Literature Review - June 2021

Dr. Erin Mathes

Dr. Mitchell Braun

Inherited ichthyosis and fungal infection: an update on pathogenesis and treatment strategies

Journal: Journal of the German Society of Dermatology

Publication Type and Date: Systematic review article, March 2021.

Reference: Miao H, Dong R, Zhang S, et al. Inherited ichthyosis and fungal infection: an update on pathogenesis and treatment strategies. J Dtsch Dermatol Ges. 2021.

Review:

People with ichthyosis may have a higher risk of developing skin fungal infections compared to the general population. Authors of this article reviewed cases of fungal infections in ichthyosis over the past 50 years to summarize the causes, signs and symptoms, diagnosis, and treatments. The increased risk of fungal infections in ichthyosis is likely multifactorial. In ichthyosis mutated proteins alter the skin’s “barrier function”, decreasing its ability to keep out organisms like bacteria and fungi. At the same time, in some forms of ichthyosis, such as KID (keratitis, ichthyosis, and deafness), cells that fight infection in the skin are missing or dysfunctional. Lastly, abnormal keratin production and impaired skin cell turnover in ichthyosis may also create a unique environment in which some fungi thrive.

It can be difficult to identify skin fungal infections in people with ichthyosis due to dry or scaling skin, itchiness, or redness at baseline. Importantly, fungal infections tend to present with new alopecia (hair loss), papules (bumps), pustules (bumps with pus), or worsening of scaling especially in warmer summer months. Both ichthyosis and fungus can also lead to yellow, thick and brittle nails. In cases of fungal infection, these changes tend to be new and affect fewer nails, sometimes only one. Treatment options include both topical and oral antifungal medications. In some people with ichthyosis, infections may be severe or recurrent, and a combination of topical and oral medications are preferred.

Summary:

People with ichthyosis have more fungal skin infections than the general population and diagnosis can be difficult. Fungal infections should be considered in new or worsening hair loss, bumps, pustules, worsening scale, or changes to nails. If any of these symptoms arise, people with ichthyosis should discuss them with their primary care doctor or dermatologist.

Use of telemedicine for ichthyosis: patient advocacy group as conduit to expert physician advice

Journal: Pediatric Dermatology

Publication Type and Date: Retrospective cohort study, January 2021.

Reference: Asch S, Swink SM, Vivar KL, et al. Use of telemedicine for ichthyosis: Patient advocacy group as conduit to expert physician advice. Pediatr Dermatol. 2021.

Review:

The FIRST Tele-Ichthyosis program began in 2009 and allows for physicians around the world to refer cases of known or possible keratinizing disorders to a group of peer and patient-selected volunteer ichthyosis experts. The goal is to increase access to care for patients who may struggle to find local expertise of these rare conditions. The authors reviewed the strengths, limitations, and use of this program over the past decade. The expert panel reviewed a total of 88 cases since the program’s inception from the United States, Canada, the Caribbean, South America, Europe, Africa, Asia, and the Middle East. The number of cases has increased over the years since inception. The submitting physicians requested insight into treatment, diagnosis, and genetic testing information. The volunteer panel diagnosed ichthyosis in 66% of cases that were reviewed. About 2/3 of submitting physicians described the service as easy to use and reported timely, clear, and beneficial advice. A re-design is underway to maximize the usability of the site. Expert advice obtained through the Tele-Ichthyosis program aided longitudinal care, as submitting providers shared advice during transitions of care to clinicians and caregivers.

Summary:

Some people with ichthyosis do not have local access to expert opinion. The FIRST Tele-Ichthyosis program provides these patients and their local providers with insights from a panel of ichthyosis experts. This program will continue providing advice on diagnosis, treatment, and other aspects of keratinizing disorders and serves as an example of how telemedicine can benefit treatment and care across the world for rare diseases.

Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents

Journal: Pediatric Dermatology

Publication Type and Date: Consensus recommendations, January 2021

Reference: Zaenglein AL, Levy ML, Stefanko NS, et al. Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents. Pediatr Dermatol. 2021.

Review:

Retinoids are vitamin A derivatives that work to reduce scaling and thickening of the skin in many ichthyoses and are essential to management. A group of expert physicians from the Pediatric Dermatology Research Alliance (PeDRA) convened to address the use of both topical and systemic retinoids in ichthyoses and other disorders of cornification. The impact of long-term retinoids on bone, eye, reproductive and psychiatric health were reviewed with the goal of creating recommendations for drug dosing and monitoring. Specific considerations and guidelines are outlined in the paper, and individuals taking systemic retinoids should work with a provider who is familiar with retinoids and disorders of cornification to minimize side effects.

Overall, the likelihood of side effects depends on many factors and tends to occur after long periods of use. The benefits of systemic retinoids in treating ichthyoses often outweigh the risks, and they should always be considered if topical therapies do not provide sufficient improvements, the burden of disease is high, or if there is a significant impact on quality of life. Proper monitoring while on systemic therapy will decrease the risk of unidentified side effects. Research will continue to improve our understanding of retinoids’ effects on the body. Updated consensus recommendations will follow as additional research is produced.

Summary:

Topical and systemic retinoids are recommended for the treatment of ichthyoses and other diseases of cornification. The benefits of systemic retinoids often outweigh the risks, and regular monitoring for side effects is an effective measure in preventing long term impacts of these medications.

Increased risk of depression and impairment in quality of life in patients with lamellar ichthyosis

Journal: Dermatologic Therapy

Publication Type and Date: Cross sectional; January 2021.

Reference: Cortés H, Rojas-Márquez M, Reyes-Hernández OD, et al. Increased risk of depression and impairment in quality of life in patients with lamellar ichthyosis. Dermatol Ther. 2021.

Review:

Lamellar icthyosis (LI) is one of the most severe clinical phenotypes of ichthyosis and is characterized by thick plate-like scales, itch, pain, alopecia (hair loss), and erythema (redness). This disease has been shown to negatively impact quality of life (QoL). In this study, the investigators identified 26 people with LI and 26 healthy controls from Mexico and used the Depression Beck Inventory II (DBI-II) and Dermatologic Life Quality Index (DLQI) to assess depression and impairment in QoL between the two groups. The Congenital Ichthyosis Severity Index (CISI) was used to determined severity of LI at the time of the surveys. There was a significant difference in DBI-II scores between people with LI and healthy volunteers, indicating higher levels of depression in people with LI. When factoring in the severity of LI using the CISI, there were no differences in levels of depression or impairments to QoL between mild or severe disease. Those with high levels of depression documented larger impairments in QoL. Although this study had a small number of patients, it highlights the impact that LI can have on mental health and to what extent it can impact quality of life, even in mild disease severity. It suggests the importance of mental healthcare in maximizing health and wellbeing in people with LI.

Summary:

LI is associated with higher rates of depression when compared to healthy controls and has a significant impact on quality of life regardless of disease severity. Mental healthcare is an important aspect of LI healthcare, and there should be regular discussions about mental health and wellbeing.

Literature Review - October 2020

Mary Sun, BS

Keith Choate, MD, PhD

Yale School of Medicine, New Haven, CT
 

Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis

Journal: American Journal of Human Genetics

Publication Type & Date: Original article, July 2, 2020

Reference: Boyden LM, Zhou J, Hu R et al. Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis. The American Journal of Human Genetics 2020; 107: 158-63.

Review: Lamellar ichthyosis featuring palmoplantar keratoderma (PPK) had exclusively been attributed to autosomal recessive mutations prior to this discovery.  Investigators sequenced the coding regions of all the genes in the genome to reveal that in four unrelated ichthyosis kindreds, ten subjects with ichthyosis and PPK had heterozygous, novel missense mutations in ASPRV1 causing autosomal dominant ichthyosis.  The mutations arose in utero in two individuals, and mutations in the other eight subjects were transmitted from one generation to the next, indicating that ASPRV1 mutations cause a dominantly inherited ichthyosis that was previously known to have recessive inheritance. ASPRV1 encodes skin aspartic protease, an enzyme that breaks down the filaggrin protein. Compared to age-matched controls, those with ASPRV1 mutations have excess unprocessed filaggrin protein and epidermal differentiation impairment resulting in thick scale and PPK. Given this desquamation defect, keratolytic agents can prove therapeutically beneficial, as two affected individuals who used keratolytics experienced complete resolution of non-palmoplantar scale.

Summary: ASPRV1 mutations cause dominantly-inherited lamellar ichthyosis with palmoplantar keratoderma, highlighting the importance of aspartic proteases (enzymes that break down filaggrin protein in the skin) in epidermal differentiation. This not only further elucidates the various causes of ichthyosis but also provides a potential target for future therapies.

3D Model of Harlequin Ichthyosis Reveals Inflammatory Therapeutic Targets

Journal: Journal of Clinical Investigation

Publication Type & Date: Original article, Aug 10, 2020

Reference: Enjalbert F, Dewan P, Caley MP et al. 3D model of harlequin ichthyosis reveals inflammatory therapeutic targets. The Journal of Clinical Investigation 2020; 130: 4798-810.

Review: Harlequin ichthyosis (HI) is a rare, severe ichthyosis with high rates of complications and death in the perinatal period.  It is caused by mutations in the gene ABCA12 which eliminate or severely reduce the function of its encoded protein. Skin inflammation is a well-known component of HI but few studies have investigated the inflammatory processes inherent in the disorder. The authors developed a 3D model of HI using CRISPR/Cas9 (a technique that edits the genome) to engineer an ABCA12 knockout cell line that closely mimicked the most severe HI phenotype. Using this model and HI skin samples, the authors discovered upregulation of cytokines in the IL-1 family and upregulation of the STAT1/NOS2 signaling pathway, which results in increased accumulation of inflammatory free radicals. Inhibition of NOS2, an enzyme with a central role in inflammatory processes, reversed the barrier defects seen in the HI model. These findings not only provide insight into the pathogenesis of HI but also reveal new therapeutic targets.

Summary: Upregulation of inflammation, in particular proinflammatory cytokines, STAT1 and NOS2 signaling drives HI redness.

Malnutrition in children with ichthyosis: recommendations for monitoring from a multidisciplinary clinic experience

Journal: JAAD

Publication Type & Date: Original article; June 2020

Reference: Rodríguez-Manchón S, Pedrón-Giner C, Cañedo-Villarroya E et al. Malnutrition in children with ichthyosis: recommendations for monitoring from a multidisciplinary clinic experience. Journal of the American Academy of Dermatology 2020.

Review: Growth failure (not meeting milestones for height and weight among other measures) is common among individuals with congenital ichthyosis but there is a paucity of data evaluating nutritional status in ichthyosis. The authors assessed 50 ichthyosis patients, majority of whom were male and under 18 years of age, in a prospective study at a hospital in Spain. Nearly one-third met WHO criteria for undernutrition. Growth impairment was found in 24% of children, especially those 5 years and younger. Ichthyosis severity positively correlated with rates of undernutrition, and nearly two-thirds of patients had micronutrient deficiencies, particularly deficits in iron, selenium, vitamin D and zinc. These results provide the rationale for early nutritional assessment and support in order to maximize growth potential.

Summary: Children, especially those who are younger and those with severe ichthyosis, are at risk of malnutrition and should have nutritional assessment at diagnosis and during follow-up.

Literature Review - June 2020

Edited by Emily Henkel, MD, MPH

Dell Medical School, Austin, TX

Secukinumab Therapy for Netherton Syndrome

Journal: JAMA Dermatology

Publication Type & Date: Case Series; May 2020
Reference: Luchsinger, Isabelle, et al. "Secukinumab Therapy for Netherton Syndrome." JAMA Dermatology.   PMID: 32459284    DOI: 10.1001/jamadermatol.2020.1019

Review: Previous research has demonstrated increased activity of the helper T cell 17/interleukin 23 pathway in patients with Netherton syndrome. When activated, these cells release IL-17, which stimulates skin cells (keratinocytes) to proliferate. A medication commonly used for psoriasis, secukinumab (Cosentyx®) is designed to stop this signal. This case series evaluated the efficacy of using secukinumab to treat four patients with Netherton syndrome. Significant improvement in ichthyosis area, severity, itch, and quality of life was seen in all patients by three months and was measured using established scales (Ichthyosis area and severity index, 5-D itch scale). The best results were seen in the two pediatric patients with the erythrodermic subtype. Three patients were followed for 6-12 months and all chose to remain on the medication. The only side effects experienced during this time were nail fungus infection and an itchy eczema reaction on the palms. This research shows promise that this medication may be beneficial to Netherton syndrome patients with severe erythema and itch and should be investigated further with more patients over a long period of time.

Summary: For patients with Netherton syndrome and severe itch and diffuse redness (erythroderma), a treatment option can be considered, as noted, in the summary above.

Ichthyosis affects mental health in adults and children: A cross-sectional study

Journal: JAAD

Publication Type & Date: Research Letter (in press); Jan 2020

Reference: Sun, Qisi, et al. "Ichthyosis affects mental health in adults and children: A cross-sectional study." Journal of the American Academy of Dermatology (2020).
PMID: 32006604 DOI: 10.1016/j.jaad.2020.01.052

Review: Patients with ichthyosis face daily challenges that may include discomfort, harassment, and difficulty engaging in work or leisure activities as a result of their disorder. This study surveyed 181 patients from the National Ichthyosis Registry to investigate the psychiatric impact of the disorder. The patients were surveyed using questionnaires (PHQ-9, GAD-7) commonly utilized to screen for anxiety, depression and quality of life in patients with other medical conditions. The results showed that among adults with ichthyosis, 34% screened positive for depression, 27% positive for anxiety, and 95% experienced impairment in their quality of life. The results were similar in the pediatric population with 30% positive for depression, 38% positive for anxiety, and 85% with quality of life impairment. Most participants surveyed had the autosomal recessive congenital ichthyosis (ARCI) subtype and the results did not differ significantly between those with severe versus those with moderate disease severity. These data highlight the need for physicians to screen ichthyosis patients in order to detect any psychologic sequelae and provide appropriate care.

Summary: As known by many patients and families impacted by any type of ichthyosis, the potential impact on personal interactions and behavioral differences cannot be overlooked.  While formal screening for, for instance, depression (as done in this study) can be considered, from a practical stance, such information should be sought from patients and/or family members when evaluating our patients.

Association of the Severity of Alopecia with the Severity of Ichthyosis

Journal: JAMA Dermatology

Publication Type & Date: Research Letter; Sept 2019

Reference: Putterman, Elana, et al. "Association of the Severity of Alopecia With the Severity of Ichthyosis." JAMA dermatology 155.9 (2019): 1077-1078.

PMID: 31365037 DOI: 10.1001/jamadermatol.2019.1520

Review: Hair loss (alopecia) is commonly reported in patients with ichthyosis, but not much is known about why this happens or if it is associated with a particular subtype or severity of ichthyosis. This small study was conducted with 86 patients from the National Registry for Ichthyosis and Related Skin Types to investigate if hair loss can be predicted based on disease severity or the genetics related to subtypes. In this study, two experts examined photographs of each patient without knowing their genetic subtype and scored the severity of hair loss and skin findings. The results showed that there was no significant relationship between the severity of skin findings and hair loss severity. However, when they separated the patients by genetic subtype, those with TGM1 and ABCA12 mutations appeared to have more severe hair loss in association with their greater skin disease severity. While previous research has shown the association of hair loss with TGM1 mutation, these results suggest that ABCA12 mutation may also be associated with hair loss in milder phenotypes in addition to the known association of severe hair loss in those with harlequin ichthyosis. Additionally, patients in these subtypes may suffer from more severe hair loss if they have severe skin symptoms than patients in these subtypes with more moderate skin findings.

Summary: While ichthyosis can, in some cases, be associated with hair loss or alopecia, there does seem to be relationship with more severe types of disease as noted by most physicians caring for these patients and by the patients, themselves.  The authors seem to confirm the relationship with certain genetic mutations which can be associated with more severe disease, overall, as well as in some of the milder clinical subtypes.