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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.

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