Literature Review - October 2020

Mary Sun, BS

Keith Choate, MD, PhD

Yale School of Medicine, New Haven, CT


Title: 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.

Title: 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.

Title: 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



Title: 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.

Title: 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.

Title: 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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