Date: 10/26/2020

FIRST Quarterly Literature Review

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.

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