Lamellar Ichthyosis · What It Is, Causes, Signs and Symptoms, Treatment, and More

Lamellar ichthyosis is most commonly caused by a mutation in the TGM1 gene, although other implicated genes have also been identified (e.g., NIPAL4, CYP4F22, ALOX12B). The TGM1 gene normally encodes for an enzyme called transglutaminase-1, which facilitates the crosslinking of each outermost skin layer (i.e., stratum corneum) cell, thereby strengthening its structural integrity. It also plays a role in cornification, which is the process in which living skin cells transform into dead, flattened skin cells. Dysfunction or deficiency of transglutaminase-1 results in impaired cornification, leading to an abnormal layer of cross-linked skin cells in the stratum corneum.  

Additionally, these skin cells are unable to shed properly, thereby leaving an abnormal accumulation of dead skin cells (e.g., scale formation). Finally, since the skin’s structural integrity is compromised, there is increased moisture loss, resulting in dry, flakey skin. Lamellar ichthyosis is inherited in an autosomal recessive manner, meaning that two copies of the mutated gene, one from each parent, are required to cause disease.

Diagnosis of lamellar ichthyosis begins with a thorough review of symptoms and medical history. In neonates, the presence of a collodion membrane, with eyes or lips turned outward, may raise suspicion for an underlying genetic skin disorder such as lamellar ichthyosis. A comprehensive skin evaluation may reveal hallmark signs of large, dark scales and dry skin. If there is eye involvement, an ophthalmologic exam can identify associated symptoms, such as dry eyes, using a slit lamp exam (i.e., a specialized microscope that allows for detailed ophthalmologic evaluation).  

The diagnosis is confirmed through genetic testing where an individual’s DNA is analyzed using a multigene panel targeting known-ichthyosis-related genes (e.g., TGM1), to identify the pathogenic variant and the specific subtype of ichthyosis. A skin biopsy, which is a procedure that removes cells from the surface of the body for histological analysis, may also reveal histologic shared features among ichthyoses including retained cell nuclei and hyperkeratosis (i.e., excessive skin thickening).  

There is currently no cure for lamellar ichthyosis, therefore treatment consists of a combination of non-pharmacologic and pharmacologic strategies aimed at improving the skin moisture barrier and the affected individual’s quality of life. Non-pharmacologic measures include the use of topical emollients and moisturizers to improve skin hydration and prevent the formation of scales. Regular bathing with mild, non-drying, or unscented cleansers or soaps is recommended. Warm water and gentle exfoliation can help remove some of the dead skin cells, but prolonged, high temperatures should be avoided to prevent excessive drying of the skin.  

Pharmacologic options include topical keratolytic agents (e.g., alpha-hydroxy acids, urea-containing topical agents), which facilitate skin cell turnover. Additionally, topical (e.g., tretinoin, adapalene) and systemic retinoids (e.g., isotretinoin) are vitamin A derivatives that can be used to help improve and regulate skin cell turnover. Multidisciplinary management with a team of specialists can help ensure comprehensive care, especially if there are several organ systems involved. For associated symptoms such as dry eyes, artificial tears can be used to provide additional lubrication. In newborns, fluid and nutrition supplementation and infection prevention (e.g., avoiding sick contacts, hand washing) are important considerations given their impaired epidermal barrier and increased metabolic demand. Genetic counseling is often recommended for affected individuals and family members as it provides further information surrounding the disease process.