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Filaggrin

Authors: Bre Ana M. David, M.D., Mark R. Wick, M.D.

Last author update: 1 March 2018

Last staff update: 25 August 2023

Copyright: 2018-2024, PathologyOutlines.com, Inc.

PubMed Search: Filaggrin stain

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Table of Contents

Cite this page: David B. Filaggrin. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsfilaggrin.html. Accessed November 27th, 2024.

Definition / general

Filament aggregating protein (filaggrin)
Histidine rich and insoluble with a molecular mass of 35 - 37 kDa
Posttranslationally hydrolyzed from larger profilaggrin precursor protein during keratinocytic terminal differentiation of the epidermis (J Invest Dermatol 2012;132:751)
Profilaggrin is encoded by the FLG gene, which is within the S100 fused type protein (SFTP) family in the epidermal differentiation complex on chromosome 1q21; profilaggrin is a major constituent of the keratohyalin granules of the stratum granulosum (J Cell Sci 2009;122:1285, Biochem Biophys Res Commun 2014;449:100)
Together with keratin, filaggrin comprises approximately 80 - 90% of epidermal proteins ( Calonje: McKee's Pathology of the Skin, 4th Edition, 2011)

Terminology

Abnormalities in filaggrin production are associated with three skin diseases: atopic dermatitis, ichthyosis vulgaris and psoriasis vulgaris ( Calonje: McKee's Pathology of the Skin, 4th Edition, 2011);
- Individuals with truncation mutations in the gene coding for filaggrin have a predilection to develop one of those conditions
- Roughly 50% of all severe cases of atopic dermatitis are associated with at least one mutated filaggrin gene
- Atopic dermatitis: severe (usually inherited) form of eczema; the exact pathophysiologic mechanism in poorly understood but is believed to be multi-factorial (environmental, hormonal, reduced skin barrier function, etc.)
- Ichthyosis vulgaris: an autosomal dominant disease associated with the mutation of the profilaggrin gene;
  - Clinically characterized as slight to moderate fine scaling varying in quality
  - Histologically characterized as mild to moderate orthohyperkeratosis with a hyperplastic, atrophic or normal epidermis and a thin / absent granular cell layer
- Psoriasis vulgaris: probably autoimmune disorder characterized by hyperproliferation of the epidermis with a relative lack of keratinocyte maturation
  - Histologically features acanthosis, partial or complete loss of the stratum granulosum, parakeratosis and hyperkeratosis, suprapapillary thinning of the epidermis and neutrophils in the upper stratum spinosum and stratum corneum

ICD coding

ICD-10:
- L20.84 - intrinsic (allergic) eczema
- Q80.0 - ichthyosis vulgaris
- L40.0 - psoriasis vulgaris

Epidemiology

Ichthyosis vulgaris
- Truncation mutations R501X and 2284del4 are common in Caucasian individuals; 7 - 10% of them have at least one copy of those aberrations
- Abnormalities in R501X and 2284del4 are generally absent in non-Caucasian individuals; restricted mutations (3321delA and S2554X) have been seen in Japanese persons (J Invest Dermatol 2008;128:1436)
- United States
  - Hereditary ichthyosis vulgaris is relatively common in the U.S., with a prevalence of ~1 in 300 persons; acquired ichthyosis is very rare and its prevalence in the U.S. is unknown
- International
  - Hereditary ichthyosis vulgaris is encountered internationally;
    - Study in England showed a frequency of 1 in 250 children
    - Acquired ichthyosis is rare worldwide and its prevalence is unknown
Atopic dermatitis (atopic eczema) and psoriasis
- Density of intra-epidermal filaggrin is decreased in both atopic dermatitis (AD) and psoriasis variants (PV); however, the aforementioned mutations in the filaggrin gene have not been identified consistently in patients with either of those diseases
- Mechanisms for alterations in filaggrin synthesis are currently unknown for AD and PV (Australas J Dermatol 1998;39:225)
- AD is seen in 15 to 20% of children and 1 to 3% of adults internationally; Between 0.3 and 2.5% of all persons have PV, according to cross sectional sections done in several countries ( Am J Manag Care 2017;23:S115)

Sites

Skin, other anatomic locations containing squamous epithelium

Pathophysiology

Essential for the proper formation of the stratum corneum for barrier formation and to reduce moisture loss (xerosis)
Functions via promoting the aggregation and disulfide bond formation of epithelial keratin intermediate filaments
Demonstrates monomeric incorporation into the lipid envelope of the stratum corneum
Also undergoes proteolysis to provide free hygroscopic acid (urocanic acid and pyrrolidone carboxylic acid) release into the stratum corneum, which aids in water retention in the natural moisturizing factor of the skin (J Cell Sci 2009;122:1285)
Loss of filaggrin or profilaggrin leads to dysfunction in formation of the stratum corneum and is the cause of ichthyosis vulgaris - the most common disorder of keratinization (PLoS One 2009;4:e5227)
Mutations are also seen in atopic dermatitis; studies have suggested that the resulting disruption in skin barrier function increases the percutaneous transfer of allergens, which may trigger an exaggerated immune response (Prz Gastroenterol 2014;9:200, J Allergy Clin Immunol 2012;129:1031)
Loss of function mutations have been postulated to increase individual susceptibility to develop skin malignancies because of decreased levels of filaggrin degradation products such as urocanic acid, which protect against damage from ultraviolet irradiation (J Eur Acad Dermatol Venereol 2018;32:242)
Although psoriasis variants (PV) definitely show a genetic (familial) association, no consistently identified abnormal gene complexes have been identified in patients with those conditions
PV does have an association with the histocompatibility antigens HLA-Cw6 and HLA-DR7 (J Invest Dermatol 2007;127:1367)

Microscopic (histologic) images

Contributed by Mark Wick, M.D.

Filaggrin

Positive staining - normal

Present in the cytoplasm of keratinocytes
Active filaggrin synthesis is present at the level of the epidermis where keratinocytes are transitioning between the nucleated granular layer and the anucleate cornified layer
Potentially seen in normal squamous mucosa

Positive staining - disease

Potentially seen in squamous cell neoplasms of the skin and other organs that contain squamous epithelium and in locations where squamous metaplasia may occur
Abnormalities in the scope and distribution of filaggrin immunoreactivity have been seen in squamous dysplasia of the uterine cervix
Interestingly, there is no difference in the filaggrin immunoreactivity of skin from patients with atopic dermatitis and skin from normal individuals

Negative staining

Normal urothelium, normal cuboidal and columnar epithelium, tumors lacking squamous differentiation

Board review style question #1

Which is one of the many essential functions of the filaggrin protein?

Association with nectin and calcium to protect against mechanical stress
Disulfide bond formation of intermediate filaments for epidermal stabilization
Regulation of cellular migration and trafficking
Storage and release of apocrine secretions

Board review style answer #1

B. Disulfide bond formation of intermediate filaments for epidermal stabilization. Answer A describes Loricrin, a terminally differentiating structural protein (J Oral Maxillofac Pathol 2015;19:64). Answer C describes GGA3 (Traffic 2016;17:670) and perhaps other proteins.

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Reference: Filaggrin

Board review style question #2

Ichthyosis vulgaris is a disorder of keratinization which is associated with profilaggrin gene truncation. Histologically, this lesion is characterized by the presence of:

Acute inflammatory infiltrate present in the upper stratum spinosum
Mild acanthosis with papillomatosis, psoriasiform hyperplasia and prominent rete ridges
Orthohyperkeratosis with diminished / absent stratum granulosum
Spongiosis with vesiculation, superficial perivascular lymphocytic infiltrate with eosinophils

Board review style answer #2

C. Orthohyperkeratosis with diminished/absent stratum granulosum

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Reference: Filaggrin

Board review style question #3

Which statement regarding filaggrin is true?

It is produced in the dermis and released in the stratum basale
Loss of function mutations are not associated with an increased risk of cutaneous malignancy
Together with keratin, it comprises 80 - 90% of epidermal proteins

Board review style answer #3

C. Together with keratin, it comprises 80 - 90% of epidermal proteins

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