Stains
Filaggrin



Senior Author: Mark R. Wick, M.D.

Topic Completed: 1 March 2018

Revised: 5 March 2019

Copyright: 2018, PathologyOutlines.com, Inc.

PubMed Search: Filaggrin stain
Page views in 2018: 160
Page views in 2019 to date: 54
Cite this page: David B. Filaggrin. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/stainsfilaggrin.html. Accessed March 22nd, 2019.
Definition / general
Essential features
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
  • 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

Images hosted on PathOut server:

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 question #1
Which is one of the many essential functions of the filaggrin protein?

  1. Association with nectin and calcium to protect against mechanical stress
  2. Disulfide bond formation of intermediate filaments for epidermal stabilization
  3. Regulation of cellular migration and trafficking
  4. Storage and release of apocrine secretions
Board review 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.
Board review 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:

  1. Acute inflammatory infiltrate present in the upper stratum spinosum
  2. Mild acanthosis with papillomatosis, psoriasiform hyperplasia and prominent rete ridges
  3. Orthohyperkeratosis with diminished / absent stratum granulosum
  4. Spongiosis with vesiculation, superficial perivascular lymphocytic infiltrate with eosinophils
Board review answer #2
C. Orthohyperkeratosis with diminished/absent stratum granulosum
Board review question #3
Which statement regarding filaggrin is true?

  1. It is produced in the dermis and released in the stratum basale
  2. Loss of function mutations are not associated with an increased risk of cutaneous malignancy
  3. Together with keratin, it comprises 80 - 90% of epidermal proteins
Board review answer #3
C. Together with keratin, it comprises 80-90% of epidermal proteins
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