Absence of the granular layer and keratohyalin define a morphologically distinct subset of individuals with ichthyosis vulgaris

Abstract

The clinical diagnosis of ichthyosis vulgaris (IV) can be difficult. Abnormalities in the granular layer and the ultrastructure of keratohyalin granules (KHG) suggest that morphology may be helpful. To clarify morphologic findings in IV, 41 clinically affected individuals and 21 unaffected family members or age- and sex-matched controls were studied by light microscopy. In these, the granular layer was totally absent in approximately 50% of affected individuals, while present in all controls. Forty-seven individuals in the light microscopy group were also studied by electron microscopy. Keratohyalin granules were absent in all affected individuals lacking the granular layer by light microscopy. Clinical severity usually correlated with the lack of a granular layer and KHG. Absence of the granular layer was consistent in different anatomic sites and in serial biopsies taken over a 1-3-year period. In a subset of clinically affected, unrelated subjects with moderate to severe involvement, four out of 11 (36%) had similar findings. Keratinocytes cultured from affected individuals with no KHG expressed virtually no detectable profilaggrin protein in vitro. The data suggest that a subset of individuals with moderate to severe IV have a consistently absent granular layer and KHG. Absence of the granular layer and lack of KHG correlated almost perfectly; thus light microscopy offers a convenient means of identifying this subtype of IV. However, both morphologic types of IV were observed within single families. Therefore, the relationship between granular layer abnormalities and IV is complex and requires the study of more affected families. One interpretation of the data is that IV is a multigenic disorder in which one of the genes alters profilaggrin expression. We propose this clinical and histologic phenotype as useful for identifying the gene(s) involved and also for determining whether it represents a modifier or a major locus of the disorder.

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…7,8,11 Histopathology, immunochemistry, and other nongenetic analyses Routine histopathological findings in most ichthyoses are nondiagnostic, often demonstrating only epidermal hyperplasia and varying degrees of orthohyperkeratosis. In combination with characteristic features, routine histology can give an important clue for IV 213,214 or EI. 52,61,62,215,216 However, one should consider that a reduced or absent SG suggestive for IV can also be seen in acquired ichthyosis, NS, Refsum syndrome, TTDs, or Conradi-Hünermann-Happle syndrome.…”

Filaggrin in the frontline: role in skin barrier function and disease

“…Several strong lines of evidence had previously supported a causative role for filaggrin in ichthyosis vulgaris; these included loss of the granular layer (as assessed histologically), absence of immunohistochemical staining for filaggrin, reduced FLG mRNA levels and reduced or indeed absent filaggrin protein in the skin of individuals with ichthyosis vulgaris (Fleckman and Brumbaugh, 2002;Nirunsuksiri et al, 1995;Sybert et al, 1985). Despite these observations, previous attempts to sequence the FLG gene were hampered by the highly repetitive DNA sequence that is common to the individual filaggrin repeats, which severely limits the choice of suitable priming sites.…”

Filaggrin Genotype in Ichthyosis Vulgaris Predicts Abnormalities in Epidermal Structure and Function

“…Decreased FLG expression results in a paucity of keratohyalin granules, which is a hallmark of ichthyosis vulgaris (IV), independent of body site and season of the year. [1][2][3][4] IV, the most prevalent disorder of cornification in humans, is characterized by the delayed, postnatal onset of generalized, fine scaling that spares the flexures, and is often associated with palmar hyperlinearity and atopic dermatitis (AD). [5][6][7] In IV and AD, both nonsense and frameshift mutations have been discovered in the gene encoding FLG, which localizes to the epidermal differentiation complex on chromosome 1q21.…”