As more has been learned about these disorders, various classification systems have been proposed. In the 1960’s, Frost and Weinstein offered a classification based upon epidermal kinetics, in which disorders were designated either primarily retention hyperkeratoses (delayed desquamation with normal rates of epidermal renewal) or hyperproliferative states 6
. In the 1980’s Elias and Williams advanced a morphological classification with disorders affecting the intercellular lipids (“mortar”) and those affecting the structural proteins of the corneocyte (“bricks”)7, 8
. As further insights have been gained into the relationships between stratum corneum structures and the barrier functions of epidermis 9
, it is now possible to integrate the epidermal kinetics model with the “Bricks and Mortar” model. This new, function-driven model provides a framework for understanding how such a wide and disparate group of genetic errors results in the ichthyosis phenotype. Of particular importance in the function-driven model is the observation that epidermal permeability barrier function is abnormal to a varying extent in virtually all of these disorders ().
Principles of a Function-Driven Model of Disorders of Cornification (with Examples)
The stratum corneum (SC) comprises a unique, two-compartment system of protein-enriched corneocytes, embedded in a lipid-enriched extracellular matrix. SC lipids are composed of extremely hydrophobic species, and organized into repeating arrays of lamellar membranes (). These membranes provide the permeability barrier, which can be demonstrated ultrastructurally using a small, electron-dense water-soluble tracer molecule, lanthanum that follows the outward movement of water in the epidermis. In normal epidermis, the movement of lanthanum is halted at the stratum granulosum – SC interface by the interposition of lamellar membrane structures in the intercellular domain of the SC 10, 11
. If the lamellar structures are inherently abnormal, as in many ichthyoses, or removed from the SC, as for example, by solvent extraction, transepidermal water loss (TEWL) rates increase, and lanthanum then can be seen to penetrate the SC through the extracellular pathway (). Acute experimental perturbations of the permeability barrier (e.g., through solvent extraction or tape strippings) result in a series of homeostatic responses aimed at repairing the barrier 12, 13
. In the first wave of responses, occurring within minutes of barrier disruption, the loss of the high calcium milieu bathing the stratum granulosum (SG), signals secretion of preformed lamellar bodies from the upper SG (“Deliver more lipid, now!”) (). In the second phase, occurring within hours and signaled in part by release of preformed IL-1α from SC stores, epidermal lipid synthesis increases (“Make more lipid!”). In the third phase, within a day and also in response to cytokine signaling, epidermal DNA synthesis increases (“Make more cells!”). In normal human epidermis, these responses result in repair of the permeability barrier within about 3 days. In disorders of cornification, where a mutation produces a barrier defect that cannot be corrected by these homeostatic responses, the repair efforts (hypermetabolism, hyperplasia) do not terminate. Thus, a mutation that produces a barrier defect will invariably be associated with epidermal hyperplasia.
Lanthanum penetration through the extracellular pathway
The corneocytes ‘bricks’ are constituents of the permeability barrier by two mechanisms. First, corneocytes serve as a critical scaffold
, required for the organization of the extracellular lipid matrix into its characteristic lamellar pattern. Second, through formation of multiple, overlapping layers of cells, they generate a tortuous
, intercellular pathway
that impedes the egress of water 14
. In addition to providing the framework for the permeability barrier, corneocytes subserve several other critical functions; including resistance
to mechanical insults
, as well as hydration and pliability, an additional set of functions related to the humidity-dependent hydrolysis of filaggrin into amino acids and their deiminated products (see below).
Another SC function that is universally impaired in the ichthyoses is desquamation. Normal desquamation is an invisible process, whereby single corneocytes at the skin surface are invisibly swept away. Normal desquamation represents an orderly process of loss of corneocyte cohesion, which is mediated by corneodesmosomes, intercellular protein connectors 15–17
. Corneodesmosome degradation is mediated by several proteases, and regulated by protease inhibitors and pH 18, 19
. In the predominantly retention hyperkeratoses (e.g., ichthyosis vulgaris), desquamation is the SC function that is primarily affected.
Due to the energy losses that accompany evaporative water loss, infants and children with severe phenotypes can exhibit growth failure due to increased caloric requirements 20, 21
. Other functional deficiencies include heat intolerance in patients with more severe generalized ichthyoses (e.g., lamellar ichthyosis), due to obstruction of sweat ducts. In certain ichthyoses there is also an increased susceptibility to cutaneous and systemic infections. Although not yet confirmed experimentally, a plausible scenario for the infectious complication is as follows: Certain SC lipids (e.g., free fatty acids) and anti-microbial peptides (defensins and cathelicidins) are lamellar body-derived residents of the SC intercellular domains that provide a first line of defense against microbial invasion (innate immune system). Failure of lamellar body secretion (e.g., EHK) or of lipid processing (required for generation of free fatty acids)(e.g., Netherton syndrome) or proteolytic inactivation of anti-microbial peptides (e.g., Netherton syndrome) may therefore account for the propensity for bacterial and fungal infections in EHK, as well as bacterial and viral infections in Netherton syndrome 22–24