Ichthyosis in Sjögren-Larsson syndrome reflects defective barrier function due to abnormal lamellar body structure and secretion

Abstract

Sjögren-Larsson syndrome is a genetic disease characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene coding for fatty aldehyde dehydrogenase, an enzyme necessary for oxidation of fatty aldehydes and fatty alcohols. We investigated the cutaneous abnormalities in 9 patients with Sjögren-Larsson syndrome to better understand how the enzymatic deficiency results in epidermal dysfunction. Histochemical staining for aldehyde oxidizing activity was profoundly reduced in the epidermis. Colloidal lanthanum perfusion studies showed abnormal movement of tracer into the extracellular spaces of the stratum corneum consistent with a leaky water barrier. The barrier defect could be attributed to the presence of abnormal lamellar bodies, many with disrupted limiting membranes or lacking lamellar contents. Entombed lamellar bodies were present in the cytoplasm of corneocytes suggesting blockade of lamellar body secretion. At the stratum granulosum-stratum corneum interface, non-lamellar material displaced or replaced secreted lamellar membranes, and in the stratum corneum, the number of lamellar bilayers declined and lamellar membrane organization was disrupted by foci of lamellar/non-lamellar phase separation. These studies demonstrate the presence of a permeability barrier abnormality in Sjögren-Larsson syndrome, which localizes to the stratum corneum interstices and can be attributed to abnormalities in lamellar body formation and secretion.

Fig. 1

Histopathology of SLS. a At low magnification, epidermal hyperplasia, spongiosis, and prominent hyperkeratosis are evident in patient #4. Note compactness of lower SC (solid arrow) and loosely organized mid- to upper-SC (open arrows). b At higher magnification, the granular layer (arrows) is normal in size. Epon embedded, 1 μm section, toluidine blue staining

Fig. 2

Histochemical staining for aldehyde (octanal) oxidizing activity in normal and SLS skin. a Normal skin shows abundant staining of the epidermis, but not of the SC. b SLS skin (patient #8) has a profound reduction in enzyme activity in the epidermis. c Control showing normal skin incubated without octanal

Fig. 3

Lanthanum perfusion demonstrates a leaky epidermal water barrier in SLS (patient #7). a Lanthanum tracer, which reflects the pathway of water movement and is completely excluded from the SC in normal skin, but breaches the SC via the extracellular spaces in SLS (arrows). b Tracer moves outward through SG (curved arrow) and remains restricted to SC interstices (a, arrows). a, b, osmium tetroxide and ruthenium tetroxide post-fixation

Fig. 4

Abnormal lamellar bodies in SLS. a–c Although the number (density) of lamellar bodies appears normal in SLS, many organelles appear empty (asterisks) or display non-lamellar contents. Moreover, the limiting membrane of many individual organelles appears disrupted or absent (arrows). Osmium tetroxide post-fixation. a, c Patient #4. b Patient #3

Fig. 5

Secretion of non-lamellar contents at stratum corneum (SC)—stratum granulosum (SG) interface in SLS (patient #4). a–c Much of the SG–SC interface is occupied by non-lamellar contents (asterisks) that displace or replace secreted lamellar material. However, the cornified lipid envelope appears normal. Osmium tetroxide post-fixation

Fig. 6

Abnormal lamellar body secretion in SLS results in entombment of organelle contents in corneocytes. a, b Unsecreted organelles become entombed in the corneocyte cytosol (a asterisks; b arrow) of patient #4. c Note the increased concentration of unsecreted lamellar bodies (arrows) at the periphery of outer SG cells in patient #3. a, b, ruthenium tetroxide post-fixation; c osmium tetroxide post-fixation

Fig. 7

Decreased lamellar bilayers and lamellar/non-lamellar phase separation in SC interstices of patient #4. a, b Entombed lamellar contents in corneocyte cytosol is evident (open arrows). Lamellar domains are interspersed with lacunae filled with non-lamellar material (asterisks). b Blockade of secretion (c.f., Fig. 6) also results in paucity of lamellar bilayers (arrows). a, b ruthenium tetroxide post-fixation