BACKGROUND: The biochemical bases for fragility in most of the rare brittle hair shaft syndromes are unknown. The hypothesis being investigated in several syndromes is that the hair cuticle cells show defects in cross-linked protein features. Since transglutaminases stabilize protein structures by cross-linking them, hair from autosomal recessive lamellar ichthyosis patients lacking keratinocyte transglutaminase was examined to find whether this enzyme participates in hair shaft stabilization. METHODS: Hair shaft samples from patients afflicted with lamellar ichthyosis or several brittle hair syndromes were examined ultrastructurally by transmission electron microscopy after vigorous extraction with detergent and reducing agent to reveal cross-linked protein features. RESULTS: In hair cuticle cells from three patients with lamellar ichthyosis the marginal band (A layer) was present but nonuniform and subject to breakage, while in a fourth sample it was missing altogether. The exocuticle appeared less dense than in normal hair, consistent with extensive protein loss during detergent extraction. In cuticle cells from trichothiodystrophy hair, the exocuticle layer was essentially fully extractable in one sample, while in two others (from siblings) the exocuticle appeared less dense and the A layer was absent or greatly reduced in thickness. A sample of proximal trichorrhexis nodosa also displayed defects in cuticle cells, in which the endocuticle layer appeared subject to rupture. The outer cuticle cells in monilethrix hair displayed a thinning of the A layer and less dense exocuticle, while the cortex exhibited regions lacking remnant cell borders. Pili annulati hair displayed large gaps in the cortex, presumably reflecting the air-filled cavities characteristic of this syndrome, and wavy borders of some cuticle cells. CONCLUSIONS: Observations with autosomal recessive lamellar ichthyosis hair indicate that keratinocyte transglutaminase has a major role in maturation of the cuticle but appears unnecessary for stabilization of cell borders in the cortex. Defective cross-linking was also evident in cuticle cells of trichothiodystrophy and monilethrix.