X-linked dominant ichthyosis with peroxisomal deficiency. An ultrastructural and ultracytochemical study of the Conradi-Hünermann syndrome and its murine homologue, the bare patches mouse.

BACKGROUND AND DESIGN: The bare patches (Bpa) mouse expresses an X-dominant disorder that may be homologous to the Conradi-Hünermann (CH) syndrome in man; ie, both express ichthyosis, cataracts, and skeletal defects. To confirm their homology, we compared the light and electron microscopy of involved (I) vs uninvolved (U) skin from an infant with CH syndrome to Bpa mice during and after resolution of the scaling disorder. The peroxisomal content of Bpa and CH skin was evaluated by diaminobenzidine (DAB) ultracytochemistry (Bpa only) and by assessment of catalase (Bpa only) and dihydroxyacetone phosphate-acyltransferase (DHAP-AT) activities in cultured I vs U fibroblasts. RESULTS: Both CH and Bpa I epidermis exhibited psoriasiform features. In addition, ultrastructurally both exhibited the following: (1) vacuolated lamellar bodies, (2) dilatation of intercellular spaces by vesicular structures and amorphous debris, and (3) abnormal mitochondria. Stratum corneum interstices were filled with vesicular structures, and no lamellar unit structures were evident using ruthenium tetroxide postfixation. Peroxisomes were poorly stained by DAB in I Bpa epidermis and dermis during the eruptive phase. Moreover, catalase and DHAP-AT activities in cultured I Bpa fibroblasts were decreased to 40% and 30% of U Bpa levels, respectively; DHAP-AT activity in cultured I CH fibroblasts was also reduced (60% of U CH). With resolution of the scaling disorder, the ultrastructural and ultracytochemical features of I and U Bpa skin became indistinguishable. CONCLUSIONS: These studies provide evidence for a self-resolving defect involving multiple organelles, including lamellar bodies, peroxisomes, and mitochondria in the I skin of CH syndrome and the Bpa mouse.

Peroxisomal abnormality in fibroblasts from involved skin of CHILD syndrome. Case study and review of peroxisomal disorders in relation to skin disease.

BACKGROUND AND DESIGN: Peroxisomal deficiency has been described in a number of syndromes characterized by chondrodysplasia punctata, including the Conradi-Hünermann (C-H) syndrome. Because of overlapping clinical features of X-chromosome inheritance, ichthyosis, and limb-reduction defects in C-H and CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndromes, we examined peroxisomal content using diaminobenzidine cytochemistry and peroxisomal functions in fibroblasts from involved vs uninvolved skin of CHILD syndrome. RESULTS: Fibroblasts from involved skin of a patient with CHILD syndrome accumulated cytoplasmic lipid, visualized with the fluorescent probe, nile-red. Ultrastructurally, fibroblasts of involved skin of CHILD syndrome accumulated lamellated membrane and vacuolar structures. By diaminobenzidine ultracytochemistry, fewer peroxisomes were present. Moreover, the activities of two peroxisomal enzymes, catalase and dihydroxyacetone phosphate acyltransferase, were decreased (approximately 30% of normal). However, peroxisomal oxidation of very-long-chain and branched-chain fatty acids was preserved. Moreover, plasma very-long-chain fatty acids, plasma phytanic acid, and erythrocyte plasmalogen content were normal. CONCLUSIONS: The CHILD, C-H, and rhizomelic chondrodysplasia punctata syndromes are all characterized by ichthyosis, chondrodysplasia punctata, and limb defects, as well as peroxisomal deficiency. Thus, these syndromes may be related pathogenically. Because peroxisomes are involved in prostaglandin metabolism, peroxisomal deficiency may directly contribute to the previously reported alterations in prostaglandin metabolism in fibroblasts of involved skin of fibroblasts.

HMG-CoA reductase inhibitors perturb fatty acid metabolism and induce peroxisomes in keratinocytes.

Topical lovastatin stimulates epidermal fatty acid synthesis in vivo; therefore, studies were undertaken to examine the effects of HMG-CoA reductase inhibitors on fatty acid metabolism in cultured keratinocytes. When exposed to fluindostatin or lovastatin for greater than or equal to 24 h, keratinocytes in serum-free media accumulated nile red-fluorescent lipid droplets. By 72 h, the triacylglycerol and phospholipid content were increased 2.5- and 1.3-fold, respectively. Reductase inhibitors (1-10 microM) increased fatty acid synthesis approximately 1.5-fold; increased synthesis was noted only after greater than 15 h exposure and was distributed among phospholipids and triacylglycerols. Oxidation of [14C]palmitate to CO2 was decreased greater than 50% in inhibitor-treated cultures, and label accumulated in triacylglycerols. Inhibitor-treated keratinocytes exhibited increased numbers of peroxisomes, using diaminobenzidene ultracytochemistry. Peroxisomal hyperplasia was also demonstrated by increased catalase activity (1.5- to 2.5-fold), increased dihydroxyacetone phosphate acyltransferase activity (1.4-fold) and increased peroxisomal (KCN-insensitive) fatty acid oxidation (1.4-fold) in inhibitor-treated cultures. Thus HMG-CoA reductase inhibitors increase fatty acid synthesis, induce triacylglycol and phospholipid accumulation, and induce peroxisomes in cultured keratinocytes. Coincubations with either low density lipoproteins or 25-hydroxycholesterol prevented both the peroxisomal hyperplasia and increased fatty acid synthesis, suggesting that these effects of reductase inhibitors may be linked to their effects on the cholesterol biosynthetic pathway.