Titanocene dichloride was capable of inhibiting the growth of different types of human tumors in vitro. A total of 14 patients with metastatic renal-cell carcinoma (RCC) received 270 mg/m2 titanocene dichloride every 3 weeks for 6 weeks. Although the toxicities and side effects encountered were mild to moderate, no partial or complete response was detectable. In conclusion, titanocene dichloride has no advantage in the therapy of RCC.

Recent reports of the impact of estrogen receptor ␣ and aromatase deficiency have shed new light on the importance of estrogen for bone formation in man. We describe a novel mutation of the CYP19 gene in a 27-yr-old homozygous male of consanguinous parents. A C to A substitution in intron V, at position ؊3 of the splicing acceptor site before exon VI of the CYP19 gene, is the likely cause of loss of aromatase activity. The mRNA of the patient leads to a frameshift and a premature stop codon 8 nucleotides downstream the end of exon V. Both parents were shown to be heterozygous for the same mutation. Apart from genua valga, kyphoscoliosis, and pectus carniatus, the physical examination was normal including secondary male characteristics with normal testicular size. To substitute for the deficiency, the patient was treated with 50 g transdermal estradiol twice weekly for 3 months, followed by 25 g twice weekly. After 6 months estrogen levels (<20 at baseline and 45 pg/ml at 6 months; normal range, 10 -50) and estrone levels (17 and 34 ng/ml; normal range, 30 -85) had normalized. Bone maturation progressed and the initially unfused carpal and phalangeal epiphyses began to close within 3 months and were almost completely closed after 6 months. I N A WIDE VARIETY of tissues, including testis, ovary, placenta, and adipose tissue, the aromatase cytochrome P450, as the product of the CYP19 gene, catalyzes the conversion of androgens to estrogens (1, 2). Reports of osteopenia and osteoporosis in animals and humans with gene defects in the estrogen receptor (3-5) and both in females and males with aromatase deficiency (6 -9) have called attention to the importance of estrogen for skeletal maturation (10). The precise role of estrogen in human male physiology remains largely unknown, especially which effects on bone mineralization and metabolism in the male are mediated by estrogens derived from the aromatization of androgens. Many studies have demonstrated that gonadal failure in males is associated with a decrease in bone mass, but less is known about the role of genetic disorders associated with estrogen resistance or deficiency (11). First descriptions of young men affected by congenital estrogen deficiency have shed new light on the importance of estrogen for bone formation in man (7,8,11,12). These findings suggest that epiphyseal closure does not develop without the action of estrogen even in males and that androgen alone is not sufficient to promote normal skeletal mineralization. Recently two mutations in the CYP19 gene in males have demonstrated the role of estrogen on bone mineralization and their effect on glucose and lipid metabolism (6 -9, 13, 14).We now present the third case of a 27-yr-old man with open epiphysis caused by a new mutation in the CYP19 gene (aromatase deficiency), the effect of estrogen replacement on bone mineralization/maturation and glucose and lipid metabolism. Subjects and Methods Case reportThe propositus was the only child of consanguineous parents (second cousins, Fig. 1). His mother d...

Congenital absence of the vas deferens (CAVD) is a frequent cause for obstructive azoospermia and accounts for 1%-2% of male infertility. A high incidence of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has recently been reported in males with CAVD. We have investigated a cohort of 106 German patients with congenital bilateral or unilateral absence of the vas deferens for mutations in the coding region, flanking intron regions and promotor sequences of the CFTR gene. Of the CAVD patients, 75% carried CFTR mutations or disease-associated CFTR variants, such as the "5T" allele, on both chromosomes. The distribution of mutation genotypes clearly differed from that observed in cystic fibrosis. None of the CAVD patients was homozygous for delta F508 and none was compound heterozygous for delta F508 and a nonsense or frameshift mutation. Instead, homozygosity was found for a few mild missense or splicing mutations, and the majority of CAVD mutations were missense substitutions. Twenty-one German CAVD patients were compound heterozygous for delta F508 and R117H, which was the most frequent CAVD genotype in our study group. Haplotype analysis indicated a common origin for R117H in our population, whereas another frequent CAVD mutation, viz. the "5T allele" was a recurrent mutation on different intragenic haplotypes and multiple ethnic backgrounds. We identified a total of 46 different mutations and variants, of which 15 mutations have not previously been reported. Thirteen novel missense mutations and one unique amino-acid insertion may be confined to the CAVD phenotype. A few splice or missense variants, such as F508C or 1716 G-->A, are proposed here as possible candidate CAVD mutations with an apparently reduced penetrance. Clinical examination of patients with CFTR mutations on both chromosomes revealed elevated sweat chloride concentrations and discrete symptoms of respiratory disease in a subset of patients. Thus, our collaborative study shows that CAVD without renal malformation is a primary genital form of cystic fibrosis in the vast majority of German patients and links the particular expression of clinical symptoms in CAVD with a distinct subset of CFTR mutation genotypes.

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