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...

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4 patients of two families with congenital persistent hyperthyroidism without detectable autoantibodies are reported. The members of the first family affected by hyperthyroidism, i.e. the mother and her two children, showed a germline mutation, a transition of GCC to GTC in the genomic DNA of the TSH receptor, leading to an exchange of alanine by valine at the position 623. The mother was thyroidectomized at two times because of recurrent nodular goiter. The third child of a healthy second family showed a transition of AGC to AAC leading to an exchange of serine by asparagine at the position 505 of the TSH receptor. The mutation of family 1, as a somatic point mutation leading to autonomous thyroid adenoma, has originally been demonstrated to constitutively activate TSH independent cAMP accumulation. The functional tests of the TSH receptor gen mutation, detected in family 2, are ongoing, but an exchange of serine by arginine at the same position has been shown to lead to constitutively active cAMP accumulation. The cases of congenital hyperthyroidism in the first family lead to a reduction of the birth weight and head circumference and to a neonatal but not fetal tachycardia. Bone age of both children was accelerated by one year. In contrast to that, congenital hyperthyroidism of the second family lead to more marked signs of intrauterine hyperthyroidism. The mother observed marked symptoms of fetal and neonatal hyperthyroidism. The bone age at a chronological age of 6 months was 4-6 years and the neonate showed a mild exophthalmus. We conclude, that congenital hyperthyroidism due to constitutively activating TSH receptor mutations has to be considered, if hyperthyroidism is not transient but persistent, and the parameters of autoimmunity are absent. Constitutively active TSH receptor germline mutations lead to different degrees of congenital hyperthyroidism. In contrast to patients with Graves' disease, more aggressive means of treatment like total thyroidectomy and/or radiation seem to be recommendable in cases with severe hyperthyroidism to control the disease.

hCG is a putative thyroid stimulator. The present studies were undertaken to examine its interaction and that of its desialylated