Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene.

[aromatase deficiency]

Recent reports of the impact of estrogen receptor alpha and aromatase deficiency have shed new light on the importance of estrogen for bone formation in man . We describe a novel mutation of the CYP 19 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 CYP 19 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 micro g transdermal estradiol twice weekly for 3 months , followed by 25 micro 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 . The bone age , assessed by roentgenographic standards for bone development by Gruelich and Pyle , was 16 .5 at baseline and 18 -18 .5 yr after 6 months of treatment . Bone density of the distal radius (left ), assessed by quantitative computed tomography , increased from 52 to 83 mg /cm (3 ) (normal range , 120 -160 ) and bone mineral density of the lumbar spine , assessed by dual-energy x-ray -absorptiometry , increased from 0 .971 to 1 .043 g /cm (2 ) (normal range , >1 .150 ). Osteocalcin as a bone formation parameter increased from 13 to 52 micro g /l (normal range , 24 -70 ) and aminoterminal collagen type I telopeptide as a bone resorption parameter increased from 62 .9 to 92 .4 nmol /mmol creatinine (normal range , 5 -54 ). Semen analysis revealed oligoazoospermia (17 .4 million /ml ; normal >20 ) at baseline . After 3 months of treatment , the sperm count increased (23 .1 million /ml ) and decreased rapidly (1 .1 million /ml ) during the following 3 months . The sperm motility was reduced at baseline and decreased further during treatment . Area under the curve of insulin , C-peptide , and blood glucose levels during oral glucose tolerance test decreased after 6 months (insulin : 277 vs . 139 micro U /ml .h ; C-peptide 52 vs . 15 ng /m .h ; area under the curve glucose : 17316 vs . 12780 mg /d .min ). Triglycerides (268 vs . 261 mmol /liter ) and total cholesterol levels (176 vs . 198 mmol /liter ) did not change significantly , but the low -density lipoprotein /high -density lipoprotein ratio decreased from 5 .37 to 3 .56 and lipoprotein (a ) increased from 19 .9 to 60 .0 mg /dl (normal range , <30 ). In this rare incidence of estrogen deficiency , estrogen replacement demonstrated its importance for bone mineralization and maturation and glucose metabolism in a male carrying a novel mutation in the CYP 19 gene .

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aromatase deficiency

pyruvate dehydrogenase deficiency

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