Clinical course of patients with nonclassical 21-hydroxylase deficiency (21-OHD) diagnosed in infancy and childhood.

We report four cases of nonclassical 21-hydroxylase deficiency (21-OHD) diagnosed in neonate or early childhood. The four patients comprised a 6-year, 5-month-old male (case 1); a 3-year, 10-month-old female (case 2); a 13-year, 11-month-old female (case 3) and a 17-year, 1-month-old male (case 4). Cases 3 and 4 were siblings. None had any signs of virilization or salt wasting at birth. 21-OHD was diagnosed using ACTH loading test and other adrenal steroid evaluations. Mutations of the CYP21 gene were detected in all patients. Three patients (cases 1, 3 and 4) had positive results in neonatal mass screening. Cases 1 and 2 showed no apparent signs of virilization and were observed without conventional treatment. In cases 3 and 4, because of increased growth velocity and accelerated bone maturation, hydrocortisone administration was initiated from their late infantile period. In spite of hydrocortisone treatment, in case 4, the final height of 159.7 cm was less than his predicted final height. Besides he revealed adrenal insufficiency at the age of 9 years and 2 months old caused by viral infection. Hydrocortisone supplementation therapy may cause adrenal insufficiency in nonclassical patients due to suppression of the hypothalamus-pituitary-adrenal axis. The clinical courses in these cases were various, and it was difficult to predict the appearance of any symptoms of virilization. Careful observation is necessary.

Colon cancer in a 14-year-old female with turner syndrome: report of a case.

A 14-year-old female with Turner syndrome (karyotype 45,X) had a history of abdominal pain with distention, constipation, and fever. She was first operated on for the suspicion of appendicitis, failed to improve, and was later hospitalized for further investigation and treatment. Studies demonstrated an obstructing tumor of the transverse colon, and an emergency laparotomy was performed. The final diagnosis was a signet-ring cell carcinoma of the colon with diffuse peritoneal dissemination and metastasis to paracolic lymph nodes. On the basis of this case, we report the association of Turner syndrome with malignancies and also some aspects of colon cancer in childhood.

Genetic analysis of Japanese patients with 21-hydroxylase deficiency: identification of a patient with a new mutation of a homozygous deletion of adenine at codon 246 and patients without demonstrable mutations within the structural gene for CYP21.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is one of the most common inherited metabolic diseases. We studied 52 Japanese 21-hydroxylase deficiency patients corresponding to 49 families (98 chromosomes) to detect the mutations in 21-hydroxylase genes using Southern blotting, PCR-restriction fragment length polymorphism, and a direct sequencing method. Among the 52 patients (49 families), 35 patients (33 families) were diagnosed as the salt-wasting type, 12 (12 families) as the simple virilizing type, and 5 (4 families) as the nonclassical type. Our findings were as follows. 1) The complete genotype that had homozygous or compound heterozygous mutations was determined in 43 of 49 families (87.8%). Among the remaining patients, no mutation was found in the structural gene of either allele in 3 cases, and a mutation was detected in only 1 allele in 3 cases. This means that at least 9 of 98 alleles have some unusual mutations or recombinations that we cannot detect by our method or gene defects outside of the structural gene. 2) Although the common mutation of Caucasian nonclassical patients is V281L, none of our 4 nonclassical families showed this mutation, and 3 of them had the P30L mutation at least on 1 allele. 3) We identified a putative new mutation, homozygous deletion of adenine at codon 246, in a salt-wasting patient. Although we have not analyzed the functional consequence of this mutation, it causes substitution noncoding for Met(256) in exon 7 and premature termination of the mRNA before the heme-binding region of the P450 polypeptide, which would result in a completely nonfunctional enzyme.

A highly specific heterologous enzyme immunoassay for 5 alpha-androstane-3 alpha, 17 beta-diol 17-glucuronide (androstanediol-17G) and developmental patterns of urinary androstanediol-17G excretions.

We established a highly specific enzyme immunoassay (EIA) for 5 alpha-androstane-3 alpha, 17 beta-diol 17-glucuronide (androstanediol-17G). Rabbit antisera raised against 5 alpha-androstane-3 alpha, 11 alpha, 17 beta-triol 17-glucuronide 11-glutaryl bovine serum albumin and a heterologous tracer of androstanediol-17G conjugated with horseradish peroxidase at the glucuronic acid group were used. The EIA showed excellent specificity: there were no remarkable cross-reactivities with related androgens. The assay range for urine samples was 0.3-30 ng/ml. Recoveries of standards added to samples were 100-108%. Intra-assay and inter-assay coefficients of variation were 2.9-4.4% and 5.7-7.9%, respectively. The EIA was applied to urine samples of 407 males and 322 females to determine developmental patterns and normal ranges of androstanediol-17G excretions in 11 age groups (0 y, 1 y, 2-3 y, 4-5 y, 6-7 y, 8-9 y, 10-11 y, 12-13 y, 14-15 y, 16-17 y, and over 18 y). Urinary androstanediol-17G/creatinine (androstanediol-17G/Cre) ratios in both sexes were high in infancy, tended to decrease during childhood, and began to increase near adolescence. While androstanediol-17G/Cre ratio in girls increased at 8-9 y and reached a plateau during adolescence, that in boys increased at 10-11 y and continued to increase throughout adolescence. Androstanediol-17G/Cre ratios in girls were higher than those in boys at 6-7 y (P < 0.05) and at 8-9 y (P < 0.01). Androstanediol-17G/Cre ratios in boys were higher than those in girls at 12-13 y and at older ages (P < 0.01). These developmental patterns are parallel to age-related changes in androgenicity and serum androstanediol-17G, suggesting that urinary androstanediol-17G/Cre ratio could be a good marker for androgenicity in childhood.