A high percentage of CYP21A2 affected alleles is detected by the 11-mutation screening study. Genotype-phenotype correlation was high, but when the phenotype is more severe than predicted by genotype, presence of two alterations in one allele should be ruled out.

Background: Three novel heterozygous SF-1 gene mutations affecting multiple members of two unrelated families with a history of 46,XY disorders of sex development (DSD) and 46,XX ovarian insufficiency are described. Methods: Clinical and mutational analysis of the SF-1 gene in 9 subjects of two families. Results: Family 1 had 2 affected 46,XY DSD subjects. One, born with severe perineal hypospadias, was raised as a male, and presented normal adolescence. The other, born with ambiguous genitalia, uterus, and mild testicular dysgenesis, was raised as a female. A W279X heterozygous mutation and an intronic deletion (g3314-3317delTCTC (IVS 4 + 8) was found in the SF-1 gene. In family 2, 4/6 affected siblings had 46,XY DSD or hypospadias. An affected 46,XX sister had normal sexual development but increased FSH levels. The 37-year-old affected mother had entered menopause. An Y183X heterozygous mutation was detected. Conclusion: An extreme within-family phenotypic variability, ranging from severe prenatal undervirilization to normal pubertal development, was observed in 46,XY-affected siblings, indicating that other unknown factors might be involved in the phenotype. Low ovarian reserve and preserved fertility in 46,XX subjects can be observed in heterozygous SF-1 gene mutations.

The aim of this study was to analyze the possible implication of changes in the GH/IGF-I axis and in insulin sensitivity for the regulation of adrenal androgen secretion of normal prepubertal and adolescent girls. A total of 61 normal girls were evaluated in prepuberty [Group (Gr)1, n = 33; early (Gr1A, n = 16) and late (Gr1B, n = 17)]; puberty (Gr3, n = 28), early (Gr3A, n = 9) and late (Gr3B, n = 19); and during the transition between prepuberty and puberty (Gr2, n = 26). Insulin sensitivity was estimated by the fasting glucose/insulin ratio (G/I). In Gr1, G/I was significantly higher, and the mean serum IGF-I and serum dehydroepiandrosterone sulfate (DHEAS) were significantly lower than in Gr3 (P < 0.0001). Mean G/I in Gr1A and Gr3A was significantly higher than in Gr1B (P < 0.01) and Gr3B (P < 0.02), respectively, and ratios in Gr1B were also significantly higher than in Gr3A (P < 0.02). However, body mass index (BMI) in Gr1A, Gr1B, and Gr3A was not significantly different, although a significant increment was observed between late prepuberty (Gr1B) and late puberty (Gr3B; P < 0.0001). On the other hand, serum IGF-I levels in Gr1A and Gr3A were significantly lower than those in Gr1B (P < 0.01) and Gr3B (P < 0.02), respectively. The mean serum DHEAS level in Gr1A and Gr3A was significantly lower than in Gr1B (P < 0.01) and Gr3B (P < 0.02), respectively, and the level in Gr1B was also significantly lower than in Gr3A (P < 0.02). Correlation studies within Gr1, Gr2, and Gr3 were also performed. There was a significant positive correlation between serum DHEAS and age and a significant negative correlation between serum DHEAS and G/I in the three groups. However, a significant positive correlation between serum DHEAS and serum IGF-I was only found in Gr1. Furthermore, a significant negative correlation between BMI and the G/I was found in Gr2 and Gr3. Therefore, changes in insulin sensitivity might be involved in adrenal androgen synthesis both in prepuberty and in puberty, as well as during the transition from prepuberty to puberty. Changes in BMI suggest that adiposity might be a mediator of this effect, particularly during late puberty. On the other hand, the GH/IGF axis might be an important metabolic signal involved in the maturational changes of human adrenal androgens during prepuberty, at the time of adrenarche. Indeed, a significant negative correlation between G/I and serum IGF-I was found in Gr1, as well as in Gr2. In conclusion, the findings of this study indicate that the GH/IGF-I axis and insulin resistance might be involved in the mechanism of adrenarche during prepuberty in normal girls. Because these relationships had not been seen in boys, we proposed that prepubertal ovarian estrogens might be responsible for the sex difference. The relationship between insulin resistance and adrenal androgens persists during the transition from prepuberty to puberty, as well as during puberty.

In humans, steroidogenic factor 1 (NR5A1/SF-1) mutations have been reported to cause gonadal dysgenesis, with or without adrenal failure, in both 46,XY and 46,XX individuals. We have previously reported extreme within-family variability in affected 46,XY patients. Even though low ovarian reserve with preserved fertility has been reported in females harboring NR5A1 gene mutations, fertility has only been observed in one reported case in affected 46,XY individuals. A kindred with multiple affected members presenting gonadal dysgenesis was studied. Four 46,XY individuals presented severe hypospadias at birth, one of them associated with micropenis and cryptorchidism. The other 3 developed spontaneous male puberty, and 1 has fathered 5 children. Four 46,XX patients presented premature ovarian failure (one of them was not available for the study) or high follicle-stimulating hormone levels. Mutational analysis of the NR5A1 gene revealed a novel heterozygous mutation, c.938G→A, predicted to cause a p.Arg313Hys amino acid change. A highly conserved amino acid of the ligand-binding domain of the mature protein is affected, predicting abnormal protein function. We confirm that preserved fertility can be observed in patients with a 46,XY disorder of sex development due to heterozygous mutations in the NR5A1 gene.

AbstractEstablishment of reliable reference intervals remains valuable for confirming validity and advancing standardization across methods and populations. Moreover, knowledge of the measurement uncertainty (U) and of the reference change value (RCV) has important applications in clinical chemistry.Starting from the information available in the laboratory data base (29,901 subjects) an initial selection was carried out by eliminating all subjects with a clinical or laboratory pathological report; data from 7581 0- to 20-year-old subjects (53.87% girls) remained in the study. These subjects, divided into nine age groups, were used to define reference distribution percentiles (2.5th, 50th and 97.5th) of serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4), and free T4 (fT4), as well as U and RCV of these assays.In early infancy, T4 and fT4 values were higher than in the older age groups. Serum T4 95th percentile reference value, useful for the diagnosis of hyperthyroidism, was 142.9 in 20-year-old boys and 230.4 nmol/L in early infants and serum T3 95th percentile was 2.6 and 3.5 nmol/L, respectively, while fT4 2.5th percentile reference value, useful for the diagnosis of hypothyroidism, was 9.6 and 13.0 pmol/L, respectively. Serum TSH 97.5th percentile showed less age variation, 4.38–4.88 mIU/L. Performance of the four assays resulted in approximately 20% Us, reflecting simple and complex imprecision, trueness, analytical and functional sensitivity. RCV of serum TSH (58.6%) was larger than for thyroid hormones (28.3%–34.7%), probably due to the high biological variation of this hormone.We have established reference interval for TSH and thyroid hormones, as well as Us for assessing reliability of measurements, and RCVs to alert users on the presence of clinical significant changes.