Challenges in managing disorders of sex development associated with adrenal dysfunction.

Introduction: Disorders of Sex Development (DSD) associated with adrenal dysfunction occur due to different defects in the proteins involved in gonadal and adrenal steroidogenesis.

Areas Covered: The deficiencies in 21-hydroxylase and 11β-hydroxylase lead to DSD in 46,XX patients, defects in StAR, P450scc, 17α-hydroxylase and 17,20-lyase lead to 46,XY DSD, and 3β-HSD2 and POR deficiencies cause both 46,XX and 46,XY DSD. Challenges in diagnosis arise from the low prevalence and the variability in serum steroid profiles.

Disorders of Sex Development of Adrenal Origin.

Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction.

Development and Validation of a Prediction Rule for Growth Hormone Deficiency Without Need for Pharmacological Stimulation Tests in Children With Risk Factors.

Introduction: Practice guidelines cannot recommend establishing a diagnosis of growth hormone deficiency (GHD) without performing growth hormone stimulation tests (GHST) in children with risk factors, due to the lack of sufficient evidence.

Objective: Our goal was to generate an evidence-based prediction rule to diagnose GHD in children with growth failure and clinically identifiable risk factors.

Methods: We studied a cohort of children with growth failure to build the prediction model, and a second, independent cohort to validate the prediction rule.

Ehlers-Danlos Syndrome: Molecular and Clinical Characterization of TNXA/TNXB Chimeras in Congenital Adrenal Hyperplasia.

Context: The syndrome CAH-X is due to a contiguous gene deletion of CYP21A2 and TNXB resulting in TNXA/TNXB chimeras.

Objective: To analyze TNXB gene status and to clinically evaluate the Ehlers-Danlos syndrome phenotype in a large cohort of Argentine congenital adrenal hyperplasia (CAH) patients to assess the prevalence of this condition in our population.

Methods: TNXB gene analysis was performed in 66 nonrelated CAH patients that were carriers of the CYP21A2 gene deletion.

Clinical, hormonal, ovarian, and genetic aspects of 46,XX patients with congenital adrenal hyperplasia due to CYP17A1 defects.

Objective: To perform a clinical, biochemical, and molecular evaluation of patients with CYP17A1 defects, including ovarian imaging.

Design: Retrospective study.

Setting: Tertiary care center.

Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia.

Context: Patients with congenital adrenal hyperplasia (CAH) often suffer from long-term complications secondary to chronic glucocorticoid therapy and suboptimal treatment regimens.

Objective: The aim of the study was to describe clinical characteristics of a large cohort of pediatric and adult CAH patients.

Design And Setting: We conducted a cross-sectional study of 244 CAH patients [183 classic, 61 nonclassic (NC)] included in a Natural History Study at the National Institutes of Health.

Junction site analysis of chimeric CYP21A1P/CYP21A2 genes in 21-hydroxylase deficiency.

Background: Chimeric CYP21A1P/CYP21A2 genes, caused by homologous recombination between CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) and its highly homologous pseudogene CYP21A1P (cytochrome P450, family 21, subfamily A, polypeptide 1 pseudogene), are common in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). A comprehensive junction site analysis of chimeric CYP21A1P/CYP21A2 genes is needed for optimizing genetic analysis strategy and determining clinical relevance.

Methods: We conducted a comprehensive genetic analysis of chimeric CYP21A1P/CYP21A2 genes in a cohort of 202 unrelated 21-OHD patients.

Phenotypic profiling of parents with cryptic nonclassic congenital adrenal hyperplasia: findings in 145 unrelated families.

Objective: To comprehensively phenotype parents identified with nonclassic congenital adrenal hyperplasia (NCCAH) by family genetic studies, termed here as cryptic NCCAH and to define the incidence of cryptic NCCAH in the parents of a large cohort of patients with 21-hydroxylase deficiency.

Design: Genotyping was performed on 249 parents of 145 unrelated congenital adrenal hyperplasia (CAH) patients. Parents with two CYP21A2 mutations underwent extensive evaluation.

Growth-inhibiting conditions slow growth plate senescence.

The mammalian growth plate undergoes programmed senescence during juvenile life, causing skeletal growth to slow with age. We previously found that hypothyroidism in rats slowed both growth plate chondrocyte proliferation and growth plate senescence, suggesting that senescence is not dependent on age per se but rather on chondrocyte proliferation. However, one alternative explanation is that the observed slowing of growth plate senescence is a specific consequence of hypothyroidism.

Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Background: Genetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.

Study Objective: The objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients.

Methods: Targeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families.

Haplotype analysis of the promoter region of phosphodiesterase type 8B (PDE8B) in correlation with inactivating PDE8B mutation and the serum thyroid-stimulating hormone levels.

Background: Human phosphodiesterase (PDE) type 8B (PDE8B) is located at 5q14.1 and is known as the PDE with the highest affinity to cAMP. We recently described a family with bilateral micronodular adrenocortical disease that was apparently caused by an inactivating PDE8B mutation (H305P).

An extensive genetic program occurring during postnatal growth in multiple tissues.

Mammalian somatic growth is rapid in early postnatal life but then slows and eventually ceases in multiple tissues. We hypothesized that there exists a postnatal gene expression program that is common to multiple tissues and is responsible for this coordinate growth deceleration. Consistent with this hypothesis, microarray analysis identified more than 1600 genes that were regulated with age (1 vs.

Changes in cell-cycle kinetics responsible for limiting somatic growth in mice.

In mammals, the rate of somatic growth is rapid in early postnatal life but then slows with age, approaching zero as the animal approaches adult body size. To investigate the underlying changes in cell-cycle kinetics, [methyl-H]thymidine and 5'-bromo-2'deoxyuridine were used to double-label proliferating cells in 1-, 2-, and 3-wk-old mice for four weeks. Proliferation of renal tubular epithelial cells and hepatocytes decreased with age.

An imprinted gene network that controls mammalian somatic growth is down-regulated during postnatal growth deceleration in multiple organs.

In mammals, somatic growth is rapid in early postnatal life but decelerates with age and eventually halts, thus determining the adult body size of the species. This growth deceleration, which reflects declining proliferation, occurs simultaneously in multiple organs yet appears not to be coordinated by a systemic mechanism. We, therefore, hypothesized that growth deceleration results from a growth-limiting genetic program that is common to multiple tissues.

Pediatric Graves' disease: outcome and treatment.

Unlabelled: Graves' disease treatment in children and adolescents includes antithyroid drugs (ATD), 131I (RI) or subtotal thyroidectomy (CX), all of which present beneficial effects and disadvantages.

Objective: To review our experience in the management of pediatric patients with Graves' disease considering the therapeutic strategies used.

Patients And Methods: Clinical and biochemical data of 116 children (23 boys) aged 11.