Androgen-responsive non-coding small RNAs extend the potential of HCG stimulation to act as a bioassay of androgen sufficiency.

BACKGROUND: It is unclear whether a short-term change in circulating androgens is associated with changes in the transcriptome of the peripheral blood mononuclear cells (PBMC). AIMS AND METHODS: To explore the effect of hCG stimulation on the PBMC transcriptome, 12 boys with a median age (range) of 0.7 years (0.3, 11.2) who received intramuscular hCG 1500u on 3 consecutive days as part of their investigations underwent transcriptomic array analysis on RNA extracted from peripheral blood mononuclear cells before and after hCG stimulation. RESULTS: Median pre- and post-hCG testosterone for the overall group was 0.7 nmol/L (<0.5, 6) and 7.9 nmol/L (<0.5, 31.5), respectively. Of the 12 boys, 3 (25%) did not respond to hCG stimulation with a pre and post median serum testosterone of <0.5 nmol/L and <0.5 nmol/L, respectively. When corrected for gene expression changes in the non-responders to exclude hCG effects, all 9 of the hCG responders consistently demonstrated a 20% or greater increase in the expression of piR-37153 and piR-39248, non-coding PIWI-interacting RNAs (piRNAs). In addition, of the 9 responders, 8, 6 and 4 demonstrated a 30, 40 and 50% rise, respectively, in a total of 2 further piRNAs. In addition, 3 of the responders showed a 50% or greater rise in the expression of another small RNA, SNORD5. On comparing fold-change in serum testosterone with fold-change in the above transcripts, a positive correlation was detected for SNORD5 (P = 0.01). CONCLUSIONS: The identification of a dynamic and androgen-responsive PBMC transcriptome extends the potential value of the hCG test for the assessment of androgen sufficiency.

An assessment of the quality of the I-DSD and the I-CAH registries - international registries for rare conditions affecting sex development.

BACKGROUND: With the proliferation of rare disease registries, there is a need for registries to undergo an assessment of their quality against agreed standards to ensure their long-term sustainability and acceptability.This study was performed to evaluate the I-DSD and I-CAH Registries and identify their strengths and weaknesses. METHODS: The design and operational aspects of the registries were evaluated against published quality indicators. Additional criteria included the level of activity, international acceptability of the registries and their use for research. RESULTS: The design of the I-DSD and I-CAH Registries provides them with the ability to perform multiple studies and meet the standards for data elements, data sources and eligibility criteria. The registries follow the standards for data security, governance, ethical and legal issues, sustainability and communication of activities. The data have a high degree of validity, consistency and accuracy and the completeness is maximal for specific conditions such as androgen insensitivity syndrome and congenital adrenal hyperplasia. In terms of research output, the external validity is strong but the wide variety of cases needs further review. The internal validity of data was condition specific and highest for conditions such as congenital adrenal hyperplasia. The shift of the registry from a European registry to an international registry and the creation of a discrete but linked CAH registry increased the number of users and stakeholders as well as the international acceptability of both registries. CONCLUSIONS: The I-DSD and I-CAH registries comply with the standards set by expert organisations. Recent modifications in their operation have allowed the registries to increase their user acceptability.

The Long-Term Outcome of Boys With Partial Androgen Insensitivity Syndrome and a Mutation in the Androgen Receptor Gene.

BACKGROUND: In boys with suspected partial androgen insensitivity syndrome (PAIS), systematic evidence that supports the long-term prognostic value of identifying a mutation in the androgen receptor gene (AR) is lacking. OBJECTIVE: To assess the clinical characteristics and long-term outcomes in young men with suspected PAIS in relation to the results of AR analysis. METHODS: Through the International Disorders of Sex Development Registry, clinical information was gathered on young men suspected of having PAIS (n = 52) who presented before the age of 16 years and had genetic analysis of AR. RESULTS: The median ages at presentation and at the time of the study were 1 month (range, 1 day to 16 years) and 22 years (range, 16 to 52 years), respectively. Of the cohort, 29 men (56%) had 20 different AR mutations reported. At diagnosis, the median external masculinization scores were 7 and 6 in cases with and without AR mutation, respectively (P = .9), and median current external masculinization scores were 9 and 10, respectively (P = .28). Thirty-five men (67%) required at least one surgical procedure, and those with a mutation were more likely to require multiple surgeries for hypospadias (P = .004). All cases with an AR mutation had gynecomastia, compared to 9% of those without an AR mutation. Of the six men who had a mastectomy, five (83%) had an AR mutation. CONCLUSIONS: Boys with genetically confirmed PAIS are likely to have a poorer clinical outcome than those with XY DSD, with normal T synthesis, and without an identifiable AR mutation. Routine genetic analysis of AR to confirm PAIS informs long-term prognosis and management.

Rationalized assessment of prolonged jaundice is safe and cost-effective.

Prolonged jaundice (PJ) in healthy term neonates is common and frequently benign. It can, however, be the earliest manifestation of underlying liver disease. Its management requires a balanced approach, avoiding over-investigation of well babies while ensuring the early identification of those with pathology. Currently marked heterogeneity exists in the assessment of PJ. Over a two-year period we prospectively audited the management of PJ in two Level 3 neonatal units prior to and after the introduction of a rationalized investigation algorithm in keeping with the recently published British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) guidelines (i.e. clinical examination and stool inspection combined with measurement of split bilirubin). In this study we reviewed initial practice and then evaluated the impact of our change in practice. A total of 197 babies, 1.5% of live births, were referred with PJ. Of these, 105 babies were included in the first part of the study and 92 babies were included in the second part. No pathology relating to PJ, such as infection, hepatitis or liver disease, was identified. Following the introduction of our rationalized algorithm, we demonstrated a statistically significant reduction in the number of return appointments (28 versus 7; P < 0.0009) and repeat investigations (37 versus 7; P < 0.0001). This represented a saving of £1575-2625 per year in laboratory costs alone. Contemporaneously, three infants presented with biliary atresia, none of whom were identified by PJ screening and all of whom were over seven weeks old at diagnosis. A rationalized approach to the assessment of PJ reduces workload and is cost-effective; however, the limitations of selective screening, irrespective of how streamlined it is, remain--if babies are not identified and referred, they cannot be screened. Population-based methodologies offer an alternative approach to the identification of cholestatic liver disease and are worthy of further consideration.

Factors that influence the decision to perform a karyotype in suspected disorders of sex development: lessons from the Scottish genital anomaly network register.

BACKGROUND: Although a karyotype represents the first objective evidence of investigating a case of suspected disorder of sex development (DSD), the factors that influence the clinician's decision to initiate investigations are unclear. METHODS: Cases of suspected DSD in Scotland were identified through the Scottish Genital Anomaly Network (SGAN) Register. The timing as well as other factors that influence the decision to perform a karyotype were subsequently studied. RESULTS: Out of the 572 cases on the register, 383 (67%) were classified as having a non-specific disorder of under-masculinisation. In 463 (81%) cases, the sex of rearing was male, in 71 (12%) female, and in 38 (7%) cases data regarding sex of rearing were unavailable. A karyotype was reported to have been performed in 153/572 (27%) cases. Infants in Scotland with suspected DSD are more likely to have a karyotype performed in the presence of a low external masculinisation score, bilateral impalpable testes, proximal hypospadias, or associated malformations. DISCUSSION: These data represent the first attempt at benchmarking the decision to check a karyotype and investigate infants with suspected DSD. Whilst this decision may be related to the complexity of the genital anomaly, there are other factors that may influence this decision, and these require further exploration through more rigorous systems for data collection.

The European disorder of sex development registry: a virtual research environment.

Disorders of sex development (DSD) are a rare group of conditions which require further research. Effective research into understanding the aetiology, as well as long-term outcome of these rare conditions, requires multicentre collaboration often across national boundaries. The EU-funded EuroDSD programme (www.eurodsd.eu) is one such collaboration involving clinical centres and clinical and genetic experts across Europe. At the heart of the EuroDSD collaboration is a European DSD registry and a targeted virtual research environment (VRE) that supports the sharing of DSD data. Security, ethics and information governance are cornerstones of this infrastructure. This paper describes the infrastructure that has been developed, the inherent challenges in security, availability and dependability that must be overcome for the enterprise to succeed and provides a sample of the data that are stored in the registry along with a summary analysis of the current data sets.