An Investigation of Multidisciplinary Pathways in Paediatric DSD: Evaluation in Tertiary Centres in the United Kingdom and Hong Kong

Differences/Disorders of Sex Development (DSD) represent a diverse spectrum of conditions that are often present at birth when a baby’s sex cannot be immediately determined based on the appearance of their genitalia. This affects approximately 1 in 4500 newborns, although the exact incidence is unknown. These conditions can present at various other stages of life too. Having a child with potential DSD creates anxiety and considerable uncertainty among families. A multidisciplinary approach to provide early support and guiding investigations to a specific diagnosis and management plan are pivotal to holistic DSD care. The four aims of this work are to: (1) map out the 25- year clinical landscape of DSD referrals and changes over time in Great Ormond Street Hospital, London; (2) evaluate the prevalence of primary adrenal insufficiency (PAI) among 46,XY children and the role of biochemical testing in 46,XY children presenting with atypical genitalia in the newborn period; (3) explore the application of targeted gene panel multiplexed sequencing as an example of state-of-the-art research genetic technology for reaching a molecular diagnosis in DSD; and (4) analyse parents’ experiences of current pathways during the early days, including the source of information, and the psychological consequences of early experiences in Queen Mary Hospital (Hong Kong). In this study, we present clinical, biochemical and genetic data from what is, to our knowledge, the largest single-centre cohort of DSD conditions in newborns, children and young people reported, over a 25-year period. We also describe a collection of early parental experiences from recent DSD families. Our data highlight the range of presentations, associated features and approximate point prevalence of these diverse conditions, as well as the imperative roles of timely clinical assessment, biochemical analysis, genetics and psychosocial support in an integrated DSD care model. This work should help to inform service commissioning going forward and initiate quality improvement exercises that would potentially impact on patients’ outcomes in the long run, as well as other aspects of DSD service improvement

Insulin-like growth factor I (IGF-I) genotypes study in Chinese idiopathic short stature children

published_or_final_versionMedicineMasterMaster of Research in Medicin

A single-center, observational study of 607 children & young people presenting with Differences in Sex Development (DSD)

Context: Differences in sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family and developing a management plan are important. Objective: We aimed to better understand the presentation and prevalence of pediatric DSD. Design: A retrospective, observational cohort study was undertaken of all children and young people (CYP) referred to a DSD multi-disciplinary team over 25 years (1995-2019). Setting: A single tertiary paediatric center. Participants: In total, 607 CYP (520 regional referrals) were included. Main Outcome Measures: Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence. Results: Amongst the three major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45, X/46, XY mosaicism), 46, XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46, XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or herniae. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46, XY children, usually due to complex associated features (46, XY girls, 8.3%; 46, XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6,347 births, and 1 in 5,101 overall throughout childhood. Conclusions: DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care

Myocardial Integrated Backscatter in Obese Adolescents: Associations with Measures of Adiposity and Left Ventricular Deformation.

Myocardial fibrosis has been proposed to play an important pathogenetic role in left ventricular (LV) dysfunction in obesity. This study tested the hypothesis that calibrated integrated backscatter (cIB) as a marker of myocardial fibrosis is altered in obese adolescents and explored its associations with adiposity, LV myocardial deformation, and metabolic parameters.Fifty-two obese adolescents and 38 non-obese controls were studied with conventional and speckle tracking echocardiography. The average cIB of ventricular septum and LV posterior wall was measured. In obese subjects, insulin resistance as estimated by homeostasis model assessment (HOMA-IR) and glucose tolerance were determined. Compared with controls, obese subjects had significantly greater cIB of ventricular septum (-16.8±7.8 dB vs -23.2±7.8 dB, p<0.001), LV posterior wall (-20.5±5.6 dBvs -25.0±5.1 dB, p<0.001) and their average (-18.7±5.7 dB vs -24.1±5.0 dB, p<0.001). For myocardial deformation, obese subjects had significantly reduced LV longitudinal systolic strain rate (SR) (p = 0.045) and early diastolic SR (p = 0.015), and LV circumferential systolic strain (p = 0.008), but greater LV longitudinal late diastolic SR (p<0.001), and radial early (p = 0.037) and late (p = 0.002) diastolic SR than controls. For the entire cohort, myocardial cIB correlated positively with body mass index (r = 0.45, p<0.001) and waist circumference (r = 0.45, p<0.001), but negatively with LV circumferential systolic strain (r = -0.23, p = 0.03) and systolic SR (r = -0.25, p = 0.016). Among obese subjects, cIB tended to correlate with HOMA-IR (r = 0.26, p = 0.07).Obese adolescents already exhibit evidence of increased myocardial fibrosis, which is associated with measures of adiposity and impaired LV circumferential myocardial deformation

Clinical characteristics of obese and non-obese subjects.

<p>Abbreviations: BMI, body mass index, DBP, diastolic blood pressure, HOMA-IR, homeostasis model assessment of insulin resistance, SBP, systolic blood pressure</p><p>*statistically significant</p><p>Clinical characteristics of obese and non-obese subjects.</p

Comparison of echocardiographic indices between obese and non-obese adolescents.

<p>Abbreviations: A, transmitral late diastolic velocity, a, mitral annular late diastolic tissue velocity, BSA, body surface area, E, transmitral early diastolic velocity, e, mitral annular early diastolic tissue velocity, EDD, end-diastolic dimension, ESD, end-systolic dimension, IVSd, interventricular septal thickness at diastole, IVA, myocardial acceleration during isovolumic contraction, LV, left ventricular, PWd, posterior wall thickness at diastole</p><p>*statistically significant</p><p>Comparison of echocardiographic indices between obese and non-obese adolescents.</p

Correlations between measures of adiposity and left ventricular deformation adjusted for systolic and diastolic blood pressure.

<p>Abbreviations as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141149#pone.0141149.t002" target="_blank">Table 2</a>.</p><p>*statistically significant</p><p>Correlations between measures of adiposity and left ventricular deformation adjusted for systolic and diastolic blood pressure.</p

Left ventricular deformation and fibrosis in obese subjects with normal and impaired glucose tolerance.

<p>Abbreviations: cIB, calibrated integrated backscatter, SRa, late diastolic strain rate, SRe, early diastolic strain rate, SRs, systolic strain rate</p><p>Left ventricular deformation and fibrosis in obese subjects with normal and impaired glucose tolerance.</p

A Single-Center, Observational Study of 607 Children and Young People Presenting With Differences of Sex Development (DSD).

CONTEXT: Differences of sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family, and developing a management plan are important. OBJECTIVE: We aimed to better understand the presentation and prevalence of pediatric DSD. METHODS: A retrospective, observational cohort study was undertaken in a single tertiary pediatric center of all children and young people (CYP) referred to a DSD multidisciplinary team over 25 years (1995-2019). In total, 607 CYP (520 regional referrals) were included. Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence. RESULTS: Among the 3 major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45,X/46,XY mosaicism), 46,XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46,XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or hernias. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46,XY children, usually due to complex associated features (46,XY girls, 8.3%; 46,XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6347 births, and 1 in 5101 overall throughout childhood. CONCLUSION: DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care