Genetic testing of XY newborns with a suspected disorder of sex development

Purpose of review: The current review focuses on the neonatal presentation of disorders of sex development, summarize the current approach to the evaluation of newborns and describes recent advances in understanding of underlying genetic aetiology of these conditions. Recent findings: Several possible candidate genes as well as other adverse environmental factors have been described as contributing to several clinical subgroups of 46,XY DSDs. Moreover, registry-based studies showed that infants with suspected DSD may have extragenital anomalies and in 46,XY cases, being small for gestational age (SGA), cardiac and neurological malformations are the commonest concomitant conditions. Summary: Considering that children and adults with DSD may be at risk of several comorbidities a clear aetiological diagnosis will guide further management. To date, a firm diagnosis is not reached in over half of the cases of 46,XY DSD. Whilst it is likely that improved diagnostic resources will bridge this gap in the future, the next challenge to the clinical community will be to show that such advances will result in an improvement in clinical care

Vascular dysfunction and increased cardiovascular risk in hypospadias

Aims Hypogonadism is associated with cardiovascular disease. However, the cardiovascular impact of hypogonadism during development is unknown. Using hypospadias as a surrogate of hypogonadism, we investigated whether hypospadias is associated with vascular dysfunction and is a risk factor for cardiovascular disease. Methods and results Our human study spanned molecular mechanistic to epidemiological investigations. Clinical vascular phenotyping was performed in adolescents with hypospadias and controls. Small subcutaneous arteries from penile skin from boys undergoing hypospadias repair and controls were isolated and functional studies were assessed by myography. Vascular smooth muscle cells were used to assess: Rho kinase, reactive oxygen species (ROS), nitric oxide synthase/nitric oxide, and DNA damage. Systemic oxidative stress was assessed in plasma and urine. Hospital episode data compared men with a history of hypospadias vs. controls. In adolescents with hypospadias, systolic blood pressure (P = 0.005), pulse pressure (P = 0.03), and carotid intima-media thickness standard deviation scores (P = 0.01) were increased. Arteries from boys with hypospadias demonstrated increased U46619-induced vasoconstriction (P = 0.009) and reduced acetylcholine-induced endothelium-dependent (P < 0.0001) and sodium nitroprusside-induced endothelium-independent vasorelaxation (P < 0.0001). Men born with hypospadias were at increased risk of arrhythmia [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.4–5.6, P = 0.003]; hypertension (OR 4.2, 95% CI 1.5–11.9, P = 0.04); and heart failure (OR 1.9, 95% CI 1.7–114.3, P = 0.02). Conclusion Hypospadias is associated with vascular dysfunction and predisposes to hypertension and cardiovascular disease in adulthood. Underlying mechanisms involve perturbed Rho kinase- and Nox5/ROS-dependent signalling. Our novel findings delineate molecular mechanisms of vascular injury in hypogonadism, and identify hypospadias as a cardiovascular risk factor in males. Key question Is hypospadias associated with vascular dysfunction? Key finding Boys with hypospadias have evidence of hypercontractility and impaired vasodilation secondary to increased Rho kinase activation and oxidative stress. This leads to raised systolic blood pressure in adolescence and increased risk of admission to hospital for cardiovascular diseases in adulthood. Take-home message Hypospadias is a risk factor for cardiovascular dysfunction in males

Studies of aetiology and long-term outcome in XY disorders of sex development

Abstract not currently available

Serum Anti-Müllerian Hormone In The Prediction Of Response To hCG Stimulation In Children With Suspected DSD

The relationship between serum anti-Müllerian hormone (AMH) and the testosterone response to hCG stimulation test is unclear. Children who had hCG stimulation tests in one tertiary centre between 2001-2018 were included (n,138). Serum testosterone (T) was measured before (D1) and after 3 days (D4) of hCG stimulation. Sixty-one of these children also had prolonged hCG stimulation for 2 more weeks and serum T measured after 21 days (D22). All children had a serum AMH measured on D1. Of the 138 children, D4 T was normal in 104 (75%). AMH was low in 24/138 (17%) children and 16 (67%) of these had a low D4 testosterone. Median AMH in those who had a normal vs low D4 T was 850 pmol/l (24, 2280) and 54 pmol/l (0.4, 1664), respectively (p<0.0001). An AMH >5th centile was associated with a low D4 testosterone in 18/118 (13%, p<0.0001). Of the 61 children who had prolonged hCG stimulation, D22 T was normal in 39 (64%). AMH was low in 10/61(16%) children and 9 (90%) of these had a low D22 testosterone. Median AMH in children who responded and did not respond by D22 was 639 pmol/l (107, 2280) and 261 pmol/l (15, 1034) (p<0.0001). A normal AMH may provide valuable information on overall testicular function. However, a low AMH does not necessarily predict a sub-optimal testosterone response to hCG stimulation. [Abstract copyright: © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: [email protected].

Serum anti-Müllerian hormone in the prediction of response to hCG stimulation in children with DSD

The relationship between serum anti-Müllerian hormone (AMH) and the testosterone response to hCG stimulation test is unclear. Children who had hCG stimulation tests in one tertiary centre between 2001-2018 were included (n,138). Serum testosterone (T) was measured before (D1) and after 3 days (D4) of hCG stimulation. Sixty-one of these children also had prolonged hCG stimulation for 2 more weeks and serum T measured after 21 days (D22). All children had a serum AMH measured on D1. Of the 138 children, D4 T was normal in 104 (75%). AMH was low in 24/138 (17%) children and 16 (67%) of these had a low D4 testosterone. Median AMH in those who had a normal vs low D4 T was 850 pmol/l (24, 2280) and 54 pmol/l (0.4, 1664), respectively (p<0.0001). An AMH >5th centile was associated with a low D4 testosterone in 18/118 (13%, p<0.0001). Of the 61 children who had prolonged hCG stimulation, D22 T was normal in 39 (64%). AMH was low in 10/61(16%) children and 9 (90%) of these had a low D22 testosterone. Median AMH in children who responded and did not respond by D22 was 639 pmol/l (107, 2280) and 261 pmol/l (15, 1034) (p<0.0001). A normal AMH may provide valuable information on overall testicular function. However, a low AMH does not necessarily predict a sub-optimal testosterone response to hCG stimulation. [Abstract copyright: © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: [email protected].