ESPE2021 ePoster Category 1 Sex Endocrinology and Gonads A (10 abstracts)
Adolescents and young adult men with non-syndromic hypospadias: testicular function and in-depth genetic screening
Lloyd Tack 1 , Anne-Françoise Spinoit 1 , Stefan Riedl 2,3 , Alexander Springer 2 , Ursula Tonnhofer 2 , Manuela Hiess 2 , Julia Weninger 2 , Ahmed Mahmoud 1 , Kelly Tilleman 1 , Erik Van Laecke 1 , Piet Hoebeke 1 , Anders Juul 4,5 , Jakob Albrethsen 4 , Elfride De Baere 1 , Hannah Verdin 1 & Martine Cools 1
1Ghent University Hospital, Ghent, Belgium; 2Medical University of Vienna, Vienna, Austria; 3St Anna Children´s Hospital, Vienna, Austria; 4Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; 5University of Copenhagen, Copenhagen, Denmark
Background: Hypospadias affects approximately 1/200 newborn males. Based on the testicular dysgenesis syndrome hypothesis, some may be suspected of having persistent testicular dysfunction later in life. Few clinical data currently support this hypothesis.
Methods: Cross-sectional assessment of hypospadias cases (n = 193) and controls (n = 50), aged 16-21 years, recruited at Ghent University Hospital and Medical University Vienna. Exams included genital examination, morning blood sampling and diagnostic semen analysis (WHO 2010). Genetic study: exome-based testing of genes (n = 241) involved in gonadal development and spermatogenesis in those born appropriate for gestational age (AGA) with poor outcome or familial hypospadias (n = 73) and all born small for gestational age (SGA) (n = 26). In the latter, a gene panel (n = 233) for low birth weight/length and poor growth was also analyzed. Oligogenic variant combinations were sought using Oligogenic Resource for Variant AnaLysis (ORVAL).
Results: None of the participants had experienced problems regarding pubertal onset and progression. Higher gonadotropin levels were found in complex hypospadias and SGA compared to controls (LH 6.7±3.87 and 6.2±2.52 versus 5.0±1.51 U/L: P = 0.001 and 0.034; FSH 5.2 (IQR: 4.25) and 3.8 (IQR: 3.94) versus 2.7 (IQR: 2.03) U/L: P < 0.001 and 0.004, respectively). There were no differences between groups in total, free testosterone and dihydrotestosterone concentrations. Insulin-like factor 3 concentrations were higher in hypospadias compared to controls (0.66 vs 0.49 ng/ml, P = 0.001). Oligo- or azoospermia was found in 19/149 AGA (12.7%) and 13/22 (59.1%) SGA cases compared to 2/50 (4%) controls (P = 0.081 and <0.001, respectively). Oligo- or azoospermia was more common in AGA cases with complex hypospadias (31.3%) compared to isolated hypospadias (P = 0.035). No difference was seen in SGA cases, stratifying for severity of hypospadias. No (likely) pathogenic variants or variant combinations were found in any of the investigated genes, although some potentially interesting variants of unknown significance were identified.
Conclusion: Steroidogenesis and pubertal development were unaffected in patients with non-syndromic hypospadias, although elevated LH levels suggest subclinical Leydig cell dysfunction in SGA and complex cases. Higher INSL3 potentially reflect relative Leydig cell hyperplasia. Fertility is a major concern, especially in SGA and complex hypospadias. In these groups, the appropriateness of diagnostic semen analyses at the end of puberty should be considered as these exams are non-invasive and inexpensive. As no monogenetic causes nor pathogenic oligogenic combinations were found, further genetic studies in familial hypospadias should focus on multifactorial mechanisms with an emphasis on non-coding variants with a small effect.
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