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Genes and Proximal Hypospadias.

In this issue of The Journal Johnson et al (page 345) present a cohort of 60 boys with proximal hypospadias, of whom they found genetic anomalies in 17. Most were diagnosed by karyotype and/or microarray but a few were diagnosed by multigene panel. Those with undescended or nonpalpable testes had a greater likelihood of having a genetic anomaly. Therefore, the authors conclude that endocrine/ genetic evaluation should be considered for boys with proximal hypospadias, and they provide us with a suggested algorithm for evaluation. Readers of this article will probably be divided into 2 camps: the skeptics who do not see the need to perform expensive genetic testing other than karyotype for a select group of patients and those who may see a possible benefit for considering genetic testing in boys with proximal hypospadias. The article has many flaws, which raise questions regarding the validity of the results. Figure 1 in the article reveals that the authors excluded more than 50% of the patients (71 of 131) with proximal hypospadias. This in itself introduced significant bias. It would be interesting if the authors considered those live patients who were excluded, and evaluated their outcomes and even compared them to the present study. How many of these patients had delayed diagnosis of a genetic or endocrine anomaly? How many had delayed diagnosis of a syndrome? What were their hypospadias repair outcomes? Supplementary table 3 in the article summarizes the 17 patients with genetic anomalies, of whom 5 had mixed gonadal dysgenesis. All of these patients had unilateral or bilateral undescended testes, for which karyotyping is standard of care and should be obtained. The case of ovotesticular disorder/ difference of sex development would have been diagnosed also since a karyotype would have been standard of care because of a nonpalpable testicle. All of the cases with other genetic anomalies would have been detected if evaluated by a geneticist as they all involved other abnormalities such as developmental delay, hypotonia, glaucoma, seizures, cleft palate, distinctive facial features and cardiac anomalies. Considering the previously published literature, a large number of articles have indicated low detection rates of genetic mutations/variants. We know that hypospadias is a polygenic condition whose expression varies depending on environmental influence, which makes it difficult to establish a universal protocol in the evaluation of this condition. The approach presented by the authors and their proposed algorithm are not based on their study results as they did not follow the algorithm when evaluating the 60 patients. A more practical algorithm should be developed that considers cost and current genetic testing availability. Karyotype might not be the best initial genetic test, and perhaps we should obtain a microarray analysis vs a polygenic panel or whole exome sequencing. Furthermore, if we want to evaluate the influence of the environment, should we also include epigenetics in the algorithm? The need to evaluate genetic tissue expression will also be of critical importance if we believe local effects have an essential role in this condition. All of these assessments are cost prohibitive today but may become mainstream in the future. Based on these arguments, the skeptics would state that today individuals with unilateral or bilateral undescended testicles and hypospadias should undergo karyotyping as standard of care. If other congenital anomalies are found, these patients should be evaluated by a geneticist and an endocrinologist and the appropriate genetic/ endocrine testing offered. For decades pediatric urologists have correlated outcomes to severity of hypospadias based on meatal location, with proximal hypospadias having the highest complication rate. More recently other parameters such as degree of penile curvature, glans width and urethral plate width have been correlated to outcomes. But even these are not good predictors of outcome. Why is it that some children with proximal hypospadias have excellent outcomes while others with the same degree of hypospadias have complications even when operated on by an experienced surgeon?