Risk of neurodevelopmental disorder in cases of hypospadias

"This is the first study to identify an increased risk for neurodevelopmental disorders in patients with hypospadias, as well as an increased risk for ASD [autism spectrum disorders] in their brothers, suggesting a common familial (genetic and/or environmental) liability".

Rainy days and Mondays... @ Wikipedia 

That was the conclusion reached in the study by Agnieszka Butwicka and colleagues [1] looking at various neurodevelopmental outcomes associated with a diagnosis of hypospadias, a congenital condition characterised by an "aberrant opening of the urethra on the underside of the penis". The authors noted that: "Patients with hypospadias were more likely to be diagnosed with intellectual disability... ADHD... and behavioral/emotional disorders" compared with asymptomatic controls. Further: "Brothers of patients with hypospadias had an increased risk of ASD" when compared with siblings of asymptomatic controls. Ergo, the possibility of a 'link' between a physical condition and neurodevelopment potentially with a familial link.

Whilst being the first study to look at the possible behavioural correlates associated with hypospadias, I might draw your attention to some mention of this condition and the presentation of autism or autistic-like behaviour as per papers like the one from Willatt and colleagues [2] or in the case of ADHD (attention-deficit hyperactivity disorder), the paper by Battaglia and colleagues [3]. In both cases, the focus of these papers were rare genetic conditions hinting as some shared role for genomic factors.

That being said, the jury is still to some degree out about the possible cause(s) of hypospadias. The paper by Sharma and colleagues [4] talked about elevated blood cadmium and/or lead levels as being "associated with the increased risk of hypospadias". Knowing what we know about something like lead for example, and it's potential to affect developmental processes in quite small amounts (see here) might tie in well with such findings. Maternal exposure to specific chemicals (yes, that word again) has also been suggested to be potentially linked to hypospadias [5]. Certain pesticides reside in that 'chemical' category association too [6]. What this collected work points to is something suggesting that genes and environment variably interacting might also be a route to hypospadias, and onwards the correlation with neurodevelopmental conditions.

Although the Butwicka paper talked about a sibling link between hypospadias and autism, my mind drifted back to the quite recent study by Rzhetsky and colleagues [4] (open-access) looking at congenital malformations of the reproductive study as surrogate markers for environmental exposures being linked to cases of autism (see here for that entry). At the time, I seem to remember there was some chatter about the usefulness of such data as surrogate markers for environmental exposure. What I think we might be able to draw from the Butwicka data is that hypospadias at least, might actual be quite a useful area for the continued study with neurodevelopmental conditions in mind.

And to complement that painting, here are The Carpenters... (which might be particularly apt after the weather we've had here in Blighty recently).

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[1] Butwicka A. et al. Hypospadias and increased risk for neurodevelopmental disorders. Journal of Child Psychology and Psychiatry. 2014. July 22.  doi: 10.1111/jcpp.12290

[2] Willatt L. et al. 3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome. Am J Hum Genet. 2005 Jul;77(1):154-60.

[3] Battaglia A. et al. The FG syndrome: report of a large Italian series. Am J Med Genet A. 2006 Oct 1;140(19):2075-9.

[4] Sharma T. et al. Heavy metal levels in adolescent and maternal blood: association with risk of hypospadias. ISRN Pediatr. 2014 Mar 4;2014:714234.

[5] Thorup J. et al. Genetic and environmental origins of hypospadias. Curr Opin Endocrinol Diabetes Obes. 2014 Jun;21(3):227-32.

[6] Michalakis M. et al. Hypospadias in offspring is associated with chronic exposure of parents to organophosphate and organochlorine pesticides. Toxicol Lett. 2013 Oct 25. pii: S0378-4274(13)01358-1.

[7] Rzhetsky A. et al. Environmental and State-Level Regulatory Factors Affect the Incidence of Autism and Intellectual Disability. PLoS Comput Biol. 2014;  10(3): e1003518.

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Butwicka A, Lichtenstein P, Landén M, Nordenvall AS, Nordenström A, Nordenskjöld A, & Frisén L (2014). Hypospadias and increased risk for neurodevelopmental disorders. Journal of child psychology and psychiatry, and allied disciplines PMID: 25048198