ESPE Abstracts (2019) 92 RFC10.2

Cryptorchid Boys with Abrogated Mini-Puberty Display Differentially Expressed Genes Involved in Sudden Infant Death Syndrome

Faruk Hadziselimovic1, Gilvydas Verkauskas2, Beate Vicel2, Michael Stadler3


1Cryptorchidism research institute, liestal, Switzerland. 2Childen's surgery center, Vilnius, Lithuania. 3Friedrich Miescher institute for Biomedical Research, Basel, Switzerland


Background: The long QT syndrome is the most frequent a well-established causative factor, among cardiac channelopathies, for the sudden infant death syndrome (SIDS). It accounts for approximately 12% of the cases. The non-transcriptional regulation of slowly activating delayed rectifier K+ currents and suppression of L-type Ca2+ currents by testosterone is a regulatory mechanism of cardiac repolarization that potentially contributes to the control of QTc intervals. SIDS has been described in patients with septo-optic dysplasia, Leopard syndrome (both have cryptorchidism in common) and mutations in TSPYL (leading to deficient T secretion). We hypothesize that impaired testosterone secretion during mini-puberty may increase the SIDS risk in cryptorchid boys by altering the expression of gene relevant for this syndrome.

Patients and Methods: 1. 15 boys with isolated cryptorchidism were selected and classified seven as Ad- (lack of Ad spermatogonia, abrogated mini-puberty, High Infertility Risk (HIR)) and eight as Ad+ (Ad spermatogonia present, intact mini-puberty, Low Infertility Risk (LIR)). During orchidopexy for bilateral cryptorchidism, biopsies are obtained for histology and RNA-Sequence analysis. 2. Seven HIR patients are randomized for treatment either with surgery followed by GnRHa treatment or surgery alone. Randomization of patients to be treated or to remain untreated was completely unbiased by any parameter other than undescended testes. Among eight biopsies, four were taken before (testis 1) and four were taken after six months of GnRHa treatment. They were compared to six samples, three of each were taken before (testis 2) and after six months of surgery alone, respectively.

Results: We analyzed 66 genes known to be implicated in SIDS. 82% (54/66) of these genes showed no differences in their mRNA levels between HIR vs LIR. Seven genes that were less expressed in the group of cryptorchid boys with defective mini-puberty are implicated in sick sinus syndrome development. Among them, CACNA1C and HCN4 positively responded to GnRH treatment. Five genes upregulated in the HIR group encode epigenetic modifiers, including CALM1, which is known to positively regulate the calcium-activated potassium channel activity of KCNH2. Curative GnRH treatment up-regulated 12 and downregulated 26 genes, indicating that testosterone is involved in their transcriptional regulation.

Conclusion: Defective mini-puberty induces differential expression of several genes important for cardiomyopathy and cardiac channelopathies. GnRHa upregulates several genes whose loss of function is implicated in SIDS indicating that testosterone may be involved as an etiological factor. As a consequence, careful cardiologic surveillance of HIR cryptorchid boys is warranted.

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