AUTHOR=Castro Sebastián , Brunello Franco G. , Sansó Gabriela , Scaglia Paula , Esnaola Azcoiti María , Izquierdo Agustín , Villegas Florencia , Bergadá Ignacio , Ropelato María Gabriela , Martí Marcelo A. , Rey Rodolfo A. , Grinspon Romina P. 

TITLE=Delayed Puberty Due to a WDR11 Truncation at Its N-Terminal Domain Leading to a Mild Form of Ciliopathy Presenting With Dissociated Central Hypogonadism: Case Report

JOURNAL=Frontiers in Pediatrics

VOLUME=Volume 10 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2022.887658

DOI=10.3389/fped.2022.887658

ISSN=2296-2360

ABSTRACT=Pubertal delay in the male is frequently due to constitutional delay of growth and puberty, but pathologic hypogonadism should be considered. After general illnesses and primary testicular failure are ruled out, the main differential diagnosis is central (or hypogonadotropic) hypogonadism, resulting from a defective function of the gonadotropin-releasing hormone (GnRH)/gonadotropin axis. Ciliopathies arising from defects in non-motile cilia are responsible for developmental disorders affecting sense organs and the reproductive system. WDR11-mediated signaling in non-motile cilia is critical for fetal development of GnRH neurons. Only missense variants of WDR11 have been reported to date in patients with central hypogonadism, suggesting that nonsense variants could lead to more complex phenotypes. We report the case of a male patient presenting with delayed puberty due Kallmann syndrome (central hypogonadism associated with hyposmia) in whom next-generation sequencing analysis identified a novel heterozygous base duplication, leading to a frameshift and a stop codon in the N-terminal region of WDR11. The variant was predicted to undergo nonsense-mediated decay and classified as likely pathogenic following the ACMG criteria. This is the first report of a variant in the WDR11 N-terminal region predicted to lead to complete expression loss that, contrary to expectations, led to a mild form of ciliopathy resulting in isolated Kallmann syndrome.