Central precocious puberty in a boy with 22q13 deletion syndrome and NOTCH-1 gene duplication

The 22q13 deletion syndrome or Phelan-McDermid syndrome is a neurodevelopmental disorder associated with developmental delay, hypotonia, delayed or absent speech, autistic-like behavior, normal to accelerated growth and dysmorphic faces. We report the occurrence of central precocious puberty in a boy diagnosed with Phelan-McDermid syndrome. At the age of 1 year, our patient presented with increased testicular volume for his age, bone age advancement and growth acceleration. Stimulated gonadotropin levels demonstrated a premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. Central precocious puberty was treated with gonadotropin-releasing hormone (GnRH) analog. Molecular diagnosis with array-comparative genomic hybridization (CGH) revealed a major deletion of 5.8 Mb at the 22q13 chromosomal region and a 25 kb duplication at the 9q34.3 region that included the

SHANK Gene Family and Autism

SHANK3 deletion/mutation is an independently replicated, genetic cause of autism (Durand et al., 2007; Gauthier et al., 2009; Moessner et al., 2007) and is the major causative gene in the 22q13 deletion syndrome known as Phelan-McDermid syndrome (Bonaglia et al., 2011; Bonaglia et al., 2001; Bonaglia et al., 2006; Chen et al., 2011; Delahaye et al., 2009; Dhar et al., 2010; Jeffries et al., 2005; Misceo et al., 2011; Sarasua et al., 2011; Wilson et al., 2003). Patients with Phelan-McDermid syndrome uniformly have delayed or absent speech and many carry the diagnosis of autism spectrum disorder (Cusmano-Ozog, Manning, & Hoyme, 2007; Havens, Visootsak, Phelan, & Graham, 2004). More recently, mutations in SHANK2 have been implicated in autism and intellectual disability (Berkel et al., 2010; Pinto et al., 2010). These recent human genetic findings provide a compelling rationale for developing a comprehensive understanding of SHANK3 function in synapses, circuits, and behavior, resulting in three different novel genetic mouse models published by more than four independent laboratories (Bangash et al., 2011; Bozdagi et al., 2010; Peca et al., 2011; Wang et al., 2011). Such studies shed light on the underlying biology of autism caused by SHANK3 mutations. This chapter examines in detail the evidence supporting a role for SHANK genes in autism and intellectual disability as well as insights from the recent genetic animal models of SHANK3 mutations.