Different karyotypes, same disease?

Abstract

High-grade aneuploidies of the sex chromosomes (HGA) presenting with a male phenotype comprise a vast and heterogeneous group of very rare conditions, once considered as “variants” of Klinefelter syndrome (KS). This association with KS was mainly based on the presence of at least one supernumerary X chromosome, high stature, and hypergonadotropic hypogonadism with severe testicular hypotrophy. However, many of the shared features show elevated severity in HGA compared to KS, while many others are unique to HGA. Different karyotypes arise from mechanisms peculiar to each HGA syndrome. Age at diagnosis ranges from prenatal to early adulthood and an increased mortality ratio has been reported in these patients, mostly from respiratory diseases and congenital abnormalities. Among physical features, the most common include facial dysmorphisms, radioulnar synostosis, clinodactyly, impaired genital development (e.g., micropenis, cryptorchidism), renal dysplasia, cardiac malformations, and taurodontism. Almost all patients show learning disabilities and intellectual deficits are common, with full scale IQs (intelligence quotient) as low as 20–40, with verbal performances being the most affected. Behaviorally, attention deficit–hyperactivity disorder (ADHD) and autism spectrum disorders are common, and patients’ temper can range from shyness to aggressiveness. Androgen replacement therapy is often necessary to start or complete pubertal development and is effective in ameliorating neuropsychiatric symptoms to some extent. Fertility is severely impaired, with all HGA patients being azoospermic, and is often not a concern, given the concurrent intellectual disability, although access to assisted reproduction techniques can be evaluated on a case-by-case basis.