164: Klinefelter Syndrome and Related Sex Chromosome Aneuploidies

Key Points

• Disease summary:

  • Klinefelter syndrome is characterized by a sex chromosome aneuploidy in males. Affected males have an extra X chromosome. Males with other rare sex chromosome aneuploidy conditions have single or multiple extra X and/or Y chromosomes.

  • Klinefelter syndrome is the most common sex chromosome abnormality with incidence of 1 in 500 live male births to 1 in 700 live male births. Often the diagnosis of Klinefelter syndrome is made after the onset of puberty.

  • Classically, males with Klinefelter syndrome present with primary hypogonadism, small testes, azoospermia or severe oligospermia, gynecomastia, an increased arm-to-leg ratio, and learning (dyslexia) and executive skill difficulties. There is an increased risk of low bone density, cardiovascular disease, immunologic diseases, and psychiatric disorders.

  • Signs and symptoms are influenced by several factors including how many cells have an additional X chromosome, the number of X chromosomes, X-chromosome gene inactivation on the extra X chromosome(s), and the number of CAG repeats in the androgen receptor gene.

• Hereditary basis:

  • Klinefelter syndrome is a chromosomal disorder that occurs due to meiotic nondisjunction. There is a near-equal distribution of maternal and paternal meiotic nondisjunction events.

  • Parental age may be related to an increased risk of Klinefelter syndrome.

  • Mitotic nondisjunction can cause postfertilization and can result in individuals with mosaic forms of Klinefelter syndrome.

• Differential diagnosis:

  • Klinefelter syndrome involves many systems (Table 164-1). The severity and pattern differ among patients. The differential diagnostic characteristics depend on the symptom complex of the individual patient.

  • The differential diagnoses based on hypogonadism include other causes of primary hypogonadism, hypogonadotropic hypogonadism (eg, Kallmann syndrome), mutations in luteinizing hormone (LH) or follicle-stimulating hormone (FSH) receptor genes, microdeletions in specific regions of the Y chromosome, cryptorchidism, fragile X syndrome (see Chap. 159), defects in 3β-hydroxysteroid dehydrogenase, and 17α-hydroxylase enzymes.

  • The differential diagnosis for learning disorders includes other causes of dyslexia. The impairment of behavioral or executive dysfunctions and behavioral disorders provide another category of diagnostic consideration (eg, ADD/ADHD).