Disorders of sex chromosomes: Pathology review

Noam, a 33 year old male, comes to the clinic after trying to conceive a baby with his wife for more than a year, with no luck. Noam is very thin and quite tall. Upon physical examination, you notice that his testes are smaller than normal, and he has enlarged breast tissue. In addition, Noam doesn’t seem to have much facial and pubic hair. You decide to run a blood test, which reveals that Noam’s testosterone and inhibin B levels are decreased, while gonadotropin and estrogen are increased. In addition, you perform a karyotype analysis on his cells and find 47 chromosomes, among which there’s two X chromosomes and one Y chromosome.

Next, you see Hadas, a 17 year old girl who’s worried because she hasn’t gotten her first menstrual period yet. The first thing you notice is that Hadas is quite short for her age. Upon physical examination, she has a webbed neck, a broad chest, and poorly developed breasts with widely spaced nipples. In addition, you notice her ring fingers are very short. A blood test shows low estrogen levels and high gonadotropins, and a karyotype analysis reveals only 45 chromosomes, with one X chromosome.

Okay, based on their presentation, both Hadas and Noam seem to have some sort of disorder of sex chromosomes. Now, humans typically have 23 pairs of chromosomes, so 46 total; out of which 22 pairs are autosomal, and 1 pair consists of sex choromosomes, which can be X or Y. Generally, an individual with two X chromosomes, or 46,XX is considered to be genetically female. However, only one X chromosome gets expressed and the other is inactivated through a process called X inactivation or lyonization, becoming a Barr body. On the other hand, an individual with one X and one Y chromosome, or 46,XY is genetically male. And since there’s only one X chromosome to begin with, there’s generally no Barr body.

Now, individuals with sex chromosome disorders have aneuploidy, meaning that there’s a missing or extra sex chromosome. Most often, this results from nondisjunction, which can occur in the egg or sperm cell during meiosis 1 or 2, where a chromosome pair or sister chromatid respectively doesn’t split apart. So the child of this individual could either receive two chromosomes from that parent and one more from the other parent, resulting in trisomy; or no chromosome from that parent and one from the other parent, resulting in monosomy. Less frequently, nondisjunction may occur during mitosis, where a sister chromatid doesn’t separate.

Now, sex chromosome disorders may result in hormonal imbalance and abnormalities in sexual development, which is normally under control of the hypothalamus-pituitary-gonadal axis. First, the hypothalamus secretes gonadotropin-releasing hormone, or GnRH for short, which goes to the anterior pituitary to stimulate the release of gonadotropic hormones, which are luteinizing hormone or LH, and follicle-stimulating hormone or FSH. LH and FSH then stimulate the gonads to produce sex hormones; in males, LH stimulates the Leydig cells of the testes to secrete testosterone, and FSH stimulates the Sertoli cells to secrete inhibin B.

Testosterone and inhibin B are responsible for the development of male primary sexual characteristics, which are the changes necessary for reproduction like enlargement of the penis and testes; as well as male secondary sexual characteristics that aren’t required for reproduction, like a deepening of the voice, and increased muscle mass, and a male pattern of hair growth on the face, chest, axillae, and genital areas.

On the other hand, in females, LH and FSH stimulate the ovaries to secrete estrogen and progesterone, which are responsible for the female primary sexual characteristics like ovulation, menstruation, and uterine development; as well as female secondary characteristics like breast development, hip widening, and hair growth mainly on the axillae and genital areas. Now, once sex hormones have done their job, they signal the hypothalamus and pituitary to turn off the secretion of GnRH, FSH, and LH.

All right, now back to sex chromosome disorders, which include Turner syndrome, Klinefelter syndrome, and XYY syndrome.

Let’s begin with Turner syndrome, which is characterized by having 45 chromosomes with only one X chromosome, so individuals are genetically females. In most cases, this happens when a nondisjunction event occurs during meiosis of the paternal gamete, so that the sperm cell lacks a sex chromosome. An important thing to note is that, since there’s only one X chromosome, there’s no Barr body. Conversely, if the nondisjunction occurs after formation of the zygote during mitosis, the result is a mosaic karyotype, meaning that some cells are 45,X and others are 46,XX, or in a few cases even 46,XY!

For your exams, you should recognize some clinical features that are characteristic for Turner syndrome. Firstly, infants may have a variety of congenital malformations. These can include a horseshoe kidney, which is when the two kidneys fuse at the bottom, forming a U shape; as well as cardiovascular abnormalities, like bicuspid aortic valve and coarctation or narrowing of the aorta, which are the most common causes of death in childhood. Another very common finding in infants are lymphatic defects, such as lymphedema or swelling of the hands and feet.

Many also develop a cystic hygroma, which is an abnormal swelling on the back of the baby’s neck due to lymphatic fluid build up, which eventually decreases as they age. This often leaves extra skin on the neck, called a webbed neck that’s wider than normal. Additionally, mosaic individuals with some 46,XY cells are at increased risk for gonadoblastoma, which is a complex neoplasm of gonadal components.

Now, the X chromosome also carries genes that are important for growth and development of tissues throughout the body. One of these is the short stature homeobox - SHOX for short - gene. So having a single copy of the SHOX gene results in, you guessed it, short stature. Other characteristic features include a shield-like or broad chest, and extensively spaced nipples. Additional features include shortened fourth metacarpals or ring fingers, low set ears, and arms that turn outward at the elbows, also called cubitus valgus.

During puberty, there’s minimal pubic hair, breast, and uterine development, as well as ovarian dysgenesis or abnormal development, leading to streak ovaries, which develop white atrophic fibrous strands. As a result, females with Turner syndrome produce decreased levels of estrogen, which leads to increased levels of both LH and FSH. Because of this, Turner syndrome is the most common cause of primary amenorrhea or absence of menstruation, and thus individuals are said to reach ‘menopause before menarche’. As a consequence, many females with Turner syndrome are infertile. Keep in mind though that pregnancy may be possible in some cases through in-vitro fertilization or treatment with exogenous estradiol-17β and progesterone.