Early Detection of Sex Chromosome Abnormality 'Klinefelter Syndrome' Possible with NIPT

Symptoms are difficult to detect. NIPT (Non-Invasive Prenatal Testing) is a method for early detection

Klinefelter syndrome is designated as a rare disease.
Symptoms are not typically apparent in childhood.
Many cases are diagnosed when patients seek infertility treatment.

The less visible symptoms include:

• Tall stature (not extreme)
• Azoospermia (lack of sperm)
• Insufficient testosterone production
• Mild learning disabilities
• Delayed language development
• Less noticeable secondary sexual characteristics

These symptoms are not always self-evident and may not occur in every individual.
However, awareness through NIPT (non-invasive prenatal testing) can lead to prevention of the complications mentioned below.

Even if natural pregnancy is difficult, IVF (In Vitro Fertilization)

In recent years, even when diagnosed with azoospermia, it has become possible to conceive children through intracytoplasmic sperm injection (ICSI). This is because sperm can be retrieved through testicular sperm extraction (TESE) under a microscope.

People diagnosed with azoospermia cannot produce sperm because their testes are damaged.

However, there are parts of the testes that are undamaged.

Microscopic testicular sperm extraction (micro-TESE) involves identifying undamaged parts under a microscope and retrieving sperm from there.

The retrieved sperm is used in intracytoplasmic sperm injection (ICSI).

Failure of meiosis leads to chromosomal abnormalities

"The failure of meiotic division results in changes in the number of sex chromosomes. The condition where the number of sex chromosomes changes is known as Klinefelter syndrome."

The failure of meiotic division is the primary cause of Klinefelter syndrome.

However, you may have these questions:

"What is meiotic division in the first place?"

"What are sex chromosomes?"

"What constitutes a failure?"

The following points aim to address these questions.

What is meiosis?

Meiosis occurs twice before sperm and egg fertilization. These two divisions halve the number of chromosomes present. This reduction is necessary to prevent an increase in chromosome number with each fertilization.

If we consider that sperm and egg each have one set of chromosomes, after fertilization, there will be two sets. When a child is conceived, their chromosome count remains at two sets. For instance, if meiosis didn't occur, sperm and egg would each have two sets of chromosomes. If a sperm with two sets fertilizes an egg with two sets, the resulting embryo would have four sets of chromosomes. This number would double in subsequent generations: eight, sixteen, thirty-two, sixty-four, and so on.

Humans normally have forty-six chromosomes, so failing to undergo meiosis would mean that our ancestors would have accumulated far more chromosomes over generations.

What constitutes failure of meiosis?

Non-disjunction in meiosis refers to the failure of chromosomes to separate properly, resulting in cells that receive an abnormal number of chromosomes. Non-disjunction can occur during either the first or second division of meiosis.

When meiosis proceeds correctly, each resulting cell contains only one set of chromosomes, which then develop into sperm or eggs. Upon fertilization in humans, it is normal for the resulting embryo to have two sets of chromosomes.

However, if non-disjunction occurs, a cell may end up with an abnormal number of chromosomes. When such a cell participates in fertilization, the resulting embryo will have an abnormal number of chromosomes, which is known as a numerical abnormality in sex chromosomes.

Types of chromosomal abnormalities

The names differ depending on the number of sex chromosomes after fertilization.

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In humans, normal conditions include disomy, while conditions like Klinefelter syndrome involve trisomy and tetrasomy.

For instance, equating failure of meiosis with male and female

To make it easier to imagine nondisjunction in meiosis, we'll use the following conditions:

• Female-derived chromosomes represent females
• Male-derived chromosomes represent males
• Cells represent rooms
• Meiosis, which normally occurs twice, will be represented here once

(1) Four women who were playing together decide to go home, each intending to return to her own room.

(2) Two out of the four women decide they want to drink more and return together to the same room.

(3) As a result, there is one room with two people, two rooms with one person each, and one empty room.

(4) A man who cohabits in the room with two women returns.

In this example, scenario 3 represents nondisjunction in meiosis.
Scenario 4 represents fertilization resulting in trisomy.

While the example attributes the cause to the female side, it can also originate from the male side.

Why is failure of meiosis bad?

The reason is that an excessive amount of substances causes malfunctions in the body.

When there are more chromosomes than normal, the amount of gene expression also increases.
Gene expression involves creating substances centered around proteins such as hormones.

For example, let's compare it to cooking.

Seasonings are essential for flavoring dishes, but if there are too many, the taste can be ruined.
A balanced blend of seasonings is crucial for delicious cooking.

Similarly, within the body, maintaining a healthy balance of various substances in moderation helps sustain a healthy physique.

Difference between chromosomes and sex chromosomes

The sex chromosome is one of the chromosomes. Chromosomes are divided into sex chromosomes and autosomes. In humans, there are 2 sex chromosomes and 44 autosomes. Sex chromosomes determine sex, while the others are called autosomes.

Sex chromosomes are represented as X and Y, where XY denotes male and XX denotes female. XY and XX are the normal forms of sex chromosomes.

Klinefelter syndrome occurs exclusively in males. The condition requires having one or more extra Y chromosomes and a total of two or more X chromosomes.

How sex chromosome abnormalities are indicated

In many texts, only the number of chromosomes and the phenotype of sex chromosomes are noted.

For a sex chromosome abnormality where the chromosome count is 47, and the sex chromosome phenotype is XXY, it is represented as (47/XXY) to simplify writing.

The normal sex chromosome phenotype is (46/XY).

Klinefelter syndrome presents with sex chromosome abnormalities, including (48/XXYY), but the most common form is (47/XXY).

Why having more X chromosomes is not good

The reason for this is that an increased expression level of genes causes malfunctions in the body.

Even if the number of X chromosomes doubles, not all gene expression levels within X chromosomes will double. In humans and mice, gene expression on all but one X chromosome is suppressed, and which X chromosome remains active is random.

This phenomenon is called lyonization (X chromosome inactivation), and it occurs to equalize gene expression levels between males and females. Thanks to lyonization, sex chromosome abnormalities pose less risk to life compared to autosomal abnormalities.

At first glance, this might seem without issue.

However, there are regions that do not undergo gene expression suppression. These are known as pseudoautosomal regions (PAR), where gene expression is not suppressed. Genes within PAR, which increase in expression proportionally to the number of X chromosomes, contribute to this effect.

One symptom of Klinefelter syndrome is tall stature, as we discussed earlier. The SHOX gene within the PAR influences height. The reason for tall stature in this syndrome is the increased expression level of the SHOX gene.

Changes in the number of X chromosomes due to meiotic errors lead to Klinefelter syndrome. The syndrome manifests with various symptoms because the normal levels of gene expression cannot be achieved due to the altered number of X chromosomes.

Early detection with NIPT (Non-Invasive Prenatal Testing) leads to prevention of complications

Klinefelter syndrome presents various complications.

Early detection through Non-Invasive Prenatal Testing (NIPT) and early treatment are effective in preventing these complications.

Sex chromosome abnormalities cannot be cured fundamentally; treatment aims at managing symptoms, not curing conditions like Klinefelter syndrome.

Complications of Klinefelter syndrome include:

1. Osteoporosis
2. Decreased bone mass
3. Reduced muscle strength
4. Type 2 diabetes
5. Malignant tumors (such as breast cancer)

Complications 1 to 3 are caused by decreased levels of male hormones. It's important to administer male hormones from adolescence onward and take preventive measures against complications.

Complications 4 and 5 are conditions that individuals with Klinefelter syndrome are more prone to develop congenitally. These are related to lifestyle diseases.

Early detection via NIPT facilitates preventive measures from infancy, focusing on maintaining a healthy lifestyle.

References

• National Center for Biomedical Research and Development - Division of Molecular Endocrinology
• Information Center for Intractable Diseases - Klinefelter's syndrome
• Hyogo Medical University - Explanatory document for pregnant women whose fetus has been diagnosed with a chromosomal abnormality by amniocentesis or chorionic villus examination.