Definition

Constitutional chromosomal abnormalities are a common cause of embryo-fetal developmental abnormalities. Chromosomal abnormalities account for approximately 50% of spontaneous abortions occurring during the first trimester of pregnancy. Two main types of chromosomal abnormalities can be diagnosed:

Chromosomal number abnormalities

The normal karyotype consists of 23 pairs of chromosomes, or 46 chromosomes. These abnormalities (also called aneuploidies) can be homozygous (present in all cells) or mosaic (present in a variable proportion of cells). The origin of homogeneous abnormalities lies either during meiosis—the process leading to the formation of reproductive cells—or during the first mitotic divisions of the zygote (egg) after fertilization. The predominant risk factor for meiosis-related chromosomal nondisjunction is advanced maternal age.

• The term "trisomy" refers to the presence of an extra chromosome, while "monosomy" refers to the loss of one of the two chromosomes in a chromosome pair. The most common trisomies at birth are trisomies 21, 18, and 13, and mosaic trisomy 8. Trisomies of the sex chromosomes are very common and affect both the X and Y chromosomes: 47,XXX, 47,XXY, 47,XYY.

• Autosomal monosomies are rarely observed at birth, likely because they are non-viable and result in early pregnancy loss. Regarding sex chromosomes, X monosomy is common and is responsible for Turner syndrome.

Chromosomal structural abnormalities

They result from the occurrence of chromosomal breaks followed by one or more abnormal rejoinings. By definition, trisomies and partial monosomies result from structural rearrangements. Structural abnormalities can affect one chromosome or multiple chromosomes (e.g., translocations). These abnormalities can be balanced or unbalanced.

• Balanced abnormalities do not cause an imbalance in chromosomal material and usually have no phenotypic effect, except in cases where the break, by interrupting a gene, leads to a corresponding genetic disorder. Balanced abnormalities can lead, during meiosis, to the formation of unbalanced gametes resulting in abnormal zygotes, which will result in miscarriages or the birth of children with congenital abnormalities.

• Unbalanced abnormalities can occur de novo, that is, spontaneously (deletions, de novo unbalanced translocations, etc.), or result from a balanced parental rearrangement.

Prenatal Screening and Diagnosis of Chromosomal Abnormalities

Prenatal chromosomal screening is offered to all pregnant women regardless of age or medical history. This screening is currently based on the combined assessment of ultrasound markers (measurement of fetal nuchal translucency) and biological markers (assessment of several substances in maternal blood) during the first trimester of pregnancy.

Prenatal diagnosis of chromosomal abnormalities is based on analysis of the fetal karyotype. It is always performed with the parents’ consent following a medical consultation for genetic counseling. A fetal karyotype is offered to couples at high risk for these abnormalities, whether this risk is predictable before the start of pregnancy (family history of chromosomal abnormalities) or unpredictable (chromosomal screening placing this pregnancy in a high-risk group, detection of abnormalities on ultrasound).

Trisomy 21 (Down Syndrome)

Trisomy 21 is a chromosomal abnormality defined by the presence of an extra chromosome 21 (complete trisomy 21) or the presence of an extra fragment of chromosome 21 (partial trisomy). Chromosomal prenatal screening and diagnosis have led to a significant decrease in the incidence at birth in the countries concerned.

This syndrome is characterized by a constant but variable intellectual disability, most often mild to moderate, frequent muscle hypotonia and joint laxity, and characteristic morphological features. Medical follow-up must be established due to the presence of frequently associated congenital malformations (particularly cardiac and gastrointestinal malformations) or complications: sensory disorders, epilepsy, leukemias, autoimmune and endocrine disorders, and premature sensory and neurocognitive aging (Alzheimer’s disease). The median life expectancy is currently over 50 years.

Karyotyping allows for diagnosis, determines the origin of the abnormality (random in the case of free trisomy with three independent chromosomes, possibly inherited from a parent carrying a balanced translocation in the case of translocation trisomy), and thus establishes the probability of recurrence for relatives.

Source: French Congenital Anomalies Registry, INSEE for births in 2011–2015

The population of women residing in and giving birth in Paris is notably older than women giving birth in France (34.5% of women aged 35 or older in Paris, compared to 19.5% in France in 2011–2013). Since the incidence of trisomy increases with maternal age, it is therefore not surprising that the prevalence of trisomy 21 is higher in Paris than in other regions.

• For more information: Orphanet (Trisomy 21 (Down syndrome)

Trisomy 18 (Edwards syndrome)

Trisomy 18 is a chromosomal abnormality caused by the presence of an extra chromosome 18. It is characterized by growth retardation and visceral malformations affecting all organs, including the heart in over 90% of cases, the limbs (clubfoot, folded and fused hands and fingers), the neural tube (anencephaly, spina bifida), the digestive tract, the kidneys, and the face (cleft lip and palate). More than 95% of affected fetuses die in utero. Hypotonia and sucking difficulties in the first few weeks progress to hypertonia, with almost no responsiveness. Severe psychomotor retardation is constant.

Source: French Congenital Anomalies Registry, INSEE for births in 2011–2015

The population of women residing in and giving birth in Paris is notably older than women giving birth in France (34.5% of women aged 35 or older in Paris, compared to 19.5% in France in 2011–2013). Since the incidence of trisomy increases with maternal age, it is therefore not surprising that the prevalence of trisomy 21 is higher in Paris than in other regions.

• For more information: Orphanet (Trisomy 18 - Edwards syndrome)

Trisomy 13 (Patau syndrome)

Trisomy 13 is a chromosomal abnormality caused by the presence of an extra chromosome 13. It is characterized by a combination of brain malformations (particularly holoprosencephaly), facial dysmorphia with a high incidence of cleft lip and palate, ocular abnormalities (microphthalmia), hand malformations (polydactyly), visceral malformations (heart disease), and very severe psychomotor retardation. More than 95% of affected fetuses die in utero. The neurological presentation is severe: hypotonia, hyporesponsiveness with almost no responsiveness. Facial abnormalities vary. Half of the children die within the first month, and 90% die before age 1 from cardiac, renal, or neurological complications.

Source: French Congenital Anomalies Registry, INSEE for births in 2011–2015

The population of women residing in and giving birth in Paris is notably older than women giving birth in France (35.4% of women aged 35 or older in Paris, compared to 19.3% in France). Since the incidence of trisomy 13 increases with maternal age, it is therefore not surprising that the prevalence of trisomy 13 is higher in Paris than in other regions.

• For more information: Orphanet (Trisomy 13 - Patau syndrome)

Turner syndrome

Turner syndrome is a chromosomal disorder caused by the complete (X monosomy) or partial absence of an X chromosome. It arises spontaneously due to non-disjunction of sex chromosomes during meiosis, resulting in the loss of an X chromosome. Partial or mosaic forms may have milder consequences. This condition affects one in 2,500 female newborns: its incidence at conception is much higher, but many 45,X conceptions result in a miscarriage during the first or second trimester.

The circumstances of diagnosis vary depending on the stage of pregnancy:

• prenatally, the detection of nuchal translucency during first-trimester chromosomal screening, and especially the presence of hygroma colli or even generalized edema—often associated with cardiac malformations—leads to the recommendation of fetal karyotyping;

• at birth, the diagnosis may be suggested in a female infant presenting with short stature, edema of the hands and feet, as well as cardiac and/or renal malformations,

• in childhood, growth retardation is the key clinical feature that must raise suspicion of the diagnosis,

• In adolescence or adulthood, the diagnosis is suggested in cases of delayed puberty or infertility in a woman of short stature.

Only forms diagnosed prenatally or in early postnatal life can be recorded in congenital malformation registries. Management focuses particularly on initiating hormone replacement therapy (for both height and sexual development), monitoring and treating any malformations, and addressing the frequently reported visual and hearing impairments.

Source: French Registries of Congenital Anomalies, INSEE for births in 2011–2015

• For more information: Orphanet (Turner syndrome)

Klinefelter syndrome

Klinefelter syndrome encompasses a group of chromosomal abnormalities characterized in humans by the presence of at least one extra X sex chromosome. The cause is random, resulting from a failure of sex chromosomes to separate during meiosis. The primary risk factor for its occurrence is advanced maternal age. The chromosomal formula is 47,XXY. In 10% to 20% of cases, this extra X chromosome is not present in all cells: this is a 47,XXY/46,XY chromosomal mosaic, the consequences of which may be milder. This syndrome affects one in 600 males. This syndrome causes testicular dysfunction, leading to delayed puberty and frequent infertility. Cognitive development is comparable to that of the general population; mild and inconsistent learning difficulties (particularly delayed language acquisition) are sometimes observed. Physical development is typically male, apart from delayed pubertal signs. Given the absence of malformations, diagnosis is often delayed until adolescence or adulthood. Prenatal diagnosis is thus incidental, particularly during chromosomal screening. Data from congenital malformation registries cannot therefore claim to be exhaustive. Klinefelter syndrome should not be confused with other chromosomal configurations such as 48,XXXY, 48,XXYY, and 49,XXXXY ("variants of Klinefelter syndrome"), which often cause intellectual disability and malformations.

Source: French Registries of Congenital Anomalies, INSEE for births in 2011–2015

• Learn more: Orphanet (Klinefelter syndrome)